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  2. 2. CELL • A cell is defined as the smallest, basic fundamental units of life that are responsible for all life's process. • It is the structural, functional and the biological units of all living beings. • It can replicate itself independently, hence known as the 'BUILDING BLOCKS OF LIFE"
  4. 4. CELLS Cells are active participants in their environment, constantly adjusting their structure and function to accommodate changing demands and extracellular stresses. Cells normally maintain a steady state called homeostasis in which the intracellular milieu is kept within a fairly narrow range of physiologic parameter. As cells encounter physiologic stresses or pathologic stimuli, they can undergo adaptation, achieving a new steady state and preserving viability and function. If the adaptive capability is exceeded or if the external stress is inherently harmful, cell injury develops
  5. 5. CELL INJURY • If the limits of adaptive responses are exceeded or if cells are exposed to injurious agents or stress, deprived of essential nutrients, or become compromised by mutations that affect essential cellular constituents, a sequence of events follows that is termed CELL INJURY
  6. 6. ETIOLOGY OF CELL INJURY: The causes of cell injury range from the gross physical trauma to the single gene defect. Most injurious stimuli can be grouped into the following categories • Oxygen deprivation • Physical agents • Chemical agents • Infectious agents • Immunologic factors • Genetic factors • Nutritional factors • Aging
  7. 7. NATURE OF INJURIOUS STIMULUS CELLULAR RESPONSE • Altered physiologic stimuli; some nonlethal injurious stimuli • Increased demand, increased stimulation (e.g., by growth factors, hormones) • Decreased nutrients, decreased stimulation • Chronic irritation (physical or chemical) Cellular adaptations Hyperplasia, hypertrophy Atrophy Metaplasia • Reduced oxygen supply; chemical injury; microbial infection • Acute and transient • Progressive and severe Cell injury Acute reversible injury Irreversible injury → cell death • Cumulative sublethal injury over long life span Cellular aging
  9. 9. CELLULAR ADAPTATIONS: The principal adaptive responses are 1. Hypertrophy 2.Hyperplasia 3.Atropy 4.Metaplasia
  10. 10. •HYPERTROPHY: Hypertrophy is an increase in the size of parenchymal cells resulting in enlargement of the organ or tissue, without any change in the number of cells. CAUSES: It is caused by increased functional demand or by hormonal stimulation. In non-dividing cells , hypertrophy occurs.
  11. 11. • Hypertrophy may be physiologic or pathologic. • A. Physiologic hypertrophy • Enlarged size of the uterus in pregnancy is an example of physiologic hypertrophy as well as hyperplasia.​ • Hypertrophy of skeletal muscle e.g. hypertrophied muscles in athletes and manual labourers.​ • B. Pathologic hypertrophy • Examples of certain diseases associated with hypertrophy are as under:​ • Hypertrophy of cardiac muscle may occur in a number of cardiovascular diseases. • Compensatory hypertrophy may occur in an organ when the contralateral organ is removed e.g. i) Following nephrectomy on one side in a young patient, there is compensatory hypertrophy as well as hyperplasia of the nephrons of the other kidney.​
  12. 12. HYPERPLASIA: Hyperplasia is an increase in the number of parenchymal cells resulting in enlargement of the organ or tissue CAUSES As with other adaptive disorders of growth, hyperplasia may also be physiologic and pathologic. A. Physiologic hyperplasia 1. Hormonal hyperplasia Hyperplasia of female breast at puberty, during pregnancy and lactation. 2. Compensatory hyperplasia Regeneration of the liver following partial hepatectomy. Regeneration of epidermis after skin abrasion. B. Pathologic hyperplasia In wound healing, there is formation of granulation tissue due to proliferation of fibroblasts and endothelial cells. Formation of skin warts from hyperplasia of epidermis due to human papilloma virus.
