pathology sheet # 3

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pathology sheet # 3

Post by Shadi Jarrar on 25/9/2010, 3:48 pm

بسم الله الرحمن الرحيم

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Pathology lecture 3 21/9/2010
Dr. Fatima Obeidat



Mechanisms of cell injury


Cell injury can be reversible or irreversible.

The response to cell injury depends on:
-Type of injury.
-Duration of injury.
-Severity of injury.

If we take small doses of toxins or there were short duration of ischemia, this will make reversible cell injury, if it was large doses or there were long duration of ischemia, irreversible cell injury happen.

The consequences of cell injury depend on:

-Type of cell (skeletal muscles can tolerate ischemia more than cardiac muscle).
-Status of the cell (if there is more glycogen, the cell can tolerate ischemia better than cells that lack glycogen because it's a source of ATP).
-Adaptability of the cell.
-Genetic makeup of the injured cell

If there is ischemia to the lower limb, irreversible cell injury will happen with death after 2-3 hours.
If there is a cut of the blood supply to the heart, cell death will happen after 20-30 min.

Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components.


The most important targets of cell injury are:

1) Mitochondria: which is the most important target and it's the site of ATP generation.
2) Cell membrane of the cell.
3) Proteins synthesis of the cell.
4) The cytoskeleton of the cell.
5) The integrity of genetic apparatus.

* The structural components of the cell are integrally connected (whatever can cause the initial injury is responsible for the effect of other components of the cell).

We took that loss of function can happen before cell death occurs. We can see first by electron microscope (after 2-3 hours) then by light microscope (after 6-12 hours) and then by gross changes (after 24 hours)



BIOCHEMICAL MECHANISMS OF CELL INJURY

1) ATP depletion: that can happen by hypoxia (loss of blood supply), toxins (like Cyanide) or mitochondrial damage.

Note: - ischemia is more dangerous than hypoxia because it includes the loss of oxygen in addition to the glycogen.





Depletion of ATP in the cell can cause the following:

* Cellular swelling: decrease in ATP  decrease in the action of Na pump  influx of Na and efflux of K.
The influx of sodium will cause more osmotic pressure that will lead to swelling

* Increase of the anaerobic glycolysis to compensate the loss of ATP, this will cause an increase of lactic acid that will make acidosis, cell acidosis activate some enzymes and inhibit some.

* Failure of Ca pump which is the most important effect. This will cause the influx of Ca inside the cell which will activate many enzymes that are responsible of cell death.

* Prolonged ATP depletion will cause detachment of ribosomes from RER which will decrease the protein synthesis inside the cell. The triglycerides inside the cell bind to proteins, if there is a decrease in protein synthesis, the triglycerides will not bind to proteins so it will deposit inside the cell and that causes fatty chain inside the cell.


2) Mitochondrial Damage:

* Mitochondria can be damaged most important by an increase of cytosolic calcium due to decrease of the activity of the ATP dependant calcium pump.

* Also it can be damaged by reactive oxygen species (ROS) and certain toxins.



The major consequences of mitochondrial damage are:

* loss of ATP production which is the most important, which is by the injury of the cell that will lead to the injury to the mitochondrial membrane and that will make certain channels in the mitochondria that we call "mitochondrial permeability transition pore", this will make efflux of hydrogen from the mitochondria (the hydrogen keeps the normal potential of the mitochondrial membrane) and this will reduce the potential of the mitochondrial membrane. Inside the mitochondria there are certain enzymes like cytochrome c oxidase that can exit to the cytosol (the importance of cytochrome c is that it activates certain enzymes like caspases that activates cell death by apoptosis).

** Necrosis and apoptosis might occur at the same time like in the situations of ischemia.


3) Influx of calcium

The intracellular calcium is 10000 times less than the extracellular.
The intracellular calcium is found in the endoplasmic reticulum and in the mitochondria.
When there is hypoxia, there is a decrease in ATP synthesis  dysfunction of the calcium pump  the influx of calcium from the extracellular to the intracellular will increase.

The function of the intracellular calcium is to activate many enzymes in the cell and the most important is the phospholipase (that degrade the phospholipids which are important to the cell membrane) that will degrade the plasma membrane. Another enzyme that is activated by the increase of the intracellular calcium is proteases that degrade the proteins. Another enzymes are the endonucleases that will damage the DNA. Also ATPase activity will increase so ATP inside the cell will be degraded by this enzyme. It will also stimulate apoptosis.
4) Free radicals

Free radicals are also important in cell injury.

* Damage by free radicals is called oxidative stress

Reactive oxygen species (ROS) are chemical species with single unpaired electron in the outer orbit, so they are unstable species, they can react with any organic and inorganic compounds.

Free radicals initiate autocatalytic reactions which are chemical reactions in which at least one of the products is also a reactant (free radical), so more damage to the cell.

The most important reactive species in cases of cell injury are oxygen-derived free radical.

There is production of free radicals inside the normal cells but they are removed by certain enzymatic and non enzymatic mechanism by the cell. Oxygen is reduced by 4 electrons into water during normal metabolism. During this process, production of free radicals can happen, but the cell can scavenge or degrade them.

Types of free radicals:

- Speroxide radical.
- Hydroxyl radical.
- Hydrogen peroxide radical.
- Copper and iron can accept and donate free radicals, and the most important reaction is the Fenton reaction (Fe²+ H2O2 → Fe³+ OH• + OH−).
- Ultraviolet radiation can produce free radicals (it hydrolyses water to hydroxyl radical and hydrogen free radical).
- Inflammatory cells produce free radicals.
- Nitric oxide.
Mechanism of removal of free radicals inside the cell during the normal metabolism:

- Superoxide dismutase which catalyzes the dismutation of superoxide into oxygen and hydrogen peroxide.

- Catalase: in the peroxisome, the hydrogen peroxide is converted by catalase into oxygen and water.

-glutathione peroxidase: which degrade the hydroxyl radical into water and oxidized glutathione.

-Vitamins E, A and C, and β carotene are antioxidant that can remove the free radicals from the cell.

- Binding the transitional metals (such as copper and iron as I said before) to storage and transport proteins (transferrin, ferritin)

What free radicals do inside the cells?

1) Lipid peroxidation: they damage the double bond inside the polyunsaturated fatty acid (it will damage the plasma membrane).
2) Cross linking of proteins by sulfhydryl group so it will be more susceptible to degradation.
3) DNA fragmentation: free radicals bind to thymine in the nuclear or mitochondrial DNA

5) Defects in membrane permeability

Biochemical mechanisms that lead to membrane damage are:

- Decreased phospholipid synthesis: synthesis of anything depends on ATP, so when the level of ATP is decreased inside the cell, synthesis of phospholipids will decrease (remember that phospholipid is the main component of the cell membrane).
- Increased phospholipid breakdown: by increased calcium inside the cell that will activate phospholipases

-ROS

- Cytoskeletal abnormalities: cytoskeleton are filaments that anchor the interior of the cell to the plasma membrane (they are important to the integrity of the plasma membrane).
We said that an increase in the intracellular calcium will activate proteases that will make damage to the cytoskeleton. Damage to these filaments will disrupt the integrity of the plasma membrane.

- Lipid breakdown products: when there is phospholipid degradation by phospholipases, there will be lipid breakdown products like unesterified free fatty acids, acylcarnitine, and lysophospholipids that will cause more damage to the membrane.

The most important membranes that are damaged are the plasma membrane and the mitochondrial membrane in addition to the lysosomal membranes.


***The recording stopped here***



Done By:
Mohammad Bader


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Shadi Jarrar
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تاريخ التسجيل : 2009-08-28
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