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Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

EVOLUTIONARY PHYSIOLOGY SCRIPT

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

PART 3
HISTOLOGY

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

TABLE OF CONTENTS
TABLE OF CONTENTS ................................................................................................................................................. 1
HISTOLOGY .................................................................................................................................................................... 1
3.1.
3.2.
3.3.
3.4.
3.5.
3.6.
3.7.

EPITHELIUM .......................................................................................................................................................... 2
EMBRYOLOGICAL ORIGIN OF EPITHELIUM: ............................................................................................. 2
INTEGRINS ............................................................................................................................................................. 5
KERATIN ............................................................................................................................................................... 7
TIGHT JUNCTION .................................................................................................................................................. 14
DESMOSOME ....................................................................................................................................................... 15
GAP JUNCTION ..................................................................................................................................................... 16

HISTOLOGY ADDENDUM ......................................................................................................................................... 34
3.8.

CONNECTIVE TISSUE .................................................................................................................................... 41

ADDENDUM II .............................................................................................................................................................. 65
THE BRITTLENESS OF AGING BONES: MORE THAN LOSS OF BONE MASS ............................................. 78
3.9.
3.10.

NEURAL TISSUE ............................................................................................................................................. 85
MUSCULAR TISSUE...................................................................................................................................... 131

ADDENDUM III:.......................................................................................................................................................... 158

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

HISTOLOGY
INTRODUCTION
The word histology comes from the ancient Greek and is a composition of two words: (histos and logos) histos = tissue,
logos . = knowledge or science( speech).
The word “Tissue” (tissu) was introduced in the anatomy by a French anatomist Xavier Bichat (1771-1802). During his
dissections, he was astonished by the fact that the body is so nicely composed by different layers of diverse texture,
consistence and aspect. He thus started to talk about les “tissus” in French, which means material, textile, and woven
cloth. He made the mental jump: of comparing biological membranous, fibrous layers of tissues, with the layers of
textile with which a mantle is made for instance: several types of fabric put together in a certain way in order to create
something new, a new level of complexity, with other characteristics, emergences or behavior than the separate pieces of
tissue: a mantle or winter cloak.
He thus continued talking about tissues, and slowly but surely it got common to use the terminology tissue in the medical
world. In the mean time the composition of the different tissues was investigated by the use of the microscope. 1 This
work is still continued today but with powerful electron microscopes and all possible luminescence and radiation
techniques, to see all parts of the tissue and cells.
Histology is thus a functional classification, which is based on the following criteria:
-WHERE: anatomical position or the place where the tissue is situated.
-HOW: how the tissue appears: cell alignment, layers, specific characteristics.
-WHY: later as it is discovered, the function of the tissues
Histology or micro anatomy knowledge and comprehension is essential for osteopaths in order to see a living picture of
the organized textures they have in the hands. It is a gigantic help to see:
- the mutual relations of cells
- the mutual relations of tissues
- to connect the dimensions between embryology, physiology and anatomy.

The intimate interrelation between structure and function or simply Form,
becomes consciously integrated and eventually a living picture, when the
histological dimension and its specific features is known and succeeds in
bridging macro anatomy and physiology into one big picture.

1

Which was invented by Anthony van Leeuwenhoek in 1674.

1

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.1. EPITHELIUM
EPITHELIAL TISSUE OR EPITHELIUM
Epithelium (Greek: that what covers the nipples) .
The membrane covering the lips gave its name to all this tissue types. This membrane covers small nipples or connective
papillae which are richly provided with capillaries
Epithelium thus became the name by which all covering tissues and delimiting membranes are called: skin, mucous
membrane etc.
Later it was discovered that the epithelium penetrates deeper into the body and forms the glands.
There are thus two kinds of epithelium in histology:
- covering and delimiting membranes
- glands that arise out of these membranes
Which brings us to the next schematic classification:

- covering & delimiting membranes
- simple
- pseudo stratified
- stratified

EPITHELIUM
- endocrine
- clump type
- follicle type
- glands
- exocrine
- simple
- composed

3.2. EMBRYOLOGICAL ORIGIN OF EPITHELIUM:
During the triple layered stage, the embryo consists of a tubular like structure that is composed of three germinating
layers:
- ECTODERM .
- MESODERM .
- ENDODERM .

2

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

And it stays that way, although it is less visible because of the displacements and differentiations that occur during
embryological development.
As the ectoderm covers and delimits the embryo on the
outside and the endoderm on the inside, both are
epithelium.
Both of these germinating layers are the origin of more or
less all further developing epithelium in the embryo and
child. Because of this fact, it is often tempting to use the
term epithelium in embryology, but for students this is
very confusing and may induce in errors because some
epithelial tissue will arise out of the mesoderm! Keep it
easy; do not mix terminology of different branches.
Epithelium is catalogued this way, because of its aspect,
position and function. Actually we could summarize it as
follows: it is classified as epithelium because it has a
similar FORM.
ENDOTHELIUM and MESOTHELIUM are exceptions to
that rule; they are look-alikes of epithelial tissue, and thus exceptions to the rule.
The cells that delimit the lymphatic and circulatory system are apparently as well in position as in function typical
epithelium.
Epithelium that is generated out of the mesoderm gets a different name:
- the cells are called endothelium and their membranes as endothelial membranes.
- the cells that delimit the body cavities and cover the organs, are called mesothelial cells and the membranes
mesothelium or mesothelial membranes.
The reason is not just because they arise out of another embryological layer, but because although they look like
epithelium they keep their mesodermal way of reacting: in pathological conditions. They develop sarcomas exactly as
connective tissues or mesodermal tissues do, while “real” epithelium develops carcinomas.
See the addendum for more details.
While both histology and embryology deal within the same dimension, and that the terminology and classification is
different it gives comprehension difficulties.
Professor Erich Blechschmidt solved the difficulties between histological and embryological terminology in a simple
way by using another classification which is functionally much more logical.
He just speaks of two types of tissues: the border or frontier tissue and the inner tissue.

Classification method

Embryology: Ectoderm

Cell aggregates or tissue

Endoderm

Mesoderm

I have used the same color classification as is in use in your script embryology of JP. Höppner D.O.,
Histology: Epithelium Neural T.

Epithelium

Connective T. Muscular T.

Blue for all ECTODERM
Red for all ENDODERM
Green for all MESODERM

3

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.2.1. GENERAL FUNCTIONS OF EPITHELIAL MEMBRANES
As epithelium covers all body surfaces, it’s clear that protection and delimitation against the environment is one function
but there are additional.
The epithelium of the mucus membrane that delimits the gastrointestinal tract must be able to digest (secret digestive
juices) and absorb the nutriments. Selective secretion and absorption are thus the second and third functions of some
epithelial membranes.
Some surfaces are kept wet or humid all the time, like in the respiratory tract or the peritoneum. Thus another function
of some epithelial membranes is selective secretion for humidity and chemical- mechanical protection.
Thus from these different functions we may expect different Forms of cells, and that is what we will be looking at now.
To make it easier we will first look at the general properties and forms before entering into details.

*Epithelial

membranes are exclusively built by cells, which are closely connected in order to form a real

membrane.

*Epithelial membranes never contain capillaries or vessels!
The consequence is that epithelial cells are always dependent on the connective tissue and its circulatory system to
provide for their extra cellular metabolism.
The connective tissue on which the epithelial membranes are resting, not only provides their metabolism but also the
mechanical support. The solid connection between connective tissue and epithelial membranes is provided by the means
of the basal membrane or lamina basalis. The lamina basalis is very permeable, has before all sticky connecting
properties between the two tissues that produced it.
Figure 1 Schematic constitution of an epithelial membrane

Epithelial membrane

lamina basalis

Connective tissue
collagene fibres
capillaries

As you see on the drawing, the lamina basalis is the glue that is produced by the two
tissues and it clearly consists of two layers. One could almost compare the lamina basalis
with performing two components glue. Each component being delivered by each tissue;
the components are called:
- lamina basalis
- lamina reticularis (collagene type IV)

4

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

BIOCHEMICAL NOTE: The connecting part of the epithelial cell membrane to the lamina basalis is done through
glycoprotein’s that are called integrins. Ca 2+ ions are very important in this connection, when the Ca2+ ions are not
present in sufficient quantity the cell to cell connection is extremely weakened. This is used in cytology to get free
epithelial cells in a suspension, by using a chelating substance, E.D.T.A. . ethylene diamine tetra acetatic acid.
All epithelial membranes are subjected to a certain dose of pull, tear and torsion forces. Some membranes such as the
skin are regularly under heavy strain, when they are breached they demonstrate high mitotic capacity to restore their
integrity, tensegrity also plays an important role in this process. Remember?

3.3. INTEGRINS
3.3.1. FROM WIKIPEDIA, THE FREE ENCYCLOPEDIA
An integrin, or integrin receptor, is an integral membrane protein in the plasma membrane of cells. It plays a role in
the attachment of a cell to the extracellular matrix (ECM) and to other cells, and in signal transduction from the ECM to
the cell. There are many types of integrin, and many cells have multiple types on their surface. Integrins are of vital
importance to all metazoans and have been found in all animals in which it was sought, from sponges to mammals.
Integrins have been very well studied in humans.
Other types of protein that play a role in cell-cell/cell-matrix interaction and communication are cadherins, CAMs and
selectins.

3.3.2. FUNCTION
Two main functions of integrins are:



Attachment of the cell to the ECM.
Signal transduction from the ECM to the cell.

However, they are also involved in a wide range of other biological activities. These include: binding of viruses,
including adenovirus, Echo viruses, Hanta viruses, foot and mouth disease viruses, to cells; immune patrolling. Cell
migration.
A very prominent function of the integrins is seen in the molecule GPIIbIIIa, an integrin on the surface of blood platelets
(thrombocytes)responsible for cross-linking platelets in fibrin within a developing blood clot. This switches its
adhesiveness for fibrin/fibrinogen from being non-adhesive to being intensely sticky, in a fast and precisely controlled
manner. As such it provides a thought-model for how many integrins are believed to be regulated. As you may have
noted, although blood is normally very rich in platelets, we do not spontaneously clot. This is clearly good news. On the
other side, and equally positively, even minor wounds are rapidly blocked by the mass of fibrin, platelets and
erythrocytes in a blood clot. A primary event in clot formation is the binding of platelets to exposed collagen in the
wound site, which leads to their "activation", and a clotting cascade. Among the many molecular events during
activation, is the switching of gpiiaiib integrin from a quiescent state, unable to bind to fibrinogen/fibrin, to an active
state, able to bind strongly to fibrinogen/fibrin. This is a remarkable event: first it involves all the gpiibiia on a single
platelet (some 50000 molecules), second it is completed within 5 seconds, third, it increases the affinity of the integrin
concerned over several orders of magnitude. Fourth, it involves wide spread changes in the molecular structure of the
GPIIbIIIa molecule, as resolved by LIBS antibodies, which gain the ability to bind GPIIbIIIa only following activation
of the platelets. Finally, it is intensely locallized to the precise region of the damage, be it a couple of square
micrometres, or the results of falling off a mountain bike at high speed.