  13. 13. METAPLASIA: Metaplasia is defined as a reversible change of one type of epithelial or mesenchymal adult cells to another type of adult epithelial or mesenchymal cells, usually in response to abnormal stimuli, and often reverts back to normal on removal of stimulus. Metaplasia is broadly divided into 2 types: epithelial and mesenchymal EPITHELIAL METAPLASIA : This is the more common type. The metaplastic change may be patchy or diff use and usually results in replacement of epithelium Depending upon the type of epithelium transformed, two types of epithelial metaplasia are seen: squamous and columnar. 1. Squamous metaplasia 2. Columnar metaplasia
  14. 14. ATROPHY Reduction of the number and size of parenchymal cells of an organ or its parts which was once normal is called atrophy . CAUSES Atrophy may occur from physiologic or pathologic causes: A. Physiologic atrophy Atrophy of thymus in adult life. B. Pathologic atrophy Starvation atrophy Ischaemic atrophy Disuse atrophy
  15. 15. MESENCHYMAL METAPLASIA Less often, there is transformation of one adult type of mesenchymal tissue to another. The examples are as under: 1. Osseous metaplasia Osseous metaplasia is formation of bone in fibrous tissue, cartilage and myxoid tissue. i) In arterial wall in old age ii) In soft tissues in myositis ossificans 2. Cartilaginous metaplasia; In healing of fractures, cartilaginous metaplasia may occur where there is undue mobility.
  16. 16. • Depletion of ATP • Mitochondrial damage and dysfunction • Influx of calcium • Accumulation of Oxygen derived free radicals • Defects in membrane permeability • Damage to DNA and Proteins VARIOUS MECHANISMS OF CELL INJURY:
  17. 17. • DEPLETION OF ATP: Effects: • 1.Decreased activity of ATP dependent sodium pumps • 2.Increased lactic acid accumulation • 3.Failure of ATP dependent Calcium pumps • 4.Structural disruption of Protein synthetic apparatus
  18. 18. • MITOCHONDRIAL DAMAGE AND DYSFUNCTION • Abnormal oxidative phosphorylation - formation of reactive oxygen species - Necrosis • Damage to mitochondria - formation of mitochondrial permeability transition pore - loss of mitochondrial membrane potential and pH changes – compromising oxidative phosphorylation. • several proteins (cytochrome C and caspases) - when released into the cytoplasm - activate a pathway of apoptosis. •
  19. 19. Increased intracellular Ca2+ causes cell injury by several mechanisms: • activates a number of enzymes with potentially deleterious effects on cells. These include phospholipases ,proteases ,endonucleases and ATPases. • results in the induction of apoptosis, by direct activation of caspases and by increasing mitochondrial permeability.
  20. 20. ACCUMULATION OF OXYGEN DERIVED FREE MOLECULES: Reactive oxygen species (ROS) are a type of oxygen derived free radical whose role in cell injury is well established. ROS are produced normally in cells during mitochondrial respiration and energy generation, but they are degraded and removed by cellular defense systems. Thus, cells are able to maintain a steady state in which free radicals may be present transiently at low concentrations but do not cause damage. Increased production or decreased scavenging of ROS may lead to an excess of these free radicals, a condition called oxidative stress. Oxidative stress has been implicated in a wide variety of pathologic processes, including cell injury, cancer, aging, and some degenerative diseases such as Alzheimer disease.
  21. 21. • DEFECTS IN MEMBRANE PERMEABILITY: • Decreased phospholipid synthesis • Increased phospholipid breakdown • Cytoskeletal abnormalities • Lipid break down products
  22. 22. • REVERSIBLE CELL INJURY : Reversible cell injury is where the functional and morphologic changes are reversible if the damaging stimulus is removed. At this stage, although there may be significant structural and functional abnormalities, the injury has typically not progressed to severe membrane damage and nuclear dissolution.
  24. 24. MORPHOLOGY OF REVERSIBLE CELL INJURY: Various morphological forms of reversible cell injury are # Hydropic change # Fatty change
  25. 25. • HYDROPIC CHANGE: • Hydropic change means accumulation of water within the cytoplasm of the cell. Microscopically, it is characterized by the following features : • i) The cells are swollen and the microvasculature compressed. • ii) Small clear vacuoles are seen in the cells and hence the term vacuolar degeneration. These vacuoles represent distended cisternae of the endoplasmic reticulum. • iii) Small cytoplasmic blebs may be seen. • iv) The nucleus may appear pale.
  26. 26. • FATTY CHANGE: • Fatty change is manifested by the appearance of triglyceride containing lipid vacuoles in the cytoplasm. • It is principally encountered in organs that are involved in lipid metabolism, such as the liver
  27. 27. IRREVERSIBLE CELL INJURY : Persistence of etiology results in irreversible damage to the structure and function of the the cell. The stage at which this point of no return or irreversibility is reached from reversible cell injury is unclear but the sequence of events is a continuation of reversibly injured cell. Two essential phenomena always distinguish irreversible from reversible cell injury Inability of the cell to reverse mitochondrial dysfunction on reperfusion or reoxygenation. Profound disturbance in cell membrane function .
