CELL INJURY (Reversible OR Irreversible Cell Injury

Definition
Cell injury is defined as changes within a cell as a result of variety of stresses that it encounters due to changes in its internal and external environment.
Diseases occur due to abnormalities at this cellular level.
Factors Affecting Cell Injury
The human body responds to these stresses in different ways.
The response of cell depends upon followings factors:
The type of cell and tissue involved.
On extent and type of cell injury.

1. CELL INJURY Prepared by: Mayuri Gamit M.Sc Nursing (OBG) Nursing tutor

2. Definition Cell injury is defined as changes within a cell as a result of variety of stresses that it encounters due to changes in its internal and external environment. Diseases occur due to abnormalities at this cellular level.

3. Factors Affecting Cell Injury The human body responds to these stresses in different ways. The response of cell depends upon followings factors: The type of cell and tissue involved. On extent and type of cell injury.

4. Acquired cause

5. 1. Hypoxia and ischemia: The most common causes for hypoxia are: ischemia, anemia, carbon monoxide poisoning, cardio-respiratory diseases.

6. 2. Physical agents Mechanical trauma (e.g., road accident, surgery) Thermal trauma (e.g., heat and cold) Electricity Radiation (e.g., Ultraviolet, radiation) Rapid changes in atmospheric pressure.

7. Increased level of chemicals and drugs cause cell injury: Chemical poisons such as cyanide, mercury Environmental pollutants Insecticides and pesticides Oxygen at high concentration Hypertonic glucose and salts Alcohol and narcotic drugs Therapeutic administration of drug 3. Chemicals and drugs:

8. 4. Microbial agents: Infective agents like bacteria, rickettsia , viruses, fungi, protozoa, etc.

9. 5. Immunological agents: Example, hypersensitivity reactions, anaphylactic reactions, autoimmune diseases.

10. 6. Nutritional derangement: Deficiency of nutrients - starvation, protein calorie malnutrion ( marasmus , kwashiorkor), anaemia . Nutritional excess-obesity, atherosclerosis, heart diseases and hypertension.

11. 8. Psychological factors: It may include mental stress, anxiety, overwork and frustration, problems of drug addiction, alcoholism and smoking.

12. 2. Genetic Cause Genetic defects cause cell injury due to deficiency of functional protein, alteration in structural proteins and accumulation of abnormal proteins. Some common genetic diseases are Down's syndrome, sickle cell anemia, Fanconi's anemia ( autosomal recessive genetic disease resulting in impaired response to DAN damage), Turners syndrome(chromosomal disorder) etc.

13. Reversible Cell Injury

14. Definition Injury to normal cell by any of the agents may result in functional and morphologic changes that are reversible if the damaging stimulus is removed. Ischemia and hypoxia are the most important cause of reversible cell injury.

15. Pathogenesis of Reversible Cell Injury Decreased supply of oxygen decreases cells aerobic respiration by mitochondria. Decreased adenosine triphosphate (ATP) generation. Shift to the cell anaerobic glycolysis takes place to generate more ATP. This result in increased accumulation of lactic acid. Thus, decreases intracellular pH.

16. Effects of Reduced pH Displacement of ribosomes from RER Clumping of chromatin network Inactivation of Na+ - K+ pump

17. Mechanism of Cell Injury Inactivation of Na+ - K+ pump leads to major structural and functional effects on the cell as: ↑Na influx inside the cell Intracellular water accumulation Cell swelling Swelling of cytoplasmic organelles

18. Mitochondrial swelling Lysosomal swelling ER swelling Intracellular protein synthesis decreases due to damage to ribosomes and polysomes .

