pathology sheet # 1

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بسمـ الله الرحمن الرحيمـ

In this semester will study cell damage, inflammation, cell repair, nuoplesia & respiratory system.
By the end of the semester we will study cardiovascular system.


Overview of cellular stress & noxious stimuli

We know that the cell is an active participant in their environment. They have to adjust there structure and function in response to accommodate changing demands and extracellular stresses.

* the cells maintain their internal environment within narrow physiologic parameters So this is called normal homeostasis.

But, the cells might be exposed to physiologic or pathologic stimuli. so they should undergo certain changes:

First :
The cell might undergo adaptation to the physiologic or pathologic stimuli. So they undergo adaptation in order to maintain the function and the viability of the cells. But the adaptive capability is limited, if the adaptive capability of the cells is exceeded or the stress is so harmful:
In the beginning the cell will undergo cell injury.
**to a certain limit the cell injury is reversible  with removal of the harmful stimulus  the cell will return to normal.
But if the stimulus is continuous or the stimulus is severe from the beginning, the cell will die & injury will become irreversible and become necrotic.

**In the diagram  the normal cell when encounter stress or cell injury  it might undergo adaptation if the adaptation is reversible the cell will return to its normal status ((in case of reversible adaptation)).
But if the adaptive capability is exceded when the stimulus is persistence, the cell might undergo injury.

Note:
We will talk later about the morphological features of reversible injury.

**With continuing injury or with severe injury, the cell will undergo irreversible cell injury and what’s so called necrosis or cell death
of course the cell death manstification can be either as necrosis or other type of cell death called apoptosis.


Cellular adaptation


We have Four forms of adaptation:
 Hypertrophy.
 Hyperplasia.
 Atrophy.
 Metaplasia.


We have 2 types of adaptation:

 Physiological adaptation.

Response of the cell to normal physiological stimuli like:
Hormones or chemical mediators.
Ex: During pregnancy there is enlargement of the uterus….
(Which is a physiologic process due to the stimulation by hormones, like: estrogen and progesterone)
So the enlargement is physiological adaptation .
This enlargement either :
1) Hypertrophy OR 2) Hyperplasia.

 Pathological adaptation.

Response of the cell to stress that allow the cells to modulate their structure and function to escape injury.
- The stimuli is not normal as in the case of physiological stimuli.
-Examples for pathological stimuli:
Bacterial infection, loss of blood supply.
- The cell responds to these changes by modulating their structure and function in order to escape injury.
- Most of the times they can’t escape cell injury and cell death will occur.



Now we are going to talk about forms of adaptation in the cells:

A. Hypertrophy:
It’s the increase in the size of the cell without increase in the number of the cells in an organ.
**Bigger cells in hypertrophy but NO new cells.
**The cells that are capable of division can adapt by both hypertrophy and hyperplasia when they are exposed to the stress.

Note:
1) Hyperplasia  increase in the number of the cells.
2) The cells that can undergo division can adapt by both hypertrophy and hyperplasia.
3) Some certain cells in the human body can’t divide such as : cardiac muscle and striated skeletal muscle in adult which have limited capacity to divide adaptation will occur by increasing the size but not the number of the
Cellshypertrophy.


4) Hypertrophy and hyperplasia can occur together.
Ex: enlargement of the uterus during pregnancy, which is composed of endometriam and muscle wall ((smooth muscle))  these smooth muscle can divide they will undergo both hypertrophy and hyperplasia. increase in size and number of the cells).
This is true also for the enlargement of the breast during pregnancy.

** The most common cause of hypertrophy is increase work load.
** Hypertrophy can be physiologic or pathologic.


 Example for physiologic hypertrophy:
Body builders have increased work load (due to exercise)  the skeletal muscle will adapt to the increased work load by hypertrophy of skeletal muscle fibers.
{Remember that skeletal muscle has limited capacity to divide  }
While its physiologic hypertrophy because the stimulus is not harmful.

 Example for pathologic hypertrophy:
Which can be caused by certain pathologic disorders, such as:
Patients suffering from hypertension or aortic valve stenosis.

There is an increase in the work load in the left ventricle of the heart due to the hypertension and aortic valve stenosis  the left ventricular muscle will have to pump more blood against the increased work load  because the heart muscle can’t divide …. Hypertrophy of the cardiac left ventricular will occur.

Mechanism of the physiology of the hypertrophy:
The stimuli will form hypertrophy  turn on certain signal transduction transferees, these will induce certain genes, and the genes will cause synthesis of more structural proteins and organelles in the cells.


** Increase of the size of the cell in the hypertrophy is caused by the increase in the number of structural proteins in the cell in order to adapt to the stimuli ((work load)).
** When we increase the number of the structural proteins then this will improve the function of the muscle in response either to physiologic or pathologic stimuli.