3.3.3. ATTACHMENT OF CELL TO THE ECM
Integrins couple the ECM outside a cell to the cytoskeleton (in particular the microfilaments) inside the cell. Which
ligand in the ECM the integrin can bind to is mainly decided by which α and β subunits the integrin is made of. Among
the ligands of integrins are fibronectin, vitronectin, collagen, and laminin. The connection between the cell and the ECM
enables the cell to endure pulling forces without being ripped out of the ECM. The ability of a cell to create this kind of
bond is also of vital importance in ontogeny.
The connections between integrin and the ligands in the ECM and the microfilaments inside the cell are indirect: they
are linked via scaffolding proteins like talin, paxillin and alpha-actinin. These act by regulating kinases like FAK (focal
adhesion kinase) and Src kinase family members to phosphorylate substrates such as p130CAS thereby recruiting
signaling adaptors such as Crk.
5

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Cell attachment to the ECM is a basic requirement to build a multicellular organism. Integrins are not simply hooks, but
give the cell critical signals about the nature of its surroundings. Together with signals arising from receptors for soluble
growth factors like VEGF, EGF and many others, they enforce a cellular decision on what biological action to take, be it
attachment, movement, death, or differentiation. Thus integrins lie at the heart, both literally and figuratively, of many
cellular biological processes.
One of their most important functions is their role in cell migration. The movement of any body requires its feet to
advance over the substratum. In this sense, integrins are the feet of the cell. Experimental evidence indicates that
integrins can be released from attaching the cell to the substrate near the back of the cell. These released molecules are
internalised by the cell by endocytosis and returned to the cell surface at the front of the cell by the endocytic cycle. In
this way they are recycled for reuse.

3.3.4. SIGNAL TRANSDUCTION
Integrins play an important role in cell signaling. Connection with ECM molecules can cause a signal to be relayed into
the cell through protein kinases that are connected with the intracellular end of the integrin molecule.
The signals the cell receives through the integrin can have relation to:






cell growth
cell division
cell survival
cellular differentiation
apoptosis (programmed cell death)

3.3.5. SELECTED VERTEBRATE INTEGRINS
The following are some of the integrins found in vertebrates.
Name

Synonyms

Distribution

Ligands

Many

Collagens, laminins

VLA-4

Many
Hematopoietic cells

Collagens, laminins
Fibronectin, VCAM-1

LFA-1
Mac-1, CR3

Fibroblasts
T-lymphocytes
Monocytes

Fibronectin
ICAM-1, ICAM-2
Serum proteins, ICAM-1

Platelets
Epithelial cells

Serum proteins, fibronectin
Laminin

α1β1
α2β1
α4β1
α5β1
αLβ2
αMβ2
αIIbβ3
α6β4

3.3.6. SIMPLE AND STRATIFIED EPITHELIUM
Epithelial membranes are, as all body tissues, the product of genotypic, and morpho-plastic factors (induced by the
environment), consequently each tissue has an adapted FORM depending on the place it is.

3.3.7. THE DIFFERENCES
EPITHELIAL MEMBRANES

BETWEEN

“DRY”

AND

“WET”

There are enormous differences between wet and dry epithelial membranes, keep this living picture in mind! We saw
that a cell membrane subsists only because its held together by the water on both sides of the membrane. In other words
when we talk about dry membranes, it must be something different than cells because they can not subsist without water
on both sides!
Example: the surface cells of the mucous membrane in the mouth are clearly epithelium, the saliva wets them constantly;
ergo:

6

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

When you pass with your finger on the inside of your cheeks, and spread it over a microscope glassplate, and than
examin it you will see healthy living epithelial cells with a round nucleus.
The epithelial cells that make our skin are not in a similar condition, they are exposed on one side to the open air, and
thus they dehydrate and die.
When the physiology of these cells is gradually getting poorer, when they are pushed further away from the lamina
basalis. Their metabolism changes dramatically: they consume themselves and start one single production line: the
protein synthesis of horn or KERATIN. Gradually the cell membranes fall apart and the different keratin masses are
joined. In the same time they get progressively greased by the sebum of the sebum glands.
As keratin is an albuminoidal type of protein (friction resistant, solid and very water-repellent as it is greased) it will
form a protective coating for the deeper lying fluidic environment and cells. As the deepest layer of cells close to the
lamina basalis is constantly stimulated by their high metabolic rate they are in constant mitosis. The older cells are
pushed away from the lamina.

3.4. KERATIN
From Wikipedia, the free encyclopedia
Keratins are a family of fibrous structural proteins; tough and insoluble, they form the hard but nonmineralized
structures found in reptiles, birds, amphibians and mammals. They are rivaled in biological toughness only by chitin.
There are various types of keratins, even within a single animal.
Variety of animal uses
Keratins are the main constituent of structures that grow from the skin:
the α-keratins in the hair (including wool), horns, nails, claws and hooves of mammals
the harder β-keratins in the scales and claws of reptiles, their shells (chelonians, such as tortoise, turtle, terrapin), and in
the feathers, beaks, and claws of birds. (These keratins are formed primarily in beta sheets. However, beta sheets are
also found in α-keratins.)
The baleen plates of filter-feeding whales are made of them.
They can be integrated in the chitinophosphatic material that makes up the shell and setae in many brachiopods.
Keratins are also found in the gastrointestinal tracts of many animals, including roundworms (who also have an outer
layer made of keratin).
Although it is now difficult to be certain, the scales, claws, some protective armour and the beaks of dinosaurs would,
almost certainly, have been composed of a type of keratin.
In Crossopterygian fish, the outer layer of cosmoid scales was keratin.
Cornification
In mammals there are soft epithelial keratins, the cytokeratins, and harder hair keratins. As certain skin cells differentiate
and become cornified, pre-keratin polypeptides are incorporated into intermediate filaments. Eventually the nucleus and
cytoplasmic organelles disappear, metabolism ceases and cells undergo a programmed death as they become fully
keratinized.
Cells in the epidermis contain a structural matrix of keratin which makes this outermost layer of the skin almost
waterproof, and along with collagen and elastin, gives skin its strength. Rubbing and pressure cause keratin to proliferate
with the formation of protective calluses — useful for athletes and on the fingertips of musicians who play stringed
instruments. Keratinized epidermal cells are constantly shed and replaced (see dandruff).
These hard, integumentary structures are formed by intercellular cementing of fibers formed from the dead, cornified
cells generated by specialized beds deep within the skin. Hair grows continuously and feathers moult and regenerate.
The constituent proteins may be phylogenetically homologous but differ somewhat in chemical structure and
supermolecular organization. The evolutionary relationships are complex and only partially known. Multiple genes have
been identified for the β-keratins in feathers, and this is probably characteristic of all keratins.
Molecular biology and biochemistry
The properties which make structural proteins like keratins useful depend on their supermolecular aggregation. These
depend on the properties of the individual polypeptide strands, which depend in turn on their amino acid composition
and sequence. The α-helix and β-sheet motifs, and disulfide bridges, are crucial to the conformations of globular,
functional proteins like enzymes, many of which operate semi-independently, but they take on a completely dominant
role in the architecture and aggregation of keratins.
Glycine and alanine
Keratins contain a high proportion of the smallest of the 20 amino acids, glycine, whose "side group" is a single
hydrogen atom; also the next smallest, alanine, with a small and uncharged methyl group. In the case of β-sheets, this
7

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

allows sterically-unhindered hydrogen bonding between the amino and carboxyl groups of peptide bonds on adjacent
protein chains, facilitating their close alignment and strong binding. Fibrous keratin molecules can twist around each
other to form helical intermediate filaments.
Limited interior space is the reason why the triple helix of the (unrelated) structural protein collagen, found in skin,
cartilage and bone, likewise has a high percentage of glycine. The connective tissue protein elastin also has a high
percentage of both glycine and alanine. Silk fibroin, considered a β-keratin, can have these two as 75–80% of the total,
with 10–15% serine, with the rest having bulky side groups. The chains are antiparallel, with an alternating C → N
orientation. A preponderance of amino acids with small, unreactive side groups is characteristic of structural proteins,
for which H-bonded close packing is more important than chemical specificity.
Disulfide bridges
In addition to intra- and intermolecular hydrogen bonds, keratins have large amounts of the sulfur-containing amino acid
cysteine, required for the disulfide bridges that confer additional strength and rigidity by permanent, thermally-stable
crosslinking—a role sulfur bridges also play in vulcanized rubber. Human hair is approximately 14% cysteine. The
pungent smells of burning hair and rubber are due to the sulfur compounds formed. Extensive disulfide bonding
contributes to the insolubility of keratins, except in dissociating or reducing agents such as urea.
The more flexible and elastic keratins of hair have fewer interchain disulfide bridges than the keratins in mammalian
fingernails, hooves and claws (homologous structures), which are harder and more like their analogs in other vertebrate
classes. Hair and other α-keratins consist of α-helically-coiled single protein strands (with regular intra-chain Hbonding), which are then further twisted into superhelical ropes that may be further coiled. The β-keratins of reptiles and
birds have β-pleated sheets twisted together, then stabilized and hardened by disulfide bridges.
Silk
The silk fibroins produced by insects and spiders are often classified as keratins, though it is unclear whether they are
phylogenetically related to vertebrate keratins.
Silk found in insect pupae, and in spider webs and egg casings, also has twisted β-pleated sheets incorporated into fibers
wound into larger supermolecular aggregates. The structure of the spinnerets on spiders’ tails, and the contributions of
their interior glands, provide remarkable control of fast extrusion. Spider silk is typically about 1 to 2 micrometres (µm)
thick, compared with about 60 µm for human hair, and more for some mammals. (Hair, or fur, occurs only in mammals.)
The biologically and commercially useful properties of silk fibers depend on the organization of multiple adjacent
protein chains into hard, crystalline regions of varying size, alternating with flexible, amorphous regions where the
chains are randomly coiled. somewhat analogous situation occurs with synthetic polymers such as nylon, developed as a
silk substitute. Silk from the hornet cocoon contains doublets about 10 µm across, with cores and coating, and may be
arranged in up to 10 layers; also in plaques of variable shape. Adult hornets also use silk as a glue, as do spiders.
Clinical significance
Some infectious fungi, such as those which cause athlete's foot and ringworm, feed on keratin.
An example that lies between wet and dry membranes is the cornea, the epithelial covering of the eyeball. Because the
tear glands produce & secret constantly the eye fluid the cornea cells do not keratinize. They are kept covered by a
constant wet film by blinking reflexively every 6 seconds. (10 blinks a minute) Not counting the “winking body
language” which has nothing to do with lubrification of the eyes.

