Dr. Gehan Mohamed Cell injury
Understand the definition of cell injury. Outline Mechanisms of Cell Injury Recognize the variability in Cellular response to injury which include : - Cellular adaptation - Reversible cell injury ( nonlethal hit) - Irreversible injury and cell death (apoptosis, necrosis ). -Identify the differences between apoptosis and necrosis. - Recognize the different types of necrosis. Learning objectives:
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 of the cell may be reversible if theaffected cells recover from the injury or cell may die (irreversible injury).
Causes of cellular injury • Hypoxia:inadequate oxygenation of tissues • Physical agents:mechanical trauma, burns, frostbite, sudden changes in pressure, radiations, electric shock • Chemical agents:poisons (toxins), insecticides, CO, asbestos, alcohol, tobacco, glucose, salt, oxygen • Infectious agents:prions, viruses, rickettsiae, bacteria, fungi, parasites • Immunologic reactions:anaphylaxis, autoimmune disease. • Nutritional imbalances:protein calorie deficiency, vitamin deficiencies, excess food intake (obesity, atherosclerosis) • Genetic derangements:congenital malformations, abnormal proteins (hemoglobinopathies), abnormal or absent enzymes (storage disorders).
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
The precise moment of transition from reversible injury to irreversible injury is known as the POINT OF NO RETURN. Irreversible Adaptation Reversible Cell death Point of no return Etiologic agent
The relationships between normal, adapted, reversibly injured, and dead myocardial cells
Cellular adaptation A- Disorders leading to diminished growth due to decrease in cell size i.e atrophy • B- Disorders leading to excessive growth i.e • - Hypertrophy: increase in size of cells as in • pregnant uterus. • hyperplasia: increase in number of the cells • e.g lactating breast
C- Disorders of cellular differentiation i.e metaplasia and dysplasia: • Metaplasia is a change of mature type of tissue into another type e.g change of transitional type of epithelium to squamous type with chronic irritation.
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.
Examples of cell injury: • Hypoxic cell injury • Ischemia- reperfusion injury • Free radical induced cell injury • Chemical injury
Hypoxia • Most common cause of cell injury. • Definition:inadequate oxygenation of tissue. • MAJOR CAUSES OF HYPOXIA. • Ischemia: decreased arterial blood flow to tissues. • Most common cause of hypoxia. • Ex: Atherosclerosis (lesion in intima = atheroma) in coronary arteries. • Hypoxemia: decrease in the amount of oxygen dissolved in plasma. Seen in: • Atelectasis, pulmonary embolus and interstitial fibrosis of lung. • Hemoglobin related abnormalities • Anemia • Carbon monoxide poisoning (CO has high affinity for hemoglobin). • Will get HEADACHES.
Consequences of tissue hypoxia • Decreased synthesis of ATPby oxidative phosphorylation causing ATP depletion. • ATP required for: • Membrane transport • Protein synthesis • Lipogenesis etc. • ATP production: two ways • Oxidative phosphorylation of ADP • Glycolytic pathway • Generation of ATP in absence of O2
Consequences of ATP depletion • Impaired Na+/K+-ATPase pump • Diffusion of Na+ and water into cells cellular swelling. • Cellular swelling:First light microscopic finding of hypoxic cell injury. • Swelling of the endoplasmic reticulum and mitochondria: First electron microscopic finding of hypoxic cell injury.
Consequences of ATP depletion 2. Anaerobic glycolysis is used for ATP synthesis: • It is accompanied by • Activation of phosphofructokinase, which stimulates the glycolytic pathway. • Depletion of glycogen stores • Accumulation of lactic acid • Decrease in intracellular pH denaturation of proteins decreased activity of many enzymes clumping of nuclear chromatin.
Consequences of ATP depletion 3. Decreased protein synthesis • Due to Detachment of ribosomes from the rough endoplasmic reticulum. • ↓protein synthesis. • Reflected as accumulation of lipid in the cell = fatty change. • Since you’re not synthesizing proteins, you’re not synthesizing apolipoproteins (lipid carriers) either! • ↓ protein synthesis ↓ synthesis of apolipoproteins(lipid carriers in blood) accumulation of lipid in the cell. 4. Impaired calcium ATPase pump • Increased cytosolic calcium.
↓ oxidative phosphorylation Ischemia ↓↓ ATP Glycolysis Na pump Ribosomal Detachment Influx of Na, H2O & Ca2+ Efflux of K Glycogen Lactic acid Protein Synthesis pH Cell Swelling ER swelling Loss of microvilli Membrane blebs Nuclear chromatin clumping
Morphology of reversible cell Injury • LIGHT MICROSCOPIC CHANGES: • Cell Swelling • First manifestation of cell injury. • Occurs when cells fail to maintain ionic and fluid homeostasis. • Manifests as small clear vacuoles. • Also known as hydropic change or vacuolar degeneration. • Fatty change • Manifested by appearance of lipid vacuoles in the cytoplasm. • Seen in kidney, heart and liver.
Normal cell Normal cell Injury (hypoxia) Recovery Cell swelling, Swelling of ER and mitochondria Reversible injury Chromatin clumping
Cell swelling - Light Microscopy Cellular Swelling = hydropic change Normal epithelium
Normal liver histology Hepatocytes showing fatty change
Ultra structural changes of Reversible cell injury • Plasma membrane alteration: • Blebbing and distortion of microvilli. • Mitochondrial changes • Swelling. • Dilation of ER • Detachment of polysomes. • Nuclear chromatin clumping.
Normal cell Endoplasmic reticulum Lysosome Nucleus Mitochondria
Surface blebs Generalized swelling ER swelling Dispersion of Ribosomes Clumping of Nuclear chromatin Mitochondrial Swelling Ultrastructural changes in Reversible injury
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
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 with their characteristic yellow color and contribute to the pathogenesis of narrowing of the blood vessels. • This is called atherosclerosis
Accumlation of 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).
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.
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). • hereditary hemochromatosis with tissue injury including liver fibrosis, heart failure, and diabetes mellitus .
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.
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
Hemosiderin • The iron ions of hemoglobin accumulate as golden-yellow hemosiderin. The iron can be identified in tissue by the Prussian blue histochemical reaction
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.
If oxygen is restored, all the above changes are reversible. • If ischemia persists, irreversible injury follows.
Mechanism Irreversible cell injury