Dr. Gehan Mohamed Cell injury
Definition Causes Mechanisms of Cell Injury Cellular response to injury: - Cellular adaptation - Reversible cell injury ( nonlethal hit) - Irreversible injury and cell death (apoptosis, necrosis and gangrene) Cell Injury
CONCEPT OF INJURY AND CELLULAR RESPONSE TO INJURY Cells are constantly exposed to a variety of stresses. At first cells try to adapt themselves to overcome this stressful condition But When stress is too severe or for prolonged duration, INJURY results. Injury alters the preceding normal steady state of the cell.
The cellular response to injurious stimuli depends on : 1. Type ,duration and severity of injurious agent. • 2-the type, status, adaptability, and genetic • makeup of the injured cell. • Cellular function is lost far before cell death occurs
Causes of cell injury • EXCESS or DEFICIENCY OF OXYGEN • PHYSICAL AGENTS • CHEMICAL AGENTS • INFECTION • IMUNOLOGICAL REACTIONS • GENETIC DERANGEMENTS • NUTRITIONAL IMBALANCE • AGING
Mechanisms of cell injury (1)Cell membrane damage leading to Loss of structural integrity and Loss of function. (2)Mitochondrial damage leading to inadequate aerobic respiration. (3)Ribosomal damage leading to altered protein synthesis. (4)Nuclear change leading to abnormal proliferation. (5)Decrease ATP production so Plasma membrane energy-dependent sodium pump is reduced, resulting in cell swelling. (6)increase intra cellular calcium. (7)Production of oxygen derived free radicals.
Cellular adaptation A- Disorders leading to diminished growth i.e atrophy B- Disorders leading to excessive growth i.e hypertrophy and hyperplasia C- Disorders of cellular differentiation i.e metaplasia and dysplasia
But when the injurious agent is sever and persist for long duration so the cell can not tolerate it even by adaptation so cell injury result either in the form of : (1)Degeneration which is change in metabolism inside cytoplasm which may lead to intracellular accumlations without affection of nucleus so degeneration is a reversible process. (2)Necrosis which is death of the cell so it is irreversible process.
Degeneration • Examples of degenerative diseases: • Osteoarthritis is a degenerative joint disease in which gradual destruction and deterioration of the bones and joint occurs. • Alzheimer's disease is a degenerative neurological disease where there is a progressive deterioration in brain function.
Some Degenerative diseases may lead to intracellular Accumulation due to : • increased rateof production of a normal substance, but metabolic rate is inadequate to remove it (e.g. fatty change in liver). • genetic or acquired defects in folding, packaging, transport, or secretion of the accumlated material .
3. An inherited defect in an enzyme may result in failure to degrade a metabolite. (e.g. Accumulations of carbon or silica particles)
Types of intracellular accumlations: • Cloudy swelling and hydropic changes: Cytoplasmic swelling and vacuolationdue to intracellular accumulation of water and electrolytes secondary to failure of energy-dependent sodium pump.
Vacuolar (hydropic) change in cells lining the proximal tubules of the kidney Reversible changes
(Steatosis) Fatty Change
Fatty Change • Fatty change refers to any abnormal accumulation of triglycerides within parenchymal cells. • Site: • liver, most common site which has a central role in fat metabolism. • it may also occur in heart as in anaemia or starvation (anorexia nervosa) • Other sites: skeletal muscle, kidney and other organs.
Causes of Fatty Change • Toxins(most importantly: Alcohol abuse) • diabetes mellitus • Protein malnutrition (starvation) • Obesity • Anoxia
Defects in any of the steps of uptake, catabolism, or secretion can lead to lipid accumulation.
The significance of fatty change • Depends on the severity of the accumulation. • Mild it may have no effect . • In the severe form, fatty change may precede cell death, and may be an early lesion in a serious liver disease called nonalcoholic steatohepatitis
Is Fatty liver reversible? • Fatty change is reversible except if some vital intracellular process is irreversibly impaired .
Prognosis of Fatty liver • In Mild cases: 3% will develop cirrhosis • Moderate to sever: inflammation, degeneration in hepatocytes, fibrosis (30% develop cirrhosis).
Other form of accumulation • Cholesteryl esters • These give atherosclerotic plaques their characteristic yellow color and contribute to the pathogenesis of the lesion • This is called atherosclerosis
Pigments are colored substances that are either: • exogenous, coming from outside the body, or • endogenous, synthesized within the body itself.
Exogenous pigment • Pigments and insoluble substances may enter the body from a variety of sources. • They may be toxic and produce inflammatory tissue reactions or they may be relatively inert. • Indian ink pigments produce effective tattoos because they are engulfed by dermal macrophages which become immobilized and permanently deposited.
Exogenous pigment • The most common is carbon • When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes.
Exogenous pigment • Aggregates of the carbon pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis).
Exogenous pigmentCarbon in Lung • Heavy accumulations may induce in a serious lung disease called coal workers' pneumoconiosis)
Endogenous pigments • Endogenous pigments include certain derivatives of hemoglobin, melanin, and lipofuscin.
Hemosiderin ( iron) • is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron.
Hemosiderin( iron) • Although hemosiderin accumulation is usually pathologic, small amounts of this pigment are normal. • Where? • in the mononuclear phagocytes of the bone marrow, spleen, and liver. • Why? • there is extensive red cell breakdown.
Hemosiderin • The iron ions of hemoglobin accumulate as golden-yellow hemosiderin. The iron can be identified in tissue by the Prussian blue histochemical reaction
Hemosiderosis(systemic overload of iron) • It is found at first in the mononuclear phagocytes of the liver, bone marrow, spleen, and lymph nodes and in scattered macrophages throughout other organs. • With progressive accumulation, parenchymal cells throughout the body (principally the liver, pancreas, heart, and endocrine organs) will be affected
Hemosiderosis • Hemosiderosis occurs in the setting of: • increased absorption of dietary iron • impaired utilization of iron • hemolytic anemias • transfusions (the transfused red cells constitute an exogenous load of iron). .
Effect of hemosiderosis • However, more extensive accumulations of iron are seen in hereditary hemochromatosis with tissue injury including liver fibrosis, heart failure, and diabetes mellitus
Lipofuscin • "wear-and-tear pigment" is an insoluble brownish-yellow granular intracellular material that seen in a variety of tissues (the heart, liver, and brain) as a function of age or atrophy. • Consists of complexes of lipid and protein that derive from the free radical-catalyzed peroxidation of polyunsaturated lipids of subcellular membranes. • It is not injurious to the cell but is important as a marker of past free-radical injury. • The brown pigment when present in large amounts, imparts an appearance to the tissue that is called brown atrophy.
Pathologic calcification • it implies the abnormal deposition of calcium salts with smaller amounts of iron, magnesium, and other minerals. • It has 2 types:
Types of Pathologic calcification • Dystrophic calcification: • When the deposition occurs in dead or dying tissues • it occurs with normal serum levels of calcium • Metastatic calcification: • The deposition of calcium salts in normal tissues • It almost always reflects hypercalcemia.
Dystrophic calcification is encountered in areas of necrosis of any type or in advanced atherosclerosis of aorta. • Dystrophic calcification of the aortic valves is an important cause of aortic stenosis in the elderly .
Metastatic calcification • Metastatic calcification can occur in normal tissues whenever there is hypercalcemia.
Cell Death Two main categories: Apoptosis and Necrosis
Apoptosis A controlled, “programmed” cell death. Morphologic characters: - shrunken cell. - Intact cell membrane. - No associated inflammatory process. - Phagocytosis and replacement by healthy cells. Pathogenesis: Activation of “suicide genes” in response to certain injurious agents?
Types of apoptosis: Physiologic: (elimination of worn-out cells) *Embryogenesis. *Endometrium. *Intestinal crypt cells. Pathologic: *Irradiation-induced injured cells. *Drug-induced injured cells. *Viral-infected cells. *Tumor regression and progression.
Necrosis Definition Morphological changes follow cell death in living tissue/organ. Two underlying processes; protein denaturation and enzymatic digestion of cytoplasmic organelles and organoids. Morphologic characteristics - Gross - Microscopic *Cell membrane changes. *Nuclear changes.