3.4.1. SYNTHESIS
EPITHELIUM

OF

THE

DIFFERENT

FORMS

OF

WET

INDEXED ACCORDING TO:
- cytology
- histology
- function
- anatomy

8

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.4.2. SIMPLE EPITHELIUM
3.4.2.1.

Simple squamous epithelium

- cytology: flattened, irregular cells with a tiny sometimes invisible cytoplasm and long flat nuclei.
- histology : small continuous not vascularized membrane.
- function : perfect form for filter function but totally inadequate for mechanical stress.
- anatomy :

the endothelium that delimits the circulatory system is formed by one membrane simple squamous
epithelium. Electron microscopy demonstrated that this situation and form is the same for the lung
alveoli’s, the peritoneum and pleura. This might evoke some questions with many so called
osteopathic visceral theories….

Figure 2 Schematic representation of simple squamous epithelium
epithelial cells
lamina basalis
connective tissue
capillaries

3.4.2.2.

Simple

cubical

epithelium

- cytology :

The cells are bigger with a big cytoplasm and round nucleus. They are not really cubical, but just look
like that way when they are viewed in a sagital microscopic cut
- histology : not vascularized membrane.
- function : ?
- anatomy : is rare, covers the ovaries.
Figure 3 Schematic representation of simple cubical epithelium
epithelium
lamina basalis
Connective Tissue

Capillaries

9

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.4.2.3.

- cytology:

Simple cylindricalal epithelium

The cells are higher than broad, the nucleus is always deep in the cell close to the lamina basalis; in
cross section the cells look hexagonal.

- histology: a solid thick epithelial membrane, not vascularized
- function:

protective cloak for the underlying tissues, usually they have a secretory function They are potent
mucus producers (mucus is viscous, disulfide bond rich containing glycoprotein.) Some of these cells
have a selective absorption role, while others have cilia in their form and move the mucus. The mucus
secreting cells are often called goblet cells. (Two anatomic examples of combined membranes and
their form)

- anatomy:

Gut: The membrane is formed by alternating goblet cells and selective absorption cylindrical cells.
Trachea: The membrane is formed by alternating goblet cells and cilia cells that move the mucus
upwards.

- microbiology: of the cells, see next

3.4.2.3.1.

Goblet cells (focus while reading this is also a living picture exercise)

Goblet cells have a free top surface that is relatively flat and through which big vesicles of mucus are released. The
vesicle melts with the cell membrane and the mucus alone is expelled on the free surface. The protein part of the mucus
is as always synthetized in the Rough EndoPlasmatic Reticulum around the nucleus at the very bottom of the cell. The
closest to the lamina basalis, this means the place where the most stimuli happen. Under the word stimuli, you should
understand changes in electrochemical potential difference and see the electromagnetic turmoil going on in there
and the cell reacting by producing what she can best: mucus. This is in fact the only way for her to conserve a kind
of dynamic balance. The sacharid compound of the mucus is formed in the smooth ER and than both (protein and
sacharid) are delivered through ER produced vesicles to the Golgi apparatus that finishes the making of mucus, by
binding both compounds into glycoprotein’s. The gel-like, sticky mucus is than concentrated in thick vesicles that are
transported by the cytoskeleton in the direction of the free surface or “exterior” world; as far away as possible from the
lamina basalis and her chemical and electromagnetic turmoil that destabilizes the cell constantly. When the mucus filled
vesicles make contact with the cell membrane they fuse and at that moment they become part of the cell membrane and
the mucus is expulsed.
Clever and aware students as you are, you have already realized that if such a constantly producing goblet cell that is a
little irritated by… lets say pipe smoke, or some pollen, and thus produces frantically mucus, would quickly get such a
huge free surface that it had to bulge out of the membrane, not?
Well, well, well, very smart of you, indeed, I must admit.
Well actually, it does not because, and there is some inertia of course in the dynamic, but once the production is
accelerated, the uptake under the form of endo-cytosis at the bottom of the cell is also accelerated, this has as effect that
the excessive parts of cell membrane are also taken away again from the cell surface. And clever and awake as you are, I
hear you think immediately: but than the cell must become conical or wedge-shaped? Logically yes, but no that is not
what happens. You know, I love it when you are adapting your focus on the cellular dimension and start too see it the
physiology happening as a dynamic movie that is just happening in front of your minds eye. This is exactly how you
should try to study your physiology, focus and see it happen, it is not a living picture but a feature movie. Okay, right,
well euh… This is exactly why the cell membrane is also often described as the fluidic mosaic model. The animal cell
membrane is not a static rigid wall, it is supple, it is a fat and greasy double layer that holds together because water
(polarized molecules) is pressing on both sides and its fatty inner part of the membrane is repulsed by water. You could
compare it to a jelly like fluidic very adaptable structure that feels and behaves almost like a truckload of Ping-Pong
balls released in a swimming pool. It may look static but in fact the balls move, glide and rub against each other while
they float on the water. The cell membrane is the same, the cytoskeleton endings, the membrane bound proteins etc, all
these structures and forms float amid the balls, or end within the double layer of balls. So the cellular membrane is
constantly in movement, re-managed, parts picked away other adjoined and so on. This is exactly why living pictures are
important, the physiologic or anatomic reality is often completely different from the sturdy, static rigid pictures that we
10

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

have in mind because that is how we learned it, stare at dead static pictures of freeze-dried preparations like a cow stares
at a train passing by. I hope this is clear now, and that you learned something about how to approach this fascinating
matter that demonstrates all the principles of Osteopathy at molecular level….

3.4.2.3.2.

Selective absorption cells

The selective absorption cells have a very particular free surface towards the exterior world; during the embryonic
development there are humongous differences of rate of growth for several parts of the gut, in fact in the embryo these
different rates and their different speeds will provoke particular anatomical and and micro-anatomical, even cytological
FORM particularities. I will come back on it later on, when we discuss the anatomical and histological particularities of
the different parts of the gut in Organ and digestive physiology. For now just know that in some parts the growing rate is
that high that in order to survive this compressive situation the only possibility the mucous membrane cells have is to
frown or plicate their cell membrane on the free surface side. These plicae are called microvilli. The cells have because
of this microvilli surface form, an enormous exchange and absorption surface with the exterior world. Histologists
estimate that there are ± 3000 microvilli (frowns or plicae) per cell. This makes for 1 square mm. mucous membrane ±
200.000.000 microvilli. Just remember that we will find these frowns, villi or papillae back at all places where the
frontier tissue has had in its embryological period enormous growth rates. (Kidneys, liver etc.)

3.4.2.3.3.

Ciliate cells

The cilia cells are otherwise identical to goblet cells, except that they also are a little frowned and do not produce
mucus, they mobilize it.
Figure 4 Schematic representations of these cells
Goblet cell

Microvilli

Cilia cell

11

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

* HOW
EPITHELIAL CELLS HOLD TOGETHER TO FORM A MEMBRANE:
Keep the image of the fluidic mosaic model in your mind when we talk about the cell membrane!
For this we must return to the cytoskeleton (or cell web) and see the connections in series and parallel between the
skeletons or webs.
In every active cell of our tissues we find this complex web of
microtubules, and different sizes of filaments.

* CYTOSKELETON :
Each eukaryote, has its own specific internal organization, and is able to
adjust its Form and move organelles. All this is only possible by the action
or reaction of the cell web or cytoskeleton. (see tensegrity)
For the cell movements the three most important parts of this complex
structured Protids network are:
- actine filaments
- microtubules
- intermediary filaments
Delicate mechanisms that are chemical, electromagnetical and or tensional regulate, increase or decrease the building
(polymerization) or depolymerization of the separate parts of the cytoskeleton. The intermediary filaments usually are
more stable and less thorn down and than built up again at some other place.
Next to the cytoskeleton there are in the cell, non polymerized protein subunits that are going to connect firmly the
cytoskeletal parts to each other and to the fluidic mosaic cell membrane.
The movements and mobilizations of the cytoskeleton are done by different proteins, but all are ATP dependent and
function similarly to the sliding filament theory of muscles.

* ROLE OF ACTIN IN NON MUSCULAR CELLS:
Actin is a very common protein in all eukaryotic cells. (in fibroblasts for instance, actine is 10 % of the total protein
masse.
Actin has mainly two properties that are used in the cells:
-they make the “cross linking ” between cytoskeleton parts
-together with myosin and other contractile proteins they mobilize the cytoskeleton and what ever it is attached to:
organelles, the membrane etc.
Figure 5 MICROVILLI OR CILLAE

*

INTERCELLULAR BONDS:
MACULA = spot
ZONULA = girdle
DESMOSOME - DESMO = stick, SOMA = body
12

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

In fact there are 4 general types of cell junctions:
zonula occludens (tight junction)
zonula adherens
macula adherens (desmosomes)
gap junctions (nexus)
These types of cell junctions are common in all tissues; they are not specific for epithelium!
- zonula occludens or tight junction:
This one not only connects one cell to another, but closes completely the intercellular space. It is best
compared with a mow seam between cells; a fusion of the two cell membranes. Zonula means girdle; in other
words it is a mow seam around the complete cell like a belt. Thus, and in general it is like this, the tight
junctions really separate two extra cellular environments from each other, for instance:
In the gut: they make the difference between inner intercellular space within the mucus membrane epithelial
cells and the exterior, free surface of the cells in the lumen of the gut.
In blood vessels of the brain: they will close the endothelial membrane in order to separate the interior of the
lumen with the rest of the intercellular space. The vessels lumen cells are tightly closed; they form the blood
brain barrier.
In fact they are the points from where the difference is made between interior and exterior.
- zonula adherens :
This zone evenly, completely surrounds the periphery of the cell, but both cell membranes are even further
away from each other than anywhere else on the cells, and the space thus created is filled by a denser material
that continues on the inside of the cell, actually it is a part of the cytoskeleton that simply runs through the
membrane and penetrates the next cell and connects to its cytoskeleton. (These are intermediary filaments that
are bridging from one cells’ cytoskeleton to the other). See tensegrity!
- macula adherens or desmosome :
This form of junction resembles the zonula adherens in structure, but they do not run like a belt around the
cell, they look more like freckles. Spread over the cell surface here and there. But these freckles are also
points where the cytoskeleton of one cell bridges the intercellular space and plunges into the next cell.
- gap junctions or nexus :
First it was thought that it was a tight junction or zonula occludens, but experiments demonstrated that there is
a gap between the two cell membranes. They are divided in two groups now:
- tight gap junction
- loose gap juntion
Each cell membrane demonstrates polygonal projections that are fusing in the extra cellular space while
several membrane bound proteins connect within these junctions. Furthermore hydrophilic channels would
help the junction: there is electrical activity or at least lowered electrical resistance at those junctions, it is
now known that the cells do communicate and even exchange ions at these junction places. They are places of
direct cell to cell communication across the intercellular space.

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Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.5. TIGHT JUNCTION
Diagram of Tight junction.

