Cell injury

Cell Injury, Adaptations & Cell Death

Homeostasis
♦Cells maintain normal homeostasis (=steady state), by maintaining their intracellular compartment within a narrow range of physiologic parameters (e.g., ion balance, pH, energy metabolism)
♦As cells encounter physiologic stresses or pathologic stimuli, they undergo functional or structural adaptations, achieving a new but altered steady state and preserving viability and function

Cell injury and death

If the limits of adaptive capability are exceeded or if the external stress is severe, cell injury develops
Within certain limit injury is reversible, and cells return to a stable baseline, however, severe or persistent stress result in irreversible injury and death of the affected cells.
LOSS OF HOMEOSTASIS = CELL INJURY

Causes of cell injury

1-Oxygen deprivation (hypoxia)
Decrease oxygen supply to the cell will interfere with oxidative ( aerobic) respiration of
the cell, it may resulted from :
A- Loss of blood supply (Ischemia), which is most common cause and occur when
arterial flow is interfered with by e.g. atherosclerosis, thrombi or emboli.
B-Inadequate blood oxygenation due to e.g. cardiac failure and/or respiratory failure.
C-Decrease in oxygen carrying capacity of the blood e.g. anemia and CO poisoning.
2-Physical agents:
mechanical trauma, extreme heat, deep cold, electric shock, radiation and sudden changes in atmospheric pressure.
3-Chemical , Toxins and Drugs :
-lead, copper , mercury
-drugs, pesticides,
-toxins- e.g., snake venom, aflatoxin, ..
-social poisons as alcohol, smoking..
4-Infectious agents.
Include viruses, bacteria, parasites, fungi.
5-Immunological reactions.
- Immune response - e.g. cell damaged as innocent bystanders in immune
response to infectious agent.
- Hypersensitivity (allergic) reactions e.g. anaphylactic reaction to a drug.
- Autoimmune diseases e.g. reaction to self antigen.
6-Genetic derangement.
Chromosomal aberration e.g. Down syndrome.
Mutated gene e.g. cystic fibrosis, sickle cell anemia.
Multifactorial inheritance- combined effect of environmental and mutated gene, e.g. neoplasia, hypertension.
7-Nutritional imbalance.
Deficiencies- deficiency of protein-calories (starvation), vitamins, minerals.
Over nutrition- excess lipid/calories lead to obesity with all of it's consequences.
8- Cell aging.
Cumulative effects of a life-time of cell damage (chemical, infectious, nutrition, etc.) leads to a diminished capacity of aged cells/tissues to maintain homeostasis and adapt to harmful stimuli.


Mechanisms of cell injury
Cellular response to injurious stimuli is dependent on:
1- Type of injury, its duration and its severity.
2- Type of injured cell, its state and adaptability, i.e. nutritional status, hormonal
factors, metabolic needs, oxygen requirement, adaptive capacity, etc.

Intracellular Mechanisms

The intracellular mechanisms of cell injury fall into one of five general pathways:
ATP Depletion
Defects in Membrane Permeability
Influx of Intracellular Calcium and Loss of Calcium Homeostasis
Mitochondrial Damage
Accumulation of Oxygen-Derived Free Radicals

(1) ATP depletion:

ATP is essential for ;
1- transport through cell membrane . 2-Protein synthesis.
3-Lipid synthesis 4-Phospholipid turnover.
ATP depletion produces the followings:
1-Reduction of the activity of plasma membrane energy dependent sodium pump.
This causes Na+ accumulation inside the cell and K+ to diffuse outside , sodium
retention holds water leads to cellular edema.
2-Switch to anaerobic glycolysis, this leads to liberation of lactic acid, so there is
drop in the intracellular (pH) that interfere with many cellular enzymes.
3-Increase in the intracellular Ca+2 due to failure in the Ca++ pump that has
damaging effect on several cellular components.
4-Structural disruption of protein synthetic apparatus, this is due to detachment of
ribosome from rough endoplasmic reticulum.


(2) Influx of Intracellular Calcium and Loss of Calcium Homeostasis:
ischemia and toxins can cause Ca2+ influx across the plasma membrane and release of Ca2+ from mitochondria and endoplasmic reticulum.
Increased cytosolic calcium activates
phospholipases that degrade membrane phospholipids;
proteases that breakdown membrane and cytoskeletal proteins;
ATPases that hasten ATP depletion; and
endonucleases that cause chromatin fragmentation.

(3) Mitochondrial Damage:

Mitochondrial damage may occur directly due to hypoxia or toxins, or as a consequence of increased cytosolic Ca2+ , oxidative stress, or phospholipids breakdown.
Damage results in formation of a high-conductance channel (mitochondrial permeability transition, or MPT) that leaks protons and also leak cytochrome c, which can trigger apoptosis.

(4) Defects In Membrane Permeability:

Several biochemical mechanisms may contribute to membrane damage :
Mitochondrial dysfunction.
Loss of membrane phospholipids.
Cytoskeletal abnormalities.
Reactive oxygen species.
Lipid breakdown products.