  28. 28. • NECROSIS: Necrosis is defined as a localised area of death of tissue followed by degradation of tissue by hydrolytic enzymes liberated from dead cells; it is invariably accompanied by inflammatory reaction. Necrosis is characterized by changes in the cytoplasm and nuclei of the injured cells CYTOPLASMIC CHANGES: Necrotic cells show increased eosinophilia. Compared with viable cells the cell may have a more glassy, homogeneous appearance, mostly because of the loss of glycogen particles. Myelin figures are more prominent in necrotic cells than during reversible injury. When enzymes have digested cytoplasmic organelles, the cytoplasm becomes vacuolated and appears "moth-eaten. By electron microscopy. necrotic cells are characterized by discontinuities in plasma and organelle membranes, marked dilation of mitochondria with the appearance of large amorphous densities, disruption of lysosomes
  29. 29. • NUCLEAR CHANGES. • Nuclear changes assume one of three patterns, all due to breakdown of DNA and chromatin. • The basophilia of the chromatin may fade (karyolysis), presumably secondary to deoxyribonuclease (DNase) activity. • A second pattern is pyknosis, characterized by nuclear shrinkage and increased basophilia; the DNA condenses into a solid shrunken mass. • In the third pattern, karyorrhexis, the pyknotic nucleus undergoes fragmentation. • Electron microscopy reveal profound nuclear changes culminating in nuclear dissolution.
  30. 30. • Coagulative necrosis: • # It is a form of necrosis in which the underlying tissue architecture is preserved for atleast several days. • # The affected tissues take on a firm texture. Presumably the injury denatures not only structural proteins but also enzymes, thereby blocking the proteolysis of the dead cells; as a result, eosinophilic, anucleate cells may persist for days or weeks. • # Leukocytes are recruited to the site of necrosis, and the dead cells are digested by the action of lysosomal enzymes of the leukocytes. The cellular debris is then removed by phagocytosis. • # Coagulative necrosis is characteristic of infarcts (areas of ischemic necrosis) in all of the solid organs except the brain
  31. 31. • Liquefactive necrosis: • 1) It is seen in focal bacterial or occasionally, fungal infections, because microbes stimulate the accumulation of inflammatory cells and the enzymes of leukocytes digest ("liquefy") the tissue. • 2) For obscure reasons, hypoxic death of cells within the central nervous system often evokes liquefactive necrosis. • 3) Whatever the pathogenesis, the dead cells are completely digested, transforming the tissue into a liquid viscous mass. Eventually, the digested tissue is removed by phagocytes. • 4) If the process was initiated by acute inflammation, as in a bacterial infection, the material is frequently creamy yellow and is called pus.
  32. 32. • Caseous necrosis: # Caseous means "cheese-like" referring to the friable yellow- white appearance of the area of necrosis. # On microscopic examination, the necrotic focus appears as a collection of fragmented or lysed cells with an amorphous granular pink appearance in the usual H&E-stained tissue. # Unlike with coagulative necrosis, the tissue architecture is completely obliterated and cellular outlines cannot be discerned. The area of caseous necrosis is often enclosed within a distinctive inflammatory border; this appearance is characteristic of a focus of inflammation known as a granuloma. # It is encountered most often in foci of tuberculous infection
  33. 33. Fat necrosis: • It refers to focal areas of fat destruction. • In acute pancreatitis, pancreatic enzymes liquefy the membranes of fat cells in the peritoneum, and lipases split the triglyceride esters contained within fat cells. • The released fatty acids combine with calcium to produce grossly visible chalky white areas which enable the surgeon and the pathologist to identify the lesions . • On histologic examination, the foci of necrosis contain shadowy outlines of necrotic fat cells with basophilic calcium deposits, surrounded by an inflammatory reaction.
  34. 34. • Fibrinoid necrosis: • It is a special form of necrosis, visible by light microscopy, usually in immune reactions in which complexes of antigens and antibodies are deposited in the walls of arteries. • The deposited immune complexes, together with fibrin that has leaked out of vessels, produce a bright pink and amorphous appearance on H&E preparations called fibrinoid (fibrin-like) by pathologists • The immunologically mediated diseases (e.g., poly- arteritis nodosa) in which this type of necrosis is seen
  35. 35. APOPTOSIS (programmed cell death) Apoptosis is a pathway of cell death in which cells activate enzymes that degrade the cell’s own nuclear DNA and cytoplasmic fragments of the apoptotic cells then break off, giving the appearance that is responsible for the name (apoptosis, "falling off").