TEM of negatively stained proximal convoluted tubule of Rat kidney tissue at a magnification of ~55,000x and 80KV
with Tight junction. Note that the three dark lines of density correspond to the density of the protein complex, and the
light lines in between correspond to the paracellular space.
Tight junctions, or zonula occludens, are the closely associated areas of two cells whose membranes join together
forming a virtual impermeable barrier to fluid. It is a type of junctional complex.
They are formed by claudin and occludin proteins, joining the cytoskeletons of the adjacent cells.

3.5.1. FUNCTIONS
They perform three vital functions:





They hold cells together
They block the movement of integral membrane proteins between the apical and basolateral surfaces of the cell,
allowing the specialized functions of each surface (for example receptor-mediated endocytosis at the apical
surface and exocytosis at the basolateral surface) to be preserved. This aims to preserve the transcellular
transport.
They prevent the passage of molecules and ions through the space between cells. So materials must actually
enter the cells (by diffusion or active transport) in order to pass through the tissue. This pathway provides
control over what substances are allowed through. (Tight junctions play this role in maintaining the blood-brain
barrier.)

3.5.2. CLASSIFICATION
Epithelia are classed as 'tight' or 'leaky' depending on the ability of the tight junctions to prevent water and solute
movement:
 Tight epithelia have tight junctions that prevent most movement between cells. An example of a tight
epithelium is the distal convoluted tubule, part of the nephron in the kidney.
 Leaky epithelia do not have these tight junctions.

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Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.6. DESMOSOME

Cell adhesion in desmosomes
A desmosome, also known as macula adherens (Latin: adhering spot), is a cell structure specialized for cell-to-cell
adhesion. A type of junctional complex, they are localized spot-like adhesions randomly arranged on the lateral sides of
plasma membranes.
Desmosomes help to resist shearing forces and are found in simple and stratified squamous epithelium. The intercellular
space is very wide (about 30nm).

3.6.1. STRUCTURE
They are molecular complexes of cell adhesion proteins and linking proteins that attach the cell surface adhesion
proteins to intracellular keratin cytoskeletal filaments.
The cell adhesion proteins of the desmosome are members of the cadherin family of cell adhesion molecules.
They are transmembrane proteins that bridge the space between adjacent epithelial cells by way of homophilic binding
of their extracellular domains to other desmosomal cadherins on the adjacent cell.
On the cytoplasmic side of the plasma membrane is a disk-like structure (attachment plaque) composed of very dense
materials.
The main desmosomal linking proteins, desmoplakins and plakoglobins, bind to the intracellular domain of cadherins
and form a connecting bridge to the cytoskeleton.

3.6.2. BLISTERING DISEASES
If the desmosomes connecting adjacent epithelial cells of the skin are not functioning correctly, layers of the skin can
pull apart and allow abnormal movements of fluid within the skin, resulting in blisters and other tissue damage.
Blistering diseases such as Pemphigus vulgaris can be due to genetic defects in desmosomal proteins or due to an
autoimmune response. These patients are often found to have antibodies that bind to the desmosomal cadherins and
disrupt the desmosomes.

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Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.6.3. HEMIDESMOSOMES
When visualized by electron microscopy, hemidesmosomes are similar in appearance to desmosomes. Rather than
linking two cells, hemidesmosomes attach one cell to the extracellular matrix. Rather than using cadherins,
hemidesmosomes use integrin cell adhesion proteins. Hemidesmosomes are asymmetrical and are found in epithelial
cells connecting the basal face to other cells.

3.7. GAP JUNCTION
3.7.1. FROM WIKIPEDIA, THE FREE ENCYCLOPEDIA
A gap junction or nexus is a junction between
certain animal cell-types that allows different
molecules and ions, mostly small intracellular
signaling molecules (intracellular mediators), to
pass freely between cells. The junction connects
the cytoplasm of cells. One gap junction is
composed of two connexons (or hemichannels)
which connect across the intercellular space.
They are analogous to the plasmodesmata that
join plant cells.

3.7.2. STRUCTURE
In vertebrates, gap junction hemichannels are
primarily homo- or hetero-hexamers of connexin
proteins. Invertebrate gap junctions comprise
proteins from the hypothetical innexin family. However, the recently characterized pannexin family, functionally similar
but genetically distinct from connexins and expressed in both vertebrates and invertebrates, probably encompasses the
innexins.
At gap junctions, the intercellular spaces narrows from 25nm to 3nm and unit connexons in the membrane of each cell
are lined up with one another.
Gap junctions formed from two identical hemichannels are called homotypic, while those with differing hemichannels
are heterotypic. In turn, hemichannels of uniform connexin composition are called homomeric, while those with
differing connexins are heteromeric. Channel composition is thought to influence the function of gap junction channels
but it is not yet known how.
Generally, the genes coding for gap junctions are classified in one of three groups, based on sequence similarity: A, B
and C (for example, GJA1, GJC1). However, genes do not code directly for the expression of gap junctions; genes can
only produce the proteins which make up gap junctions (connexins). An alternative naming system based on this
protein's molecular weight is also popular (for example: connexin43, connexin30.3).

3.7.3. LEVELS OF ORGANIZATION
1
2
3
4
5

6

DNA to RNA to Connexin protein.
One connexin protein has four transmembrane domains
Six Connexins create one Connexon (hemichannel). When different connexins join together to form one
connexon, it is called a heteromeric connexon
Two hemichannels, joined together across a cell membrane comprise a Gap Junction.
When two identical connexons come together to form a Gap junction, it is called a homotypic GJ. When one
homomeric connexon and one heteromeric connexon come together, it is called a heterotypic gap junction.
When two heteromeric connexons join, it is also called a heteromeric Gap Junction.
Several gap junctions (hundreds) assemble into a macromolecular complex called a plaque.

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Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.7.4. PROPERTIES
1
2

3

Allows for direct electrical communication between cells, although different connexin subunits can impart
different single channel conductances, from about 30 pS to 500 pS.
Allows for chemical communication between cells, through the transmission of small second messengers, such
as IP3 and Ca2+, although different connexin subunits can impart different selectivity for particular small
molecules.
Generally allows molecules smaller than 1,000 Daltons to pass through, although different connexin subunits
can impart different pore sizes and different charge selectivity. Large biomolecules, for example, nucleic acid
and protein, are not allowed to be shared.

3.7.5. AREAS OF ELECTRICAL COUPLING
3.7.6. HEART
Gap junctions are particularly important in the cardiac muscle: the signal to contract is passed efficiently through the gap
junctions, allowing the heart muscle cells to contract in tandem. However, gap junctions are now known to be expressed
in virtually all tissues of the body, with the exception of mobile cell types such as sperm or erythrocytes. Several human
genetic disorders are now associated with mutations in gap junction genes. Many of those affect the skin, because this
tissue is heavily dependent upon gap junction communication for the regulation of differentiation and proliferation.
Figure 6 Schematic representation of the cell junctions

17

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 7 Cell junctions

Figure 8 Schematic cut through a gap junction

18

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 9 Schematic relations between epithelium/ lamina basalis/ blood vessel/ connective tissue

Figure 10 Schema of the cell junctions, cilia and cytoskeleton

19

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 11 Schema of a desmosome

3.7.7. PSEUDO STRATIFIED CYLINDRICALAL EPITHELIUM
The condition required to define stratified epithelium is:
NOT ONE SINGLE CELL MAY STAY IN DIRECT CONTACT WITH THE LAMINA BASALIS AND
REACH WITH ITS TOPS’FREE SURFACE THE EXTERIOR WORLD.
And exactly this happens with all cells in this layer; therefore it is called PSEUDO STRATIFIED.
- cytology: The cells are cylindrical, but not identical, their nuclei lie at different heights from the lamina basalis, and
the cells are twisted. A histological cut thus gives the impression of two or three layers of cells, while here
or there it is visible that it is one layer. The membrane cells are goblet and ciliate cells.
- histology: Obviously supplementary solid membrane than simple membranes, thicker too, and not vascularized.
- function: cilia and goblet cells (See simple epithelium).
- anatomy: the trachea, and urinary and end gut, always at the junction between stratified and simple epithelium.
(Explanation: see embryology of the membrane bucco-pharyngea & cloacalis)
- microbiology: See figures 5,6 and 10(detail of the cilia) cilia are anchored in the cytoplasm on a structure called basal
body. These basal bodies resemble a lot the centrosome or centrioles in structure. As they are identical in the vegetal
reign as in the animal reign, they have got to be evolutionary very ancient structures, even from before the splitting up in
these two reigns. In a longitudinal cut we see 2 central tubules, surrounded by 9 pairs filaments; the 2 central tubules
end on the basal plate (a kind of diaphragm), the 9 pair’s filaments end in the basal body. Between there is a network of
contractile proteins (actins and others)

20

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

This is a cut through the trachea from Gray’s anatomy, historically interesting because they still talk about Stratified
ciliated epithelium. We know now that this is a “contra dictio in terminis”: stratified epithelium as we will see is never
ciliated, nor does it contain goblet cells.
It must thus be simple layered.
If you watch closely you will see some are.
Come back and take also a look at the duct of the gland, when you have read about stratified cylindrical epithelium.

21

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.7.8. STRATIFIED EPITHELIUM
These membranes are much tougher but as they are much thicker to their absorption capacity is very relative. They have
very limited mucus secretion, thus their function is absolutely protective for all kinds of stress, but mostly for
mechanical stress. (Depending on the histologists, cylindrical and columnar is used to describe the cells)

3.7.8.1.

Stratified squamous non keratinizing epithelium

This type of membranes is found on wet surfaces that can be submitted to heavy mechanical stress. The wet environment
is not secreted by the membrane itself but provided from the bigger environment. (mouth = salivary glands; end gut =
the rest of the gut; uro-genital system = urine or glands.)
The name is treacherous because in these membranes there are all kinds of epithelial cell forms: the closest to the lamina
basalis they are cylindrical and on the free top surface of the membrane they become squamous, in between they are
polyhedral.
Figure 12 Schematic representation of stratified squamous non keratinizing epithelium

Free surface.
squamous cells
Polyhedral form

cylindrical cells

basal membrane
Connective
capillaries

3.7.8.2.

tissue

Stratified cylindrical epithelium

This type of membrane is on a mechanical resistance level, somewhere between pseudo stratified and stratified non
keratinizing epithelium. Usually it is found in the bigger ducts of the glands.

22

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.7.8.3.

Transitional epithelium

In all respects very resembling to stratified non keratinizing epithelium, except on one point: the most superficial cells
are having big rounded surfaces that are relatively loose and elastic (cytoskeleton). This permits the cells to be elongated
without rupturing. They will be found as delimiting cells in cavities that can stretch a lot like the urinary bladder. Very
often they have two nuclei, which mean that in fact they are probably composed by two cells that melted together, I see
you think. No in fact they have never split.
WALKER described this phenomenon: during mitosis the nuclei stay together and in stead doubling into two daughter
cells you get just one big cell with two nuclei!2

2

WALKER BE. Polyploidy and differentiation in the transitional epithelium of mouse urinary bladder. Chromosoma.
1958;9(2):105–118.
WALKER BE. Renewal of cell populations in the female mouse. Am J Anat. 1960 Sep;107:95–105
B F Martin, Cell replacement and differentiation in transitional epithelium: a histological and autoradiographic study of the guineapig bladder and ureter. J Anat. 1972 September; 112(Pt 3): 433–455.