But with continuing stimuli on the cardiac muscle due to hypertension (hypertension is a chronic disease) or aortic valve stenosis (it’s not repaired by surgery), a limit will be reached for the hypertrophic muscle beyond which the enlargement muscle can NO longer compensate for the increased work load  the adaptive capability will be exceeded and can’t compensate for the increased work load.
** because the blood supply for hypertrophic cardiac muscle is the same as for the normal muscle  the hypertrophic muscle will receive reduced blood supply  ischemia will occur  causing fragmentation of contractile proteins  the hypertrophic muscle will dilate causing cardiac failure.



{This is an example of how the adaptive capability can be exceeded and lead to significant cell injury if the stress remain continuous}.








B. Hyperplasia:
Increase in the number of the cells so it occurs only in the cells that are capable of division.
Ex:
As In case of the enlargement of the uterus by hypertrophy and hyperplasia of the smooth muscles of the uterus.


• Physiologic hyperplasia:
**Can be induced by hormonal stimulus  enlargement of the breast due to pregnancy and puberty and also the enlargement of the uterus during pregnancy.
• Compensatory hyperplasia:
**In case of donation of the liver: portion of the liver will undergo compensatory hyperplasia due to the release of growth factors from:
1) Remnant hypatocytes. 2) Non baranchimal cells of the liver.
Which will cause the stimulation for increase division of the cells of the liver mitosis starts after 12 hours of resection of the portion of the liver and after few days the normal weight of the liver will be restored.
• Pathological hyperplasia:
Increase in number of the cells in response to pathological stimuli.

**We are going to talk about 3 examples:
1. Endometrial hyperplasia:
We have 3 phases in menstrual cycle:
-Menstrual phase - Proliferatry phase -secretary phase.
After menstruation proliferation of the endometrial glands due to estrogen, then inhibition will occur by progesterone then the secretary phase will start, after that the shedding of the endometriam will occur.

But what if we have imbalance between estrogen and progesterone?!
The estrogen level is increasedthe endometrium will remain in the proliferative phase and hyperplasia of the endomatruim gland will occur.

Note:
Estrogen is increased due to polycystic ovary disease.
 Pituitary abnormality in releasing the luteinizing hormone and follicle stimulating hormone.

The endometrial hyperplasia remains responding to the normal regulatory mechanism.
 If it’s not under the response, the hyperplasia will be converted into endometrial carcinoma (marked proliferation).

2. Connective tissue hyperplasia in wound healing.
In wounds either surgical or non-surgical we need to repair it.

In non-surgical wounds we need to cover this injury by scar tissue.
Scars are composed of:
- Fibroblast - fibrous tissue -blood vessels (Which is very important in cell repair.)

 How to produce a scar?
After wound injury hyperplasia pf the fibroblast (which is a baranchimal cell) will produce collagen matrix or the fibrous tissue and form the scar that aid in repairing the wound.
3. Certain viruses like human pslpiluma virus cause skin warts.
Infection by this virus might cause release of growth factors; these growth factors will cause hyperplasia of the sequamus epithelium (which will cause the skin warts). Also it might cause mucosal lesions in other parts of the body such as the mouth.


**In all of these situations the hyperplasia process remain controlled, if hormonal or growth factor stimulation are removed the hyperplasia will stop.
Ex: in case of endometrial hyperplasia, if the estrogen is removed (the stimulus is removed) hyperplasic endometriam will return to the normal endometrial gland.

**Sensitivity to normal regulatory control mechanism that distinguish between benign pathologic hyperplasia and cancerous perforation
Nevertheless pathological hyperplasia, still a fertile soil from which cancerous perforation might occur (by certain mutation).

** 3% of patients with endometrial hyperplasia will suffer from endometrial carcinoma.





C. Atrophy:
Decrease in cell size due to decrease in cell substance (structural proteins and organelles) to escape injury.
**Acute loss of blood in a skeletal muscle will cause necrosis.
** In chronic loss of blood supply to the skeletal muscle (ischemic muscle)  it will undergo atrophy (decrease in proteins & organelles) to balance between the blood supply & the size of the cell & the cell will escape injury.
**It’s a form of adaptation characterized by decrease the size of the cell.
**In sufficient number of cells that is reduced in size shrinkage of the whole organ will occur.
**Although atrophic cells have diminished function {due to loss of structural proteins & organelles}, the cell is not dead.


Causes of atrophy:
a) Decrease work load immobilization of the limb due to fractures. That’s why we need to introduce physiotherapy to these patients.
b) Loss of innervation  in case of poliomyelitis ( شلل الأطفال)
c) Chronic decrease in blood supply the cell might adapt to the decrease the cell size in order to escape injury.
d) Inadequate nutrition.
e) Aging might cause brain atrophy.
f) Loss of endocrine stimulation, such as in post menopause estrogen will be decreased endometrial atrophy will occur.