19. Serum Markers of Cell Injury Due to cellular swelling and impaired function of the cell membrane, certain enzymes are released and their serum levels are raised. These are used as guide for diagnosis of cell injury in various organs. Lipase, amylase etc during pancreatic cell injury CK-MB, LDH etc during myocardial injury. AST, ALT, CPK etc during hepato -cellular damage

20. Cell Injury Due to Hypoxia/ Ishemia The most common cause of reversible cell injury is reduced oxygen supply to tissue, i.e., hypoxia. Hypoxia is caused primarily by obstruction to blood flow or ischemia. Ischemic injury is seen in organs like brain, heart, kidney etc. If the hypoxia/ischemia is of short duration, the cell injury may be reversible.

21. Decreased generation of cellular ATP: In ischemia, aerobic respiration as well as glucose availability both are compromised. In hypoxia from other causes (RBC disorders, heart disease, lung disease), anaerobic glycolytic ATP generation continues,

22. Intracellular lactic acidosis: Anaerobic glycolytic pathway activates and generates ATP. This results in accumulation of lactic acid which lowers the intracellular pH. It results in clumping of nuclear chromatin.

23. Damage to plasma membrane pumps: Lack of ATP damages membrane pumps operating for regulation of sodium and calcium. This results in intracellular accumulation of sodium and diffusion of potassium out of cell. Accumulation of sodium in the cell leads to increase in intracellular water, which is known as hydropic swelling.

24. Failure of calcium pump: Membrane damage causes disturbance in the calcium iron exchange across the cell membrane. Excess of calcium moves into the cell causing its swelling and deposition of phospholipid rich amorphous densities.

25. Reduced protein synthesis: Due to continuous hypoxia, membranes of endoplasmic reticulum and Golgi apparatus are damaged and cause swelling. Ribosomes are detached from granular endoplasmic reticulum, inactivating their function and inhibiting protein synthesis.

26. Morphological Changes in Reversible Cell Injury The biochemical and structural changes in a cell cause changes in the appearance of cell as seen under light and electron microscope. Following Morphological Changes in Reversible Cell Injury are included under this… 1. Hydropic change or cloudy swelling 2. Hyaline change 3. Mucoid change 4. Fatty change

27. This is the earliest and commonest form of cell injury. There is accumulation of water in the cell which imparts it a vacuolar appearance. 1. Hydropic change or cloudy swelling :

28. 2. Hyaline change : The cells have glassy and eosinophilic appearance due to accumulation of a variety of substances like protein, fibrin, amyloid , collagen or intermediate filaments.

29. 3. Mucoid change : Mucus, the secretion of epithelial cells of gland may accumulate in tissue in cases of obstruction to flow of mucus, inflammation or neoplasms of glandular tissue.

30. 4. Fatty change : Intracellular accumulation of neutral fat in the parenchymal cells is called Fatty change. Most common organ affected by fatty change is liver; it may also be seen in heart, skeletal muscles and kidney.

31. FATTY LIVER (HEPATIC STEATOSIS) Liver is the commonest organ affected by fatty change because of its prime role in fat metabolism.

32. Causes of Fatty Liver Excess fat in body Diabetes mellitus Obesity Congenital hyperlipidemia Liver cell damage : Alcohol abuse Toxins- aflatoxin from mould affected rotten food Protein malnutrition Fatty liver of pregnancy Hypoxia- anemia, cardiac failure Chronic diseases like tuberculosis

33. Pathogenesis of Fatty Liver

34. In alcoholic fatty liver following mechanisms are involved- 1. Increased lipolysis 2. Increased free fatty acid synthesis 3. Decreased triglyceride utilization 4. Decreased oxidation to ketone bodies 5. Block in lipoprotein secretion.

35. Gross Appearance of Liver Initially the organ enlarges and becomes increasingly yellow, soft and greasy. In extreme instances, the liver may weigh upto 3 to 6 kilograms.

36. Microscopic Appearance The liver cells show small vacuoles in the cytoplasm around the nucleus ( microvesicular steatosis ), which progresses to macrovesicularsteatosis and forms fatty cysts.

37. Special Stains To identify the fat, it is necessary to prepare frozen tissue sections. The sections are stained with Sudan IV or Oil Red-O, both of which impart an orange-red color to the contained lipids.