  36. 36. Apoptosis in Physiologic Situations:
  37. 37. Apoptosis in Physiologic Situations:
  38. 38. Apoptosis in Pathologic Conditions : Death by apoptosis is responsible for loss of cells in a variety of pathologic states: 1)DNA damage. 2) Accumulation of misfolded proteins 3 )Pathological atrophy in parenchymal organs after duct obstruction
  39. 39. • MECHANISMS: Apoptosis results from the activation of enzymes called caspases. The activation of caspases depends on a finely tuned balance between production of pro- and anti- apoptotic proteins. Two distinct converge on caspase activation: 1. The Mitochondrial (Intrinsic)pathway 2.The Death receptor (Extrinsic) pathway
  40. 40. ■ Mitochondrial (intrinsic) pathway: Damage Sensors activated BH3 proteins – BCL receptor Activate Bax and Bak (Proapoptotic proteins) Channels in mitochondria Leakage of mitochondrial proteins and cytochrome C Cytochrome C activates Caspase 9 Caspase cascade activation
  41. 41. ■ Death receptor (extrinsic) pathway: expression of death receptors (TNF receptor 1 and fas receptor) Fas ligand expressed on activated T lymphocytes attaches to the cells expressing fas receptor FADD domain binds to inactive form of caspase 8 Multiple pro caspase 8 comes to its proximity and cleaves them to become active caspase 8 Caspase 8 cleaves and activates Bid ( Proapoptotic proteins) feeding into mitochondrial pathway Combined activation leads to lethal blow to the cell
  42. 42. EXECUTION PHASE APOPTOSIS: activation of the initiator caspase-9 ( in mitochondrial pathway) initiator caspases-8 and -10 (in death receptor pathway) initiator caspase cleaved to become active form, which thereby activates the executioner caspases. Executioner caspases (caspase-3 and -6) act on many cellular components. For instance, these once activated, cleave an inhibitor of a cytoplasmic DNase and thus make the DNase enzymatically active; this enzyme induces cleavage of DNA. Caspases also degrade structural components of the nuclear matrix and thus promote fragmentation of nuclei.
  43. 43. Apoptotic bodies makes it edible for phagocytes by Flipping of phosphotidylserine to outside of plasma membrane Coated by thrombospondin Secreting soluble factors coated with natural antibodies and proteins of the complement system, notably C1q recognized by phagocytes dead cells disappear, often within minutes, and without leaving a trace.
  44. 44. Feature Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage Nucleus Pyknosis Karyohexsis Karyolysis Fragmentation Plasma membrane Distrupted Intact,altered structure Cellular contents Enzymatic digestion, may leakout of cell Intact, released in apoptotic bodies Inflammation Frequent No Physiologic or pathologic role Invariably pathologic Often physiologic but may be pathologic at times DIFFERENCES:
  45. 45. AUTOPHAGY / AUTOLYSIS: • Autophagy is a process in which a cell eats its own contents (Greek: auto, self; phagy, eating). • Autophagy is an adaptive response that is enhanced during nutrient deprivation, allowing the cell to cannibalize itself to survive. • Autophagy is implicated in many physiologic states (e.g., aging and exercise) and pathologic states including cancers, inflammatory bowel diseases, and neurodegenerative disorders.
  46. 46. It proceeds through several steps • Formation of an isolation membrane, also called phagophore, believed to be derived from the ER • Elongation of the vesicle • Maturation of the autophagosome, its fusion with lysosomes, and eventual degradation of the contents
  47. 47. NECROPTOSIS: ■ Necroptosis resembles necrosis morphologically and apoptosis mechanistically as a form of programmed cell death. It is also programmed cell death but without caspase activation
  48. 48. MECHANISM; ■ Necroptosis is triggered by ligation of TNFR1, and viral proteins of RNA and DNA viruses. ■ Necroptosis is caspase-independent but dependent on signaling by the RIP1 and RIP3 complex. ■ RIP1-RIP3 signaling reduces mitochondrial ATP generation, causes production of ROS, and permeabilizes lysosomal membranes, thereby causing cellular swelling and membrane damage as occurs in necrosis. ■ Release of cellular contents evokes an inflammatory reaction