23

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.7.9. SYNTHESIS OF DRY EPITHELIAL MEMBRANES
3.7.10. STRATIFIED DRY EPITHELIUM
3.7.10.1. Stratified squamous keratinized epithelium

This is in almost all respects the same as the non keratinizing version, the only difference in form is:
- cytology: the closest to the lamina basalis they are cylindrical and on the free top surface of the membrane they
become squamous, in between they are polyhedral. But on the top of the squamous cells there is a layer of
keratin.
- histology: Very abrasion resistant membrane, water repellent and not vascularized.
- function: Protection: mechanical, fluidic, biochemical and in some measure chemical.
- anatomy: The skin of course (epidermis)
Figure 13 Schematic representation of the skin (epidermis)
keratin
squamous cells

polyhedral cells

cylindric cells
lamina basalis

24

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.7.11. EPITHELIAL GLANDS
Almost all glands are ingrowths or outgrowths depending on how you look at it, from the epithelial membranes towards
the connective tissue. Or to say it in an even simpler way, using Blechschmidts’ terminology: almost all glands arise
from the frontier tissue, as ingrowths in the direction of the inner tissue.

These glands will specialize as they differentiate during the organisms’ development, but the first big step in their
development makes them exocrine, endocrine or mixed. If you understand this drawing above and combine it with the
more detailed histological below it will be of great help.
So let us take a look, once understood, embryology, physiology and anatomy in all its dimensions becomes a lot easier.
Try to make a living picture of it.
Essential principles to understand and keep in mind: (indicated by a
effects and implications of the principle)

*,

in normal writing: the consequences,

*Frontier tissue or epithelium and all that derives from it later are polarized tissues, built by polarized cells.
Frontier cells are:





ectoderm (blue)
endoderm (red)
Epithelium (light blue, red and some of the green stuff: endothelium and mesothelium,
remember? If not return to it this is basis)
Neural cells (dark blue).

Polarized tissues have two different environments that influence them:
 On one side they have a wet, nutrition rich environment, the lamina basalis, and connective
tissue with its circulatory system. (Always on the green side of the drawing!)
 On the other side a dry or wet environment, towards which they excrete or secrete. (Always
opposite from the green stuff, lamina basalis or connective tissue.
 Remember this: All actions and reactions (in fact they are always reactions on the changes
in the environment) that happen in physiology are induced and center on differences in
electrochemical potential difference. Each bond or transformations that we are trained
and educated to view as chemical are in fact electrical phenomena that are each one of
them paired with an electro magnetic micro-field! (attraction -repulsion)

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Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015



In other words the stimuli rich side (lamina basalis, green stuff) stimulates, understand
destabilizes the electrochemical potential of the cell; the stronger the difference the heavier
the turmoil or chaos, the heavier the secretion or the polarized reaction to maintain balance
for the cell. (remember that life functions on the edge of chaos, but tries to self organize
and order, the balance is exactly along this line)

*Why frontier cells are polarized:


Tensegrity & secretion direction: remember tension induction as well as the
electrochemical potential disbalance comes from the lamina basalis, so it is in the base of
the cell that it is first noticed. The cell will try to “digest” or adapt to the disbalance, she
can do this by transforming or transmutation of the substances, if this is not sufficient to
recreate a dynamic balance. She will metabolize the substance, but if all these actions are
not sufficient she must get rid of the surplus with the help of her organelles (nucleus,
RER, SER and Golgi complex) and the cytoskeleton. Remember that it reacts on tension,
thus it is logical that the cytoskeleton will transport the granules or vesicles away from the
basal tension zone: this why frontier tissue cells are polarized.

*Frontier tissue will always develop and organize in the direction of the stimuli; if the stimuli are too much to
cope with, the cell will divide into two daughter cells. When the stimuli source (lamina basalis and green stuff)
stays very active and destabilizing enough (much concentration gradient = high electrochemical potential
difference) the process of cell division will go on towards the source of the chaos. (Always the green stuff and
lamina basalis) So a cell trail (track, path and even stalk) will develop and grow towards the source, eventually
resulting in the development of a clump of polarized cells or even bigger a gland of polarized cells; or even much
bigger an organ of polarized cells that in all cases secrete: in the opposite direction of the stimuli source (lamina
basalis and green stuff)
Examples of this process are plenty:
 The liver and bile ducts
 The gallbladder
 The brain
 The lungs and bronchi
 The pancreas
 The uterus
 The kidney
 The oxyntic glands of the stomach
 The sweat glands
 The salivary glands
 The Brunner glands
 The thyroid
 The adenohypofyse
 The nerves
 The eye
 The ear etc.

*Frontier tissue will maintain this behavior, however complex and differentiate it grows to be in time.
Examples plenty when we will look at the physiology of neural tissue, muscles or the liver or stomach or kidney…
These are principles of behavior or mechanisms of functioning if you understand the mechanism, physiology, histology,
anatomy or embryology, all turn out to be almost child’s play. So take the time to understand these, and see them…

26

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

*The relationship between frontier tissue and the inner tissue (green stuff, lamina basalis) will determine how
the further development goes. If the process reaches a dynamic balance the growth rate will slow down and also
achieve a dynamic steady state (1). If in the process the inner tissue is lost the frontier tissue cells have no source
of stimuli anymore, thus the cell membranes fall apart and the cells are destroyed. (2) If the frontier cell clump
or gland grows too far away of its source of origin or if the inner tissue endure too heavy changes and stress
around the stalk , the frontier tissue stalk or cell trail may die and disappear. When this happens the glands turn
into endocrine glands because they stay polarized in their nature. (3)
Examples of these different possibilities are for instance:
(1) Example situation
 Every frontier tissue organ you know anatomically
 The eye, the tympanum
(2) Example situation
 The membrana cloacalis
 The membrane buccopharyngea
(3) Example situation
 Every hormonal gland you know anatomically

*The Forms that these complex cell aggregations (clumps, glands, organs) take, and the twists and turns they
make, that give them the strange anatomical features they have, are always the result or consequence of: the
growth rates they developed in comparison to their environments and the form transformation or changes the
whole and parts of the total organism goes through. Therefore especially the brain and visceral (endodermic
outgrows) have a complex convoluted turned upside down Form. (Morphology)
I know this is heavy stuff because it is not the classical way of learning nor thinking, and may thus take some
time to integrate but take that time it will make your Osteopathy and other basic sciences translucid and easy. It
is knowledge. Not knowledge in the sense of acquiring information (although you will), but knowledge in the
sense of knowing.

27

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure14 Schematic representation of the development of frontier tissue glands and organs

3.7.12. CLASSIFICATION OF EXOCRINE GLANDS
Back to classic histology: There are many different types of classification in use; they depend on the author and culture
from which he comes. I will try to make use of the most common and that lies the most in line with the ways of this
course script. (FORM = structure and function or MORPHOLOGY)

3.7.12.1. 1.7.1.1 CLASSIFICATION BY THE MORPHOLOGIC ASPECT (FORM)
- Tubular glands
- Grape form glands
- Mixed form glands
* tubular glands: the most active secreting cells lie on the end of a clearly delimited duct, that has the form of a tube.

28

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 15 Schemata of exocrine glands

Free
surface
duct

secreting cells

Lamina
basalis

* Mixed forms: some glands are really mixed in form, usually they get the two names of the most present forms, a pure
morphologic description, functionally not so important for us. For example: tubulo-alveolar glands or acino-tubular
glands.
Figure 16 Schema’s of exocrine glands

ductus

ducti
Secreting
cells

* There are more morphological subdivisions by the ducts for instance: Composed or simple glands :
Simple glands is in use when the ducts are not branched but one hollow tube.
Figure 17 schema’s exocrine glands

ductus

gland

29

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

When the ducts are branched, the term is composed glands. Most big glands in mammals are composed with a wide
network of branched ducts.
These big glands are usually encapsulated by inner tissue or connective tissue, the consequence is that anatomically they
can be divided in lobes with connective septa in between the lobes.
Osteopathy: The trophicity and metabolism of the gland is directly related to
the condition of the inner tissue or connective tissue that surrounds and
“divides” the gland and her vasculo-nervous pedicle. (Tensegrity practice!)

3.7.12.2. CLASSIFICATION ACCORDING TO THE SECRETION METHOD OF THE POLARIZED GLAND
CELLS




Holocrine glands
Merocrine glands
Apocrine glands

* Holocrine glands
The basal cells closest to the lamina basalis proliferate and accumulate the secretory vesicles packed by the
Golgi complex in their cytoplasm. (There is thus a clear disbalance between the stimulus and the way the cell
has to compensate). The cells are filled by secretory vesicles and die, they disintegrate and in fact it is the
whole cell and her contents that is secreted in the free space.
* Merocrine glands
With this type of secretion, no part of the cell is lost: de cell releases the contents of the vesicles while the
vesicle membrane is incorporated in the cell membrane, there is not even loss of cytoplasm. (Mero = pure,
merocrine = clean secretion)
* Apocrine glands
These even so have a secretion through granules or vesicles, but they contain a small part cytoplasm next to
the secreted substance. Thus by each secreted vesicle there is a loss of cytoplasm and cellular membrane.

(Keeping up dynamic balance)

30

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 18 Schematic representation of an endocrine gland

Inner
capillaries

tissue

Secreting cells

- EXTRA CELLULAR STORAGE:
When de glandular cells secrete opposite to the lamina basalis, as soon as the intracellular capacity is reached they
secrete in the intercellular space. These lumps of endocrine cells when they all do this, start with extra cellular storage,
the effect is follicle formation. See the next drawing. When the drainage of the follicle is much slower than the
production rate of the cells, the follicle’s reservoir can get too big and this gives nodules: inflammatory process in the
inner tissue due to overstretching. In time they can calcify: protective reaction of the inner tissue see later connective
tissue.
Figure 19 Schema of a starting follicle
Capillaries &
inner tissue

Follicle formation

Figure 20 Schema of a “ripe” full follicle gland

capillary

31

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

SECRETORY GRANULES
These are packed in the Golgicomplex and transported by the microtubules of the cytoskeleton. The secretion is variable
see above secretion methods.
Tensegrity & secretion direction: remember tension induction as well as the electrochemical potential disbalance comes
from the lamina basalis, so it is in the base of the cell that it is first noticed. The cell will try to “digest” or adapt to the
disbalance, she can do this by transforming or transmutation of the substances, if this is not sufficient to recreate a
dynamic balance. She will metabolize the substance, but if all these actions are not sufficient she must get rid of the
surplus with the help of her organelles (nucleus, RER, SER and Golgi complex) and the cytoskeleton. Remember that it
reacts on tension, thus it is logical that the cytoskeleton will transport the granules or vesicles away from the basal
tension zone: this why frontier tissue cells are polarized. (Living picture)

3.7.13. GLANDS THAT ARE EXO- AND ENDOCRINE
The pancreas is the easiest example. The gland develops as an epithelial gland out of the frontier tissue of the duodenum
(mucous membrane) usually it starts from two places and therefore develops two ducts: the canals of Santorini and
Wirsung.
Later during the embryonic development under the influence of their environment (mechanism) they will be pushed
together so that anatomically they appear to form one organ, but in reality this is not the case they stay separate glands
which are not imbricated. This major part will be thus two exocrine pancreases that we have but during the pressing
together some small parts get disrupted from their duct that wil degenerate and transform in connective tissue. These
isles of forced endocrine glands are what we call the islets of Langerhans. This happens at several anatomical spots in
the pancreas but mostly in the tail which is the most compressed part. See drawing.

