mechanisms of cell injury

General pathology

The outcome of pathological stimuli depend on the following:

• Type of the harmful stimuli, (Causative agents).
• Duration of injury, (prolonged injury cause more effect than short lived stimuli).
• Type of the affected cell and the regenerative capability of the affected cells and tissues.

Mechanisms of cellular injury:
The four cell systems particularly affected during cell injury are:
1- Cell membrane integrity critical to cellular ionic and osmotic homeostasis.
2- ATP (Adenosine Tri-Phosphate), generation by mitochondrial aerobic respiration.
3- Protein synthesis.
4- Integrity of genetic apparatus.

Hypoxic/Ischemic Injury:

1-First consequence is loss of oxidative phosphorylation and reduction in ATP production.

Reduction of ATP lead to the following:
• Failure of ATP dependent Na/K ATPase enzyme that responsible for pumps Na outside the cell , and maintains high cell K and low cell Na and Ca. So now K decreases and Na and Ca increase within the cell. When Na level increase within the cell this well trap a lot of water and this lead to cell swelling. Increase Ca influx lead to many effects like activation of phospholipase enzyme that disrupt the cell membrane.
• Decrease in ATP lead to increases glycolysis, the process of glycogen degradation leads to production of lactic acid and decrease pH within the cell and decrease glycogen stores.

2- Decrease protein synthesis, due to loss of ATP needed for synthesis of proteins and detaching of ribosomes from RER due to ER swells. Reduction of protein synthesis well lead to membrane disruption, decreased mitochondrial function, and disruption of the cytoskeleton.

3-Cell membrane defect: Membrane function depends mostly on mitochondrial function, phospholipid loss of membrane components, mostly from endogenous phospholipase activation, and decreased synthesis of new phospholipids. Cytoskeleton attaches to plasma membrane and strengthens it. Proteases may damage this connection and the plasma membrane is thus more susceptible to rupture.

4- Lysosomal membrane injury causes release of enzyme contents that eventually lead to irreversible nuclear damage.


Reperfusion injury:
Much of the damage from ischemia or hypoxia occurs on the re-establishment of circulation: reperfusion can help restore health to reversibly damaged cells, but can also lead to cell death.

Mechanisms of reperfusion injury:
1-Circulation brings PMNs (neutrophils especially) that release toxic oxygen radicals that do damage to membranes. Damaged cells may express cytokines that attract PMNs to them and cause inflammation with additional injury.
2- Reperfusion brings a massive influx of Ca++ which leads to activation of phospholipases, endonucleases, proteases (cytoskeleton), and DNAases
3- Formation of oxygen free radicals, (O•, H2O2, and •OH).

Oxygen radicals (free unpaired electron in outer orbit) do three main things:
1. Lipid peroxidation: the free radicals attack the double bonds in the unsaturated fatty acid of the membrane phospholipids and cause a damage to the cell membrane.
2. Promotes sulfhydryl mediated protein cross linking that creates disulfide bonds which inactivate enzymes
3. Interact with DNA causing mutations, especially with thymine causing single strand breaks







Apoptosis:
Cellular events associated with apoptosis
Apoptosis differs significantly from necrosis. It is an energy dependent physiological process involved in removing unwanted individual cells and is a specialized form of programmed cell death that is characterized by:
o chromatin condensation and formation of cytoplasmic membrane blebs (cell surface deformities caused by a cytoskeleton disruption)
o breakdown of DNA into nucleosome-sized fragments
o a minimal inflammatory response

It has a central role in morphogenesis, maintaining organ size, and atrophy.
Apoptosis can also occur in the removal of defective cells.
Mechanisms :
Apoptosis begins with the activation of endogenous proteases and endonucleases , this results in the degradation of the cytoskeletal structure, fragmentation of DNA and loss of mitochondrial function.
The cell shrinks, retaining its plasma membrane, however, if the plasma membrane is altered, phagocytosis occurs. Cells not phagocytosed break into smaller membrane-bound fragments called apoptotic bodies. These is no inflammatory reaction to these bodies.

Apoptosis vs. Necrosis
Feature Necrosis Apoptosis
Induction Invariably due to pathological injury May be induced by physiological or pathological stimuli
Affects Cell groups Single cells
Biochemical events Impairment or cessation of ion homeostasis
Lysosomes leak lytic enzymes Energy-dependent fragmentation of DNA by endogenous endonucleases
Lysosomes intact
Morphology Cell swelling and lysis Cell shrinkage and fragmentation to form apoptotic bodies with dense chromatin
Inflammatory response Common None
Fate of dead cells Phagocytosed by neutrophil polymorphs and macrophages Phagocytosed by neighboring cells

programmed cell death that occurs normally in many contexts:
1- Aging.
2-Development .
3-Defense mechanism in the immune system. Specific examples include T cell deletions in thymus.
4-Embyrogenesis (loss of tissue between fingers),
5-Hormone dependent involution (return of uterine lining to normal following pregnancy).
6-Cell death in tumors.
7-Neutrophilic death in acute inflammation.

Morphological changes:
cells are smaller with dense cytoplasm. The chromatin is condensed in fragments near the nuclear periphery. Apoptotic bodies form, which are membrane bound with some cytoplasm and organelles and sometimes nuclear fragments. These are taken up by normal cells nearby and degraded in lysosomes.

Unregulated apoptosis plays a role in a variety of diseases:

A- When inhibited, cells may survive longer as in cancer and autoimmune disorders.
B- When accelerated, cells may die sooner as in AIDS depletion of lymphocytes and degenerative neurological disorders.