(5) Free Radical Cell Injury:

Free radicals are compounds with a single unpaired electrons in the outer orbit. Such chemical states are extremely unstable and readily react with adjacent molecules; when generated in cells, they attack and degrade nucleic acids as well as a variety of membrane molecules.
Free radical-induced injury is an important mechanism of cell damage in;
-ischemic reperfusion injury.
-chemical and radiation injury
- toxicity from oxygen, O2 .- may damage retinal tissue, causing
blindness.
-cellular aging
-microbial killing by phagocytic cells
- inflammatory cell damage
-tumor destruction by macrophage


Free radicals may be generated within cells by:
A- O2-derived free radicals are produced as a byproduct of mitochondrial
respiration.
♦ superoxides (O2.- ): neutralized by superoxide dismutase
♦ hydroxyl anions (OH. ): neutralized by glutathione peroxidase
♦ hydrogen peroxide (H2O2 ): neutralized by catalase and
glutathione peroxidase
B- Drugs and chemical free radicals: conversion to free radicals occurs via the
cytochrome P-450 system in the liver e.g. Carbon tetrachloride (CCl4 ) is
converted to CCl3., leading to liver cell necrosis with fatty changes.
C- Nitric Oxide (NO), an important chemical mediator normally synthesized by a
variety of cell types that can act as a free radical .
D- The absorption of radiant energy (e.g., UV, X-rays). Ionizing radiation can
hydrolyze water into hydroxyl ( OH. ) and hydrogen ( H. ) free radicals.

Consequences of free radical injury:

* Lipid peroxidation of membrane, leading to increased permeability of cells
and organelles.
* DNA fragmentation, implicated in both cell killing and the malignant
transformation of cells.
* Cross-linking of proteins, resulting in enhanced rates of degradation or
loss of enzymatic activity.


Ischemia/ reperfusion injury
If cells are reversibly injured, the restoration of blood flow can result in cell recovery. However, under certain circumstances, the restoration of blood flow to ischemic but otherwise viable tissues results, paradoxically, in exacerbated and accelerated injury.
Reperfusion into ischemic tissues may cause further damage by the following means:
Restoration of blood flow bathes compromised cells in high concentrations of calcium when they are not able to fully regulate their ionic environment; increased intracellular calcium activates enzymes and causes a loss of cellular integrity.
Reperfusion of injured cells result in a locally augmented recruitment of inflammatory cells; these cells release high levels of oxygen-derived reactive species
Damaged mitochondria in compromised but still viable cells yield incomplete oxygen reduction and therefore increased of free radical species; in addition, ischemically injured cells have compromised antioxidant defense mechanisms

Cellular response to injurious stimuli

1-Cellular adaptive processes: e.g. hypertrophy, hyperplasia, atrophy, metaplasia
2-Acute cell injury:
-Non-lethal (reversible cell injury): e.g. hydropic swelling and fatty changes.
-Lethal (irreversible cell injury/cell death) : necrosis and apoptosis.
3-Subcelluar alterations.
4-Intracellular storage (accumulations) :e.g. lipid, glycogen, protein, pigment.
5-Cell aging.

Cellular Adaptation To Stress

Hypertrophy
Increase in cell size and functional capacity without cellular proliferation.
Etiology: It can be physiologic or pathologic
-physiologic: e.g. -- increase in muscle cell size with exercise
--massive enlargement of the uterus and mammary
glands during pregnancy/lactation.
-Pathologic: e.g., -- enlargement of myocardial fibers in case of heart
failure or hypertension.


Hyperplasia
Increase in organ size or tissue mass caused by increased number of constituent cells; occurs in tissues whose cells are capable of replication.
Hyperplasia can be physiologic or pathologic.
a- Physiologic hyperplasia;
hormonal hyperplasia e.g., proliferation of glandular epithelium of female
breast at puberty and during pregnancy.
2) compensatory hyperplasia, e.g., hyperplasia that occurs when portion of
tissue is removed or diseased; e.g. when a liver is partially resected.
b- Pathologic hyperplasia:
1- endometrial hyperplasia due to hormonal disturbance.
2-hyperplasia as an important response of connective tissue cells in wound
healing, in which proliferating fibroblasts and blood vessels aid in repair.
3- hyperplasia associated with certain viral infections; e.g., papilloma viruses
cause skin warts and mucosal lesions composed of masses of hyperplastic
epithelium

Atrophy

Shrinkage of cell size by the loss of cell substances; i.e. catabolic processes exceed anabolic processes.
It is a decrease in cell size or function of an organ that occurs under pathologic or physiologic circumstances, It is an adaptation to diminished need or resources for a cell's activities.
When a sufficient number cells is involved, the entire tissue or organ diminishes in size, becoming atrophic.
Although atrophic cells may have diminished functional capacity, they are not dead.
Causes of Atrophy
Decreased work load (=disuse atrophy) e.g., immobilization of a limb in a cast to permit fracture healing.
Loss of innervation (denervation atrophy)
Diminished blood supply/hypoxia (e.g., partial ischemia)
Inadequate nutrition (e.g., starvation associated with chronic disease)
Loss of endocrine stimulation (e.g., endometrium atrophy after menopause)
Aging (senile atrophy)


Metaplasia
A reversible change in which one differentiated cell type is replace by another differentiated cell type.
In this type of cellular adaptation, cells sensitive to a particular stress are replaced by other cell types better able to withstand the adverse environment.
Epithelial metaplasia is exemplified by squamous change that occurs in the respiratory epithelium in habitual cigarette smokers, due to prolonged exposure of the bronchial epithelium to tobacco smoke (squamous metaplasia)
Although the metaplastic squamous epithelium has survival advantages, important protective mechanisms are lost, such as mucous secretion and ciliary clearance of particulate matter.
The influences that induce metaplastic transformation, if persistent, may predispose to malignant transformation of the epithelium.
E.g., it is thought that cigarette smoking initially causes squamous metaplasia of the respiratory epithelium and lung cancer (composed of malignant squamous cells) arises later in some of altered foci.








7-10-2018 Dr. Ziyad

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