38. Irreversible Cell Injury

39. Irreversible Cell Injury With continuing exposure to stress, the damage to cell becomes permanent. This leads to structural damage and loss of function. The sequence of events is in continuation with those of reversible cell injury.

40. Irreversible Cell Damage are: Extensive physical damage to the cells, like mitochondria Complete ATP reduce Influx of calcium and loss of calcium homeostasis Accumulation of oxygen free radicals DNA damage.

41. Morphological Changes in irreversible Cell Injury(cell death) Cell death is a state of irreversible injury. It may occur in the living body as a local change that result in end of the life. Processes involved in cell death are described below: 1. Autolysis 2. Necrosis 3. Gangrene 4. Apoptosis

42. 1. Autolysis Autolysis means self-destruction (Auto = self, lysis = rupture). In other words, autolysis refers to the enzymatic breakdown of cellular material done by a cells own enzymes. It is rapid in some tissues rich in hydrolytic enzymes such as in the pancreas and gastric mucosa, intermediate in tissues like the heart , liver and kidney and slow in fibrous tissue.

43. Morphologically it is identified by homogeneous and eosinophilic cytoplasm with loss of cellular details and remains of cell as debris.

44. It is defined as localized area of tissue death and degradation of tissue by hydrolytic enzymes released from injured cell. It is always pathological. It is always accompanied by inflammatory reaction. It occurs after irreversible cell injury. 2. Necrosis

45. The necrotic cells show increased eosinophilia (i.e., pink staining from the eosin dye of "H and E"). This is attributable in part to increased binding of eosin to denatured cytoplasmic proteins and in part to loss of the basophilia due to ribonucleic acid (RNA) in the cytoplasm. The cytoplasm becomes vacuolated and appears moth-eaten. Morphology

46. Dead cells may ultimately be replaced by large, phospholipid masses called myelin figures. Nuclear changes assume one of the three patterns, all due to breakdown of DNA and chromatin.

47. Pyknosis : Characterized by nuclear shrinkage and increased basophilia ; the DNA condenses into a solid shrunken mass. Karyorrhexis : The pyknotic nucleus undergoes fragmentation (breakdown). Karyolysis : Basophilia of the nuclear fading. In a few days, the nucleus in a dead cell completely disappears.

48. Types of Necrosis

49. 1. Coagulative Necrosis: It is a form of tissue necrosis in which the component cells are dead but the basic tissue architecture is preserved for at least several days. The affected tissues take on a firm texture. The injury denatures not only structural proteins but also enzymes. Proteolysis(breakdown of proteins) of the dead cells is blocked.

50. The necrotic cells are removed by phagocytosis of the cellular debris by infiltrating leukocytes. Coagulative necrosis is characteristic of infarcts (areas of ischemic necrosis) in all solid organs like heart, kidney, spleen etc. except the brain.

51. 2. Liquefactive Necrosis It is seen in focal bacterial or occasionally fungal infections, As the microbes stimulate the accumulation of inflammatory cells, the enzymes of leukocytes digest ( liquify ) the tissue. Liquefaction completely digests the dead cells, resulting in transformation of the tissue into a thick viscous liquid.

52. Hypoxic death of cells within the central nervous system (brain) often evokes liquefactive necrosis. Abscess formation results due to degradation of tissue into whitish liquid -pus, after infection by supportive bacteria like Staphylococcus, Streptococcus, Haemophilus etc.

53. 3. Gangrenous Necrosis Necrosis in which there is bacterial infection causing putrefaction ( after death of organism production of foul smell) is known as gangrenous necrosis.

54. Types of Gangrene

55. 1. Dry Gangrene It represents an area of coagulative necrosis resulting from infarction followed by mummification. It develops slowly. Mainly results from arterial obstruction.

56. Organs affected: The extremities of the body like toes, fingers, feet, tip of nose. Causes of dry gangrene Toxins Atherosclerosis(T here is a build up of plaques inside arteries) Smoking Cold

57. Gross pathology Affected part is dry Brown to black in colour (due to formation of iron sulphide : iron from haemoglobin degradation, sulphide from putrefaction ) There is well defined line of demarcation between normal and gangrenous tissue.

58. 2. Wet Gangrene This occurs when deeper tissues are injured by infection and bacteria. Affected tissue becomes soft and swollen. This leads to blockage of blood supply, mainly venous drainage and worsening of infection. This spreads very quickly. It can lead to septic shock.

59. Causes of wet gangrene Diabetic foot. Bed sores Burns and deep wounds

60. The affected parts are soft, moist and reddish brown to black. Foul smelling due to presence hydrogen sulphide , ammonia. Pus discharge is present Line of demarcation between normal and gangrenous tissue is not well defined. Gross pathology of wet gangrene

61. 3. Gas Gangrene Gas gangrene is a highly lethal infection of deep soft tissue. It is caused mainly by Clostridium perfringens . As the bacteria grow inside the body, it makes gas (nitrogen, hydrogen sulphide and CO₂) and harmful substances (toxins) that cause necrosis of body tissues, cells, and blood vessels.

62. Risk factors War-related wound infections Puncture wounds Surgical wounds of GI and the biliary tract

63. 4. Caseous Necrosis It is encountered in foci of tuberculous infection (Mycobacterium tuberculi ). The term " caseous " means cheese-like, is derived from the friable yellow- white appearance of the area of necrosis.

64. Microscopic Examination of Caseous Necrosis The necrotic focus appears as amorphous granular debris composed of fragmented cells It is surrounded by a cuff of inflammatory cells- lymphocytes and macrophages. Many macrophages become specialized and form epitheloid cells and multinucleated cell. This is limited by fibroblasts proliferation in outermost area. This focus is known as a granuloma .

65. 5. Fat Necrosis Typically results from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. This occurs in acute pancreatitis. The released fatty acids combine with calcium to produce chalky white areas. It can also be seen in breast tissue after any trauma or radiation therapy.

66. 6. Fibrinoid Necrosis It is special type of necrosis occurring in arteriolar walls. Fibrinoid necrosis is caused by deposition of antigen- antibody complex in arteriolar walls. There is leakage of fibrin and other plasma proteins into vessel wall which result in bright pink amorphous appearance in H( hematoxylin ) &E(eosin) stain.

67. 4. Apoptosis Apoptosis is a pathway of programmed cell death that is induced by regulated intracellular program in which cells activate enzymes that degrade the cells own nuclear DNA and nuclear and cytoplasmic proteins. The cell's plasma membrane remains intact.

68. The dead cells are rapidly cleared by phagocytes, before the contents are leak out. There is no inflammatory reaction in the tissue Too much or too little apoptosis is thought to underlie many diseases, such as degenerative diseases and cancer respectively.

69. Apoptosis in physiologic condition: The programmed destruction of cells during embryogenesis, organogenesis and development of fetus. Hormone dependent involution in the endometrial cell during the menstrual cycle. Cell deletion in proliferating epithelial cell population in intestine. Elimination of potentially harmful self-reactive lymphocytes. If left uncontrolled can lead to autoimmune diseases

70. Apoptosis in pathologic condition Cell death produced by a variety of injurious stimuli. For instance in radiation and cytotoxic anticancer drugs. Cell injury in certain viral diseases, such as viral hepatitis. Pathologic atrophy in parenchymal organs after duct obstruction. Cell death in large tumors which overgrow their blood supply.

71. Apoptosis Necrosis Programmed death of individual cells Affects groups of cells Induced by physiological stimuli Induced by non-physiological mechanisms such as toxins, viruses, ischemia etc No inflammation Inflammation Shrinking of cytoplasm and nucleus Swelling of the cytoplasm and mitochondria Blebbing of plasma membrane with no loss of integrity Loss of plasma membrane integrity Energy requirement (ATP) No energy requirement(Passive process) Cell death pathway activation Calcium overload

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