32

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Figure 21 Sagital cut of the body.

33

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Histology addendum
http://www.webmd.com/content/Article/85/98736.htm
Introduction to cancer for patients
Cancer is the general term for abnormal growth of cells—a cluster of cells that go out of control and multiply. When the
abnormal cell reproduces, it has the ability to invade, or metastasize, to other parts of the body. The actual word cancer
means "crab." The characteristics of the crab—slow moving, persistent, roundish, with multiple legs that can reach
out—represent the "spirit" of a cancer cell but really don't give an accurate description of what a malignant cell looks or
acts like.
Unlike bacteria or viruses, the cancer cell itself is not dangerous, but its impact on the rest of your organs is. As it
spreads into various parts of your body, it interferes with regular cells, confuses other organs, and can wreak havoc on
your body. It's basically a "terrorist" cell that hijacks organs and other cells. Cancer cells use the lymph system to get
into the bloodstream and travel throughout the body. These cells love organs that have multiple blood vessels and
nutrients, such as the bones, lungs, and brain.
Cancer cells are classified into two groups: carcinoma and sarcoma. A carcinoma refers to cancerous cells made of
epithelial cells, which line various tissues. You'll find carcinomas in organs that secrete milk, mucus, digestive juices,
and so on. Common sites for carcinomas are the breasts, lungs, skin, and colon; common gynecological sites are the
breasts, ovaries, cervix, and endometrium. Carcinomas account for 80 to 90 percent of all human cancers, are generally
slow growing, and tend to spread through the nerve endings.
The word carcinoma means the cells are malignant. A prefix attached to the word carcinoma will tell you where the
carcinoma is growing and the kinds of cells that are involved. An adenocarcinoma, for example, is a carcinoma made of
glandular cells. When you see the word oma by itself, it means "benign." An adenoma refers to a clump of benign
glandular cells, a fibroma refers to a clump of benign fibrous cells, and so on.
Sarcomas are cancerous cells made up of supporting connective tissue, such as the uterus. Sarcomas are rare and account
for only 2 percent of all human cancers, but they tend to be more aggressive than carcinomas. Again, the prefixes before
the word tell you where the sarcoma is located, what it's made of, what shape it is, and so forth.
The difference between a carcinoma and a sarcoma is similar to the difference between a sweater and a boot—both are
different but related. They have different physical properties and are made of different material. (You can also have a
carcinosarcoma—a carcinoma and sarcoma all in one.)
The words in situ and invasive are used in conjunction with a carcinoma or a sarcoma. In situ means "in one place." A
carcinoma in situ is cancer that is confined to a specific area and has not spread. This is good news and means your
cancer is not invasive. Invasive carcinoma is cancer that has spread to surrounding tissue, the lymph nodes, or other
organs. This is not good news and means your cancer can spread.
GYN cancers can involve a lymphoma, which refers to malignant cells that originate in the lymph nodes, seen in
Hodgkin's disease, for example. Here, malignant cells spread to other parts of your body, such as the breast or
reproductive organs, through the lymph nodes. Lymphomas involve white blood cells that go astray and attack
functioning organs. Although lymphomas may involve the reproductive organs and breasts, this kind of cancer rarely
originates in these areas.
Cancer cells fall into two behavioral categories: differentiated and undifferentiated. These terms refer to the
sophistication of the cancer cells. Differentiated cancer cells resemble the cells of their origin. A differentiated cancer
cell that originates in the breast ducts looks more like a normal ductal cell than does an undifferentiated cancer cell in
the breast ducts. For this reason, differentiated cancer is more treatable and carries higher survival rates. Often you won't
find a purely differentiated cell. It may look just moderately abnormal. Because of this, there are subclassifications:
mildly differentiated, moderately differentiated, well differentiated, or poorly differentiated. These classifications refer
to the cell's grading. A high grade means that the cell is immature, poorly differentiated, and fast growing; a low-grade
cancer cell is mature, well differentiated, slow growing, and less aggressive.
Undifferentiated cancer is made up of very primitive cells that look "wild" and untamed, bearing little or no resemblance
to the cells of origin. They don't assist the body at all and are therefore able to spend all of their time reproducing. This
is more dangerous because the cells may then spread faster. There are times, though, where undifferentiated cancer is
not very aggressive, despite the fact that it's a more primitive cell. This is often the case in breast cancers.
There are also mixes of these different cells, which affect the aggressiveness of the disease. For example, you can have
mostly differentiated cells mixed in with a few undifferentiated cells, or vice versa. Whatever you have the most of will
affect the behavior of the cancer; differentiated cells will slow down whatever undifferentiated cells exist, while
undifferentiated cells will speed up whatever differentiated cells exist.
34

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

List of exocrine glands
Glands typically may be referred to by two or more means, though some terms are rarely seen. The names of the
anatomists who first described them are often employed, as:
name(s)
apocrine sweat glands
Bartholin's
glands,
Tiedmann's
glands,
vulvovaginal glands
Bauhin's glands, anterior lingual glands

location
skin
vulva, vagina

product
-

structure
coiled tubular
-

tongue, near tip

-

Brunner's glands, duodenal glands

duodenum

nonserous or
mixed
mucous

bulbourethral glands, Cowper's glands, Mery's
glands
Ciaccio's glands, accessory lacrimal glands
Cobelli's glands

penis, base

-

compound
tubular
-

eye
esophagus, just above the
cardia, in the mucosa
vagina, on either side
tongue
skin
esophagus
pancreas
vocal cords, below the edge
stomach
coccyx, near the tip

mucous

-

mucous
mucous
serous
serous
-

coiled tubular
racemose
tubulo-acinar
-

digestive tract, respiratory tract

mucous

eyelids, in the conjuctiva
vagina
conjunctiva, middle portion
intestines, surface of mucous
membrane
spongy portion of the urethra
breast

mucous
-

simple
unicellular
tubular
simple tubular

Meibomian gland
Moll's glands
Montgomery's glands
Naboth's glands
olfactory glands, Bowman's glands
Paneth cells
parathyroid glands, Gley's glands, Sandstroem's
glands
parotid gland
Peyer's patches (or glands)
pyloric glands

eyelids
eyelids
mammary areola
cervix and os uteri
nose, olfactory region
small intestine
thyroid, on surface

sebaceous
sebaceous
mucous
serous
-

mouth
ileum, lymphatic glands
stomach

serous
mucous

sebaceous gland

skin

sebum

Skene's glands, Guérin's glands
sublingual gland, Rivini's gland

vagina
mouth

submandibular gland

mouth

mucus
(primarily)
mixed (M+S)

Duverney's gland
Ebner's glands
eccrine sweat glands
esophageal glands
exocrine pancreas
Fränkel's glands
gastric chief cell, Wasmann's glands
glomus coccygeum, coccygeal gland, Luschka's
gland or ganglion
goblet cells
Henle's glands
Huguier's glands
Krause's glands
Lieberkuhn's glands
Littré's glands, Morgagni's glands
mammary gland

-

racemose
compound
tubulo-acinar
tubulo-alveolar
simple
branched
tubular
acinar
branched
tubulo-alveolar
tubulo-alveolar
35

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

sudoriparous glands, Boerhaave's glands
Sigmund's glands
Suzanne's gland
Weber's glands
Glands of Zeis

skin
epitrochlear lymph nodes
mouth, beneath the alveolingual
groove
tongue
eyelids, free edges

mucous

-

mucous
sebaceous

tubular
-

Endocrine glands and the hormones secreted
Hypothalamus produces
 Thyrotropin-releasing hormone (TRH) Parvocellular neurosecretory neurons
 Gonadotropin-releasing hormone (GnRH) Neuroendocine cells of the Preoptic area
 Growth hormone-releasing hormone (GHRH) Neuroendocrine neurons of the Arcuate nucleus
 Corticotropin-releasing hormone (CRH) Parvocellular neurosecretory neurons
 Vasopressin Parvocellular neurosecretory neurons
 Somatostatin (SS; also GHIH, growth hormone-inhibiting hormone) Neuroendocrince cells of the
Periventricular nucleus
 Dopamine (DA) Dopamine neurons of the arcuate nucleus
Pineal body produces
Melatonin(Primarily) Pinealocytes


Pituitary gland (hypophysis) produces
o

o

o

Anterior pituitary lobe (adenohypophysis)


Growth hormone (GH) Somatotropes



Prolactin (PRL) Lactotropes



Adrenocorticotropic hormone (ACTH, corticotropin) Corticotropes



Lipotropin Corticotropes



Thyroid-stimulating hormone (TSH, thyrotropin) Thyrotropes



Follicle-stimulating hormone (FSH) Gonadotropes



Luteinizing hormone (LH) Gonadotropes

Posterior pituitary lobe (neurohypophysis)


Oxytocin Magnocellular neurosecretory cells



Vasopressin (AVP; also ADH, antidiuretic hormone) Magnocellular neurosecretory cells

Intermediate pituitary lobe (pars intermedia)


Melanocyte-stimulating hormone (MSH) Melanotroph

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Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015





Thyroid produces
o

Triiodothyronine (T3), the potent form of thyroid hormone Thyroid epithelial cell

o

Thyroxine (T4), a less active form of thyroid hormone (Primarily) Thyroid epithelial cells

o

Calcitonin Parafollicular cells

Parathyroid produces
o





Heart produces
o

Atrial-natriuretic peptide (ANP) Cardiac myocytes

o

Brain natriuretic peptide (BNP) Cardiac myocytes

o

Adenosine Cardiac myocytes

Striated muscle produces
o







Thrombopoietin Myocytes

Skin produces
o



Parathyroid hormone (PTH) Parathyroid chief cell

Vitamin D3 (calciferol)

Adipose tissue
o

Leptin (Primarily) Adipocytes

o

Estrogens (mainly Estrone) Adipocytes

Stomach produces
o

Gastrin(Primarily) G cells

o

Ghrelin P/D1 cells

o

Neuropeptide Y (NPY)

o

Secretin S cells

o

Somatostatin D cells

o

Histamine ECL cells

o

Endothelin X cells

Duodenum produces
o

Cholecystokinin I cells

37

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015









Liver produces
o

Insulin-like growth factor (IGF) (Primarily) Hepatocytes

o

Angiotensinogen Hepatocytes

o

Thrombopoietin Hepatocytes

Pancreas produces
o

Insulin (Primarily) β Islet cells

o

Glucagon (Also Primarily) α Islet cells

o

Somatostatin δ Islet cells

o

Pancreatic polypeptide PP cells

Kidney produces
o

Renin (Primarily) Juxtaglomerular cells

o

Erythropoietin (EPO) Extraglomerular mesangial cells

o

Calcitriol (the active form of vitamin D3)

o

Thrombopoietin

Adrenal glands
o

o



Adrenal cortex produces


Glucocorticoids (chiefly cortisol) Zona fasciculata and Zona reticularis cells



Mineralocorticoids (chiefly aldosterone) Zona glomerulosa cells



Androgens (including DHEA and testosterone) Zona fasciculata and Zona reticularis cells

Adrenal medulla produces


Adrenaline (epinephrine) (Primarily) Chromaffin cells



Noradrenaline (norepinephrine) Chromaffin cells



Dopamine Chromaffin cells



Enkephalin Chromaffin cells

Testes
o

Androgens (chiefly testosterone) Leydig cells

o

Estradiol Sertoli cells

o

Inhibin Sertoli cells

38

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015







Ovarian follicle/Corpus luteum
o

Progesterone Granulosa cells, Theca cells

o

Androstenedione Theca cells

o

Estrogens (mainly estradiol) Granulosa cells

o

Inhibin Granulosa cells

Placenta (when pregnant)
o

Progesterone (Primarily)

o

Estrogens (mainly Estriol) (Also Primarily)

o

Human chorionic gonadotropin (HCG) Syncytiotrophoblast

o

Human placental lactogen (HPL) Syncytiotrophoblast

o

Inhibin Fetal Trophoblasts

Uterus (when pregnant)
o

Prolactin (PRL) Decidual cells

o

Relaxin Decidual cells

3.7.14. ENDOCRINE DISRUPTOR
3.7.14.1. From Wikipedia, the free encyclopedia
Endocrine disruptors are exogenous substances that interfere with the endocrine system and disrupt the physiologic
function of hormones. Studies have linked endocrine disruptors to adverse biological effects in animals, giving rise to
concerns that low-level exposure might cause similar effects in human beings.

3.7.15. THE ENDOCRINE SYSTEM
Endocrine systems are found in most varieties of animal life. The endocrine system is made up of glands, which secrete
hormones, and receptor cells which detect and react to the hormones.
Hormones are released by glands and travel throughout the body, acting as chemical messengers. Hormones interface
with cells that contain matching receptors in or on their surfaces. The hormone binds with the receptor, much like a key
would fit into a lock.

3.7.16. ENDOCRINE DISRUPTORS
Disruption of the endocrine system can occur in various ways. Some chemicals mimic a natural hormone, fooling the
body into over-responding to the stimulus, or responding at inappropriate times. Other endocrine disruptors block the
effects of a hormone from certain receptors by blocking the receptor site on a cell. Still others directly stimulate or
inhibit the endocrine system and cause overproduction or underproduction of hormones. Medical interventions
commonly manipulate the endocrine system for the betterment of a patient, and side effects of such therapy can be
interpreted as due to endocrine disruption. Substances in question are also known as Endocrine Disrupting Chemicals
(EDCs) or Hormone Disrupting Chemicals (HDCs), and belong to the group of xenobiotics, foreign chemicals that
affect a biological system.

39

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

Some of the most well-known examples of EDCs are 17-alpha ethinylestradiol (the contraceptive pill), Dioxins, PCBs,
PAHs, furans, phenols and several pesticides (most prominent DDT and its derivatives). Substances with estrogenic side
effects include the xenoestrogens. There is a long list of substances which may disrupt the endocrine system but have not
yet been scientifically proven to do so.
In recent years, some scientists have proposed that chemicals might inadvertently be disrupting the endocrine system of
humans and wildlife. A variety of chemicals have been found to disrupt the endocrine systems of animals in laboratory
studies, and there is strong evidence that chemical exposure has been associated with adverse developmental and
reproductive effects on fish and wildlife in particular locations. The relationship of human diseases of the endocrine
system and exposure to environmental contaminants, however, is poorly understood and scientifically controversial
(Kavlock et al., 1996, EPA, 1997).
One example of the devastating consequences of the exposure of developing animals, including humans, to endocrine
disruptors is the case of the potent drug diethylstilbestrol (DES), a synthetic estrogen. Prior to its ban in the early 1970s,
doctors mistakenly prescribed DES to as many as five million pregnant women to block spontaneous abortion and
promote fetal growth. It was discovered after the children went through puberty that DES affected the development of
the reproductive system and caused vaginal cancer.
In addition to disruption of reproductive endocrinology, modulation of adrenal, thyroid and growth hormone function
have also been described for various compounds in both humans and some animals, although the significance of these
effects have not yet been fully determined.

3.7.17. LEGAL APPROACH
The Congress of the United States has improved the evaluation and regulation process of drugs and other chemicals. The
Food Quality Protection Act of 1996 and the Safe Drinking Water Act of 1996 simultaneously provided the first
legislative direction requiring the EPA to address endocrine disruption through establishment of a program for screening
and testing of chemical substances.
In 1998 the EPA began the endocrine disruptor screening and testing program by establishment of a framework for
priority setting, screening and testing more than 85,000 chemicals in commerce. As of this writing ((2006)) the EPA is
continuing to validate test methods for this program and has issued a notice of intent to begin the initial priority setting
process. The basic concept behind the program is that prioritization will be based on existing information about
chemical uses, production volume, structure-activity and toxicity. Screening is done by use of in vitro test systems (by
examining, for instance, if an agent interacts with the estrogen receptor or the androgen receptor) and via the use of in
animal models, such as development of tadpoles and uterine growth in prepubertal rodents. Full scale testing will
examine effects not only in mammals (rats) but also in a number of other species (frogs, fish, birds and invertebrates).
The multitude of possible endocrine disruptors are technically regulated in the United States by many laws, including:
the Toxic Substances Control Act, the Federal Insecticide, Fungicide, and Rodenticide Act, the Food, Drug and
Cosmetic Act, the Clean Water, the Safe Drinking Water Act, and the Clean Air Act.

40

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

System reaction options for selfmaintenance: from the cell on
Form = Structure and function in one
Form = Morphology
1 Metabolise (function)

Reaction
chronology
depending on the
input coming
from the
environment

Transform, store, excrete

INPUT

2 Adapt form: differentiation
3 Cleavage: (structure)
4 Apoptose: cell death
Reducing or falling back in
complexity

EVOST:
EVOST: Evolutionary Medicine
in the Osteopathic Field,
Max Girardin D.O.

23

3.8. CONNECTIVE TISSUE
3.8.1. THE CONNECTIVE TISSUE
The second of the four basic tissues in histology is the connective tissue; it got its name because it is the tissue that
connects and surrounds almost all the other tissues (the green stuff). The skeleton that carries all the other tissues
directly or indirectly is also connective tissue. And thus the tone is set; the connective tissue not only connects but has an
important support and mechanical stress transmission function.
These last functions are based on the fact that some cells of the connective tissue produce substances that glue
everything together; therefore it gets the name amorphous matrix or amorphous intercellular substance. Its anatomical
position: between the cells gives it an excellent opportunity: being the siege of most of the physiological extra cellular
processes.
After these classic definitions, it is time for a more Osteopathic approach:
 Amorphous: having no apparent shape or organization
 Matrix: the extracellular substance in which tissue cells (as of connective tissue) are embedded; or something
(as a surrounding or pervading substance or element) within which something else originates or takes form or
develops
If you get the definitions there is a “contradictio in terminis” again here: The matrix is certainly not devoid of
organization, on the contrary as we will see.
As to the: something (as a surrounding or pervading substance or element) within which something else originates or
takes form or develops, this is the evolution not the start.
41

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

The matrix is generated as an interaction between water and the cells.
Matrix is a complex fluid with different viscosity forms; it organizes or disorganizes more or less depending on the
environmental conditions. The only thing that I could agree on fundamentally with the classical definitions is the fact
that it is extracellular. More about this later...

3.8.2. MATRIX
The intercellular matrix is classically described as being a non living material that can greatly vary in viscosity or
consistence. The second hardest being the bones where everything else is hung upon.
Generally the cells have a gelatinous consistence; without the intercellular matrix, our bodies would resemble a giant
slug, very supple but with the same type of mobility and form probably. Some even go as far as to say that the matrix
forms the building “body” in which the cells live. The amorphous intercellular ground substance is colorless, transparent
and homogenous. It consists mainly of two basic components: glycosaminoglycans or proteoglycans and structural
glycoproteins .

3.8.3. GLYCOSAMINOGLYCANS
These molecules used to be called: acid polymuccosacharides . Since some years the term proteoglycans and recently
glycosaminoglycans are the most common in use. I will use GAG or proteoglycans. But what are they?
The proteoglycans are linear chains of disacharides that are attached through a covalent bond to a protein axis. The
characteristics: they are strong water-attractors and behave as poly-anions (-); thus they can bind a large amount of
cations (+) by electrostatic bonds, usually this concerns mainly sodium ions (Na+).
The water, they attract and bind surrounds the molecules with a voluminous water mantle: hydratation mantle.
Hyaluronic acid, chondroitinsulphate and heparin are the most commonly known of the GAG’s.
The production of the GAG’s takes place in the RER for the protein part, and the SER for the sacharid part, both are
joined in the Golgi complex, reduction or lysis in the cytoplasm is taken care of by lysosomal enzymes.
Examples of GAGs include:
Name
Sugar 1
Chondroitin
Nsulphate
Acetylgalactosamine
Dermatan
iduronic acid
sulphate
Keratan
galactose
sulphate
Heparin
glucuronic acid
Heparan
sulphate
Hyaluronan

Sugar 2
glucuronic acid

Linkage
beta (1,3)

Unique features
Most prevalent GAG

NAcetylgalactosamine
(varies)

beta (1,3)

Only one with iduronic acid

beta (1,4)

Very variable

glucosamine

alpha
(1,4)
alpha
(1,4)
beta (1,3)

Only one intracellular; high negative
charge density
Similar to heparin but extracellular

glucuronic acid

glucosamine

glucuronic acid

N-Acetylglucosamine

Only bacterial one, only one without
sulfur

3.8.4. STRUCTURAL GLYCOPROTEINS
In contradiction to the proteoglycans, is it the protein component that dominates here. The glycoproteins are made by
the same organelles as the proteoglycans. Insight in their biological meaning is a discovery of the end of last century.
There are three types of glycoproteins common in connective tissue known that all have another origin in time
(Chronology and hierarchy). The glycoproteins are fibronectins, laminins and chondronectins.
Laminins are typical for the lamina basalis
Fibronectins are typical for all forms of connective tissue Chondronectins are typical for cartilage.

42

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.8.4.1.

Fibronectins (Fibronectins Scientific American June 1986)

Fibronectin molecules can assemble to fibrils, bind to a cell en help bind cells to the other fibril types in the extra
cellular matrix. Fibronectin also plays a crucial role in the internal organization of cells, and its adhesive characteristics
make it so important in blood clotting and in tracing the pathways for cellular growth and the pathways of development
in embryology. The fibronectins are considered as the pathfinders that trace the developmental routes that the cells
follow. (Frontier tissue and glands for instance)
Experimentally there was a gel made with normal epithelial cells and cancerous cells, on the cancerous cells one
important protein was found missing: fibronectin.
Than fibronectins were extracted form normal cells and introduced in a culture of tumor cells; immediately something
crucial happened, the cells agglutinated. Some time after this was observed the cells were examined; the cytoskeletons
had completely reorganized and reshaped the cells. They did continue to reproduce at an abnormal elevated rate,
nevertheless.
Staining techniques permitted to demonstrate that the fibronectin fibrils penetrate the cell membrane and are linked to
the cytoskeleton and its actins.
In embryologic studies it was demonstrated the developmental pathways are characterized by a higher concentration of
fibronectin pathways. (Try to connect this with what you know of polarized epithelium cells)

3.8.4.2.

Laminins

The laminins play an important role in the fixation of the epithelial cells to the lamina basalis; they are the glue so to
speak.

3.8.4.3.

Chondronectins

Chondronectin is one of the glycoproteins that were isolated out of cartilage; it is the glue that connects the cells, matrix
and fibers to each other.

3.8.5. TISSUE FLUID
In connective tissue there is always a variable quantity of tissue fluid. The constitution is mainly water, ions and some
water soluble substances, and some low weight proteins that were pushed out of the bloodstream by the hydrostatic
pressure actually it is very similar to blood plasma. Under normal conditions, the quantity of volume of tissue fluid is
relatively small. (After trauma it may accumulate and than we call it edema 3) The tissue fluid is the medium for the
metabolic exchanges between tissue and circulatory system; as such the connective tissue (inner tissue) can be seen as
the filter between epithelial cells (frontier tissue) and the circulatory system. (Inner tissue) As you can see this is twice
inner tissue but with a very different organization of matrix and viscosity.
The tissue fluid or liquor is in physiology usually named the interstitium or the interstitial fluid, although interstitium, in
histology never was clearly defined; histologists talk about extracellular fluid that moves around in the intercellular
spaces and matrix.

3

Histology describes edema as: widened space between connective tissue components filled with a colloid solution of tissue fluid that is bound to the
matrix.

43

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

3.8.6. FIBRES
3.8.6.1.

General introduction

There are two main types of fibres common in connective tissue: the collagen and elastic fibers.
In ancient literature you can find a third type of fiber described: reticular fibers composed of reticulin proteins; in fact it
was demonstrated that they are just a particular form of collagen fibers.
Biochemistry evolving and developing succeeded in demonstrating that in fact only collagen and elastic fibers have
different protein units of which they are constituted. Good for the students, connective tissue has only two types of
fibers: collagen and elastic. The very different form of behavior of connective tissues is in fact largely depending on the
amount of fibers present and their proportions. (In all connective tissue you always have both elastic and collagen but
the proportion of each can vary immensely, and some forms of connective tissue have few fibers.)
When, during evolution, the stage of multicellular complexity was reached, the organisms started to build more
extracellular proteins that self organized into complexer structures, up to finally complex fibers that we know today as
the many different types of collagen.
Collagen is the most common protein in the human body; it is 30 % of the total dry bodyweight. (Except in vegetarians
there it is a little less, if you know a strict vegetarian, pull at his skin you’ll see that usually it is very flaccid not to say
flabby, probably due to chronic AA shortage.) Collagen is produced by different cell types.
The subdivision of the different collagen types is based upon their:
 Chemical composition
 Behavior (mechanical and chemical)
 Morphology or form
 Anatomic presence
 Other properties
 They are well known now but as the classification is a little blurry, there are new fibers discovered regularly;
does not mean much to us, never mind.
The most common amino acids that are employed to build collagen are:
- glycin
- prolin
- hydroxiprolin
- hydroxilysin
Essential amino acids note: (Refine a little you biochemistry)
Nine amino acids are generally regarded as essential for humans. They are: isoleucine, leucine, lysine, threonine,
tryptophan, methionine, histidine, valine and phenylalanine. A mnemonic used to remember these acids runs: I Like
Light That Tries Making Home Very Pretty.
In addition, the amino acids arginine, cysteine, glycine, glutamine and tyrosine are considered conditionally essential,
meaning they are not normally required in the diet, but must be supplied exogenously to specific populations that do not
synthesize it in adequate amounts. An example would be with the disease Phenylketonuria (PKU). Individuals living
with PKU must keep their intake of phenylalanine extremely low to prevent mental retardation and other metabolic
complications. However, phenylalanine is the precursor for tyrosine synthesis. Without phenylalanine, tyrosine cannot
be made and so tyrosine becomes essential in the diet of PKU patients.
Which amino acids are essential varies from species to species, as different metabolisms are able to synthesize different
substances. For instance, taurine (which is not, by strict definition, an amino acid) is essential for cats, but not for dogs.
Thus, dog food is not nutritionally sufficient for cats, and taurine is added to commercial cat food, but not to dog food.
The distinction between essential and non-essential amino acids is somewhat unclear, as some amino acids can be
produced from others. The sulfur-containing amino acids, methionine and homocysteine, can be converted into each
other but neither can be synthesized de novo in humans. Likewise, cysteine can be made from homocysteine but cannot
44

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

be synthesized on its own. So, for convenience, sulfur-containing amino acids are sometimes considered a single pool of
nutritionally-equivalent amino acids. Likewise arginine, ornithine, and citrulline, which are interconvertible by the urea
cycle, are considered a single group.

3.8.7. REVIEW OF THE MAIN CHARACTERISTICS OF THE
COLLAGEN TYPES
* COLLAGEN TYPE I
composition : 2 1 and 1 2 chains
anatomy
: dermis , bone , tendon , dentine , fascias , fibrous cartilage
synthesis by : fibroblasts , osteoblasts , chondroblasts , odontoblasts
function : very solid to traction, not elastic
* COLLAGEN TYPE II
composition : 3 1 type II chains
anatomy
: hyaline and elastic cartilage
synthesis by : chondroblasts
function : bieden vooral weerstand aan intermitterende druk
* COLLAGEN TYPE III
Composition: 3 1 type III chains
anatomy
: smooth muscle cells , endoneurium , arteriës , liver , spleen , kidney , lung
synthesis by : smooth muscle cell, fibroblast, reticulumcell, cell of Schwann, hepatocyt
function : structural maintenance of form by organ changes (fibrosis or inflammation)
* COLLAGEN TYPE IV
composition : 3 1 type IV chains
anatomy
: laminae basales of the epithelium and endothelium
synthesis by : epithelium and endothelium cells
function : support, fixation, filtration
* COLLAGEN TYPE V
composition : 3 A and 3 B chains
anatomy
: laminae basales of the placenta & some vessels like the umbilical cord
synthesis by : insufficient data
Function
: insufficient data
Etc. in the mean time there are 23 different types of collagen fibers in the official classification, for us, practically this
absolute nonsense, because it brings us away from the essence the understanding of the mechanism.
(www.wikipedia .org is following this up if you want to have an idea, enjoy)
The protein units from which by spontaneous self organization and polymerization the collagen fibrils are made of,
are long stretched molecules: TROPOCOLAGEN , that consists of three polypeptide subunits, which will twist in
each other until a triple helix is formed. ( see biochemistry / Protids)
The differences in collagen types as you could see is among others dependant on the differences in polypeptide chains
that polymerize: alfa chains: 1 and 2, while in the 1 chains there are 5 variations. With the collagen of type I, II and
III, it will be the way they polymerize and attach to long fibril strands that will make the difference. (It will be the HH
bridges and their hydrophobic action that will be determining. The cross-links between the molecules will also differ.)

45

Physiology: Introduction
M.Girardin D.O., Evost Fellow, Pro-sector
1995, reeditions 2007, 2014, 2015

In the collagen types IV and VI, the polymerization will not lead to long fibrils but amorphous, granulated like layers as
in the lamina basalis.
Collagen fibrils are thin structures with a diameter of 40 to 80 nm, which are easily recognizable under the electron
microscope because of their characteristic striated pattern. This pattern is provoked by the way the tropocollagen
molecules cover each other. The dark bands appear where there are more free binding groups. (They absorb more
contrast substance, gold powder in scanning electron microscopy)

3.8.8. BIO SYNTHESIS OF COLLAGEN
- Polypeptide  chains are formed by the poly ribosomes of the RER and delivered by the cisterns (small RER
vacuoles).
- During the formation of the polypeptide chains, hydroxylation of the AA, proline and lysine is done.
- Glycosylation of the hydroxylysine happens next. The different collagen types contain different amounts of sacharids
bond to the hydroxylysine. (Galactose.)
- Each  chain is synthesized with extra pieces of peptides that will be attached as well on the NH2 end group as well as
to the COOH end group. These, so called registration peptides will make that the  chains for a specific collagen
molecule in making, is coupled in the right chronology and order. (Which from evolutionary point of view is purely
biochemists non sense as there is no end goal) The registration peptides keep the molecules of procolagen in solution,
to prevent intracellular precipitation. (And this makes sense from evolutionary point of view; the cells that did not do
this would have engorged themselves quickly and died). As such the procolagen is delivered to the extra cellular matrix.
- Once the release out of the cell is a fact, the registration peptides are cut off the molecule by the enzyme: procolagen
peptidase. The procolagen now gets a new name: tropocollagen.
Tropocollagen is hydrophobic and can thus not stay solved in the watery extracellular environment, it will thus
polymerize spontaneously with its pairs. (Self organization)
This spontaneous polymerisation leads to collagen fibrils. The residual hydroxyproline will help the stability of the triple
helix of collagen by building the HH bridges between the polypeptidchains.
- In the collagen types I and III the fibrils will self assemble to long fibers. Proteoglycans and structural glycoproteins
play a role in the conjunction of molecules to fibrils and finally to fibers.
(In microtubules these are called MAP’s microtubule associated proteins that will come back in neural tissue because
of their importance there. )
- The fibril structure is solidified by the formation of covalent crosslinks .

46



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