Some of these stimulations can be physiologic, such as [e], while others can be pathologic [a].
Whatever the stimulation is, adaptation that is established by decrease structural proteins are done either by:
1) Decrease synthesis 2) Increase degradation.
 under the microscope there is another feature in the atrophic organs called autophagic vacuoles(self-eating)  process in which cells eat it’s own components in attempt to provide nutrients and to survive and to escape injury.
Some of the remaining particles that cannot be digested in the cellwill be found in vacuoles (contain remnant of the digested particles & organelles o& proteins inside the cell).
Ex: testicular atrophy  in Dr. slides :
Left is normal where’s the right is atrophic.

**In case of decrease of the blood supply to the heart  myocardial infarction (necrosis).

D. Metaplasia :

Changes of one adult cell type by one other adult cell type (either epithelium or paranchemal) .
 Normally the bronchi is lined with ciliated columnar epithelium (fragile epithelium can’t survive the effects of cigarette smoking) it will be replaced into seguamus epithelium which is more able to survive the damaging effect of cigarettes smoking.
So, metapleiasa  cells which are sensitive to a particular stress are replaced by other cell types that are able to withstand the adverse environment.

But how metaplasia occurs?!
We know that tissues have stem cells  in case of cigarette smoking, the stem cells found in the bronchi will produce stratified sequamus epithelium instead of ciliated columnar epithelium (arises from genetic reprogramming of the stem cells).
Rather than transdifferentitation of already differentiated cells) also it’s caused by vitamin A deficiency.

 All forms of adaptations are reversible adaptation (after removal of stress the cell will return to normal).
Although the cells are able to survive the harmful effect of smoking, the normal protective mechanisms that are found in normal cells (ciliated columnar epithelium) will be lost:
1) mucus secretion 2) cilliary movement that remove certain particles or bacteria..

These patients are :
More susceptible to be infected by infection.
With time if patients doesn’t stop smoking  metaplastic epithelium may transferred into malignant sequamus cell carcinoma.

But metaplasia does not mean malignancy so it’s not a factor for malignancy precancerous.
 In females in case of infection, erosion, lacerations and cervix (lined normally with mucus secreting columnar epithelium) can’t withstand the harmful effect.
This epithelium will be replaced by sequamus epithelium.
Most common cancer in lungs is sequamus cell carcinoma.
Usually the metaplasia is in the direction of glandular epithelium to sequamus, but in gastroesopheageal reflex disease (reflex of gastric contents to the esophagus).
With time replacement of sequamus to either gastric type of epithelium or intestinal will occur.
**In case of malignancy adenocarcenoma, because of the glandular epithelium
**Also there is sequamus cell carcinoma for the original cells,

In Dr. slides:
Respiratory epithelium to the right(ciliated columnar epithelium), Left replacement of stratified sequamus metaplastic..


Cell injury (cell death):
Result when the cell is stressed so severely that they are no longer able to adapt (adaptive capability to be exceeded)
Like in left heart ventricle hypertrophy will be converted to fragmentation of contractile elements & cell injury will occur.

Causes:
• Harmful stimulus.
• Intrinsic genetic abnormalities inside cells.

**If outside stimulus is so harmful sudden cut of blood supply to the heart  reversible cell injury irreversible cell injury (necrosis).
**The cell injury may progress in the process of reversible cell injury. If the stimulus is continuous cell death will occur.
**We see reversible cell injury in mild forms or early stages of cell injury.
**In early stages of cell injury the morphological & functional changes are reversible if the external stimulus is removed.



Although there are significant functional & structural abnormalities in cases of reversible cell injury, the most important thing that there is no severe damage to the cell membrane either:
1) Cytoplasmic membrane 2) organelles membrane.
& there is no severe dysfunction for the mitochondria.

 If there is profound changes in the membrane (discontinuity or breaks) of the cytoplasm or organelles & there is severe damage to the mitochondria the reversible cell injury will be converted to irreversible cell injury (cell death).

**There are 2 forms of cell death:
1 )necrosis 2) apoptosis

**In case of irreversible injurydiscontinuity & changes (abnormalities) in membranes will occur  abnormalities in lysosomal membrane (which contain enzymes that will be released to the cytoplasm & damage or cause necrosis of the cell) will occur.
Also, there is damage to cytoplasmic membrane  the cellular contents & the damaged contents will leak out to the outside environment which will attract inflammatory cells.

**Necrosis is usually associated with inflammatory cells.
**Apoptosis cell death, which occur when the cell is mainly deprived from growth factors, the cell’s DNA or damaged proteins that can’t be repaired it will kill itself.

Q: what is the difference between apaptosis & autophagic?
Apoptosis  cell death.
Autophages the starved cell eats its own components to find nutrients & survive But the cell remain intact.

**Apoptosis is an active, energy dependant form of cell death that may occur under pathologic or physiological function conditions.
** Necrosis  - only under pathologic conditions.
-It’s the most common form of death.
Causes of irreversible injury (for necrosis)  you can find it in the slides 
Note: in number 1 hypoxia: respiratory disease such as pneumonia.

“Life is like a coin …You can spend it any way you wish, but you only spend it once.”
Done By: Tara Elyass.
Date of the lec : 19/9/10.
Dr.Fatima 3bedat.
Corrections are more than welcomed.