Cell injury

1. Cell injury By Dr. AbdelatyShawky Dr. Gehan Mohamed

2. Fatty Change * Definition: 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.

3. * Causes: • Toxins(most importantly: Alcohol abuse) • Diabetes mellitus • Protein malnutrition (starvation) • Obesity • Anoxia

4. * The significance of fatty change: • Depends on the severity of the accumulation. • Mild:it may have no effect . • Severe: form, fatty change may precede cell death, and may be an early lesion in a serious liver disease called nonalcoholic steatohepatitis

6. * Is Fatty liver reversible? • Fatty change is reversible except if some vital intracellular process is irreversibly impaired .

7. * Prognosis of Fatty liver: • In Mild cases:3% will develop cirrhosis • Moderate to sever: inflammation, degeneration in hepatocytes, fibrosis (30% develop cirrhosis).

8. 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

9. Accumlation of Exogenous pigment • Tattooing: Indian ink pigments produce effective tattoos because they are engulfed by dermal macrophages which become immobilized and permanently deposited. • Anthracosis: inhalation of carbon dust particles. When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes.

10. Anthracosis

11. Hemosiderin ( iron) Accumulation of Endogenous pigments • 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. • Iron is normally carried by specific transport proteins, transferrins. In cells, it is stored in association with a protein, apoferritin, to form ferritin micelles. Ferritin is a constituent of most cell types. When there is a local or systemic excess of iron, ferritin forms hemosiderin granules.

12. Hemosiderosis * Causes of Hemosiderosis: • Increased absorption of dietary iron • Impaired utilization of iron • Hemolytic anemias • Repeated blood transfusions (the transfused red cells constitute an exogenous load of iron). • Hereditary hemochromatosis with tissue injury including liver fibrosis, heart failure, and diabetes mellitus .

13. 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.

14. 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

15. Hemosiderin H&E: golden brown pigmentPrussian blue stain: blue

16. Lipofuscin • “Wear-and-tear pigment" is a brownish-yellow granular intracellular material that seen normally 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 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.

17. Pathological calcification • It implies the abnormal deposition of calcium salts in tissues rather than bone and teeth. • It has 2 types: • Dystrophic calcification: • When the deposition occurs in dead or dying tissues e.g. areas of necrosis or atherosclerotic patches. • it occurs with normal serum levels of calcium • Metastatic calcification: • The deposition of calcium salts in normal tissues • It almost always reflects hypercalcemia.

18. Irreversible cell injury

19. * Mechanism: • Persistent or severe injury (hypoxia) takes the cell to the "point of no return" where the injury becomes irreversible. • At this point no intervention can save the cell. • Two phenomenon characterize irreversible injury: • Mitochondrial damage. • Damage to the structural integrity of plasma membrane. • Calcium plays a major role in irreversible injury.

20. 1. Mitochondrial damage: • Marked reduction in ATP production leads to mitochondrial damage results in formation of high conductance channels (Mitochondrial Permeability Transition (MPT) channels)which Release cytochrome c into cytosol which is a trigger for apoptosis.

21. MITOCHONDRIAL DYSFUNCTION or INJURY ↓ATP production H+ Cytochrome C Mitochondrial Permeability Transition (MPT) Apoptosis

22. 2. Damage to plasma membrane: • Due to: • Decreased production of membrane phospholipids: due to mitochondrial dysfunction and decreased ATP production. • Loss of membrane phospholipids: due to the action of phospholipases. • Damage to cytoskeleton due to the action of proteases.

23. * Consequences of membrane damage: • Mitochondrial membrane: • Formation of MPT (mitochondrial permeability transition channels). • Release of cytochrome c  activates apoptosis. • Plasma membrane: • Loss of osmotic balance. • Influx of fluids and ions. • Loss of proteins, enzymes, RNA. • Lysosomal membrane: • Leakage of lysosomal enzymes and their activation • RNases, DNases, proteases, phosphatases, glucosidases. • Enzymatic digestion of cell components • Cell death by necrosis.

24. * Role of calcium in irreversible cell injury: • Increased cytosolic calcium: Leads to : • Enzyme activation: • ATPases: Hasten ATP depletion • Phospholipases : cause membrane damage  increased permeability. • Proteases damages membrane and structural proteins • Endonucleases  damages nuclear chromatin and DNA, causing fragmentation (karyorrhexis). • Increased mitochondrial permeability : release of cytochrome c (activates apoptosis)

25. INJURIOUS AGENT Ca 2+ Ca 2+ Ca 2+ Increased Cytosolic Ca2+ ATPase Phospholipase Protease Endonuclease Disruption of membrane & cytoskeletal Proteins Nuclear Chromatin damage ATP  Phospholipids

26. Morphology of irreversible cell injury

27. Light microscopy of irreversible cell injury • Pyknosis = Shrinkage and darkening of the nucleus. • Karyorrhexis= fragmentation and breakdown of the nucleus, (into "nuclear dust"). • Karyolysis= dissolution of the nucleus.

29. Karyorrhexis Nuclear pyknosis Karyolysis

30. * Types of cell death: • Necrosis: local death of a group of cells within the living body. • Apoptosis: genetically controlled programmed single cell death.

31. Some important terms! • Autolysis: degradation of cell and its constituents caused by its own enzymes. • Heterolysis: degradation of cell and its constituents by enzymes derived from sources extrinsic to the cell (e.g. neutrophils, bacteria). • Putrefaction: lysis of dead tissue by bacterial enzymes.

32. Morphological types of necrosis: • Coagulation necrosis. • Liquefactive necrosis. • Caseation necrosis. • Fat necrosis. • Traumatic. • Enzymatic . • Fibrinoid necrosis. • Gangrenous necrosis. • Gummatous necrosis.

33. Coagulative necrosis * Mechanism: • Denaturation and coagulation of structural and enzymatic proteins due to intracellular acidosis. • Denaturation of lysosomal enzymes by intracellular acidosis prevents autolysis. • Preserving cell outlines and tissue architecture.

34. * Etiology: • ischemia (secondary to atherosclerosis  thrombus formation). The most common cause. • Heavy metal poisoning (lead). • Irradiation. * Organs affected: Commonly seen in solid organs like Heart, kidney, spleen

35. Infarction • Refers to a localized area of tissue necrosis resulting from loss or reduction in blood supply (= ischemic necrosis). • The dead tissue is called an infarct. • Coagulativenecrosis is the type of necrosis associated with infarction except in infarction of brain. • In Brain: • Lack of good structural support. • Cells rich in lysosomal enzymes result in liquefactive necrosis.

36. Infarction of the spleen (ischemic coagulative necrosis)

37. * Morphology of Coagulation necrosis: * GROSS APPEARANCE: • The necrotic tissue appears firm and dry. • Cut surface: grey white. * MICROSCOPY: • Loss of the nucleus but preservation of cellular shape. • Increased cytoplasmic eosinophilia.

38. Area of necrosis Area of Necrosis • Preservation of cellular shape. Increased cytoplasmic eosinophilia

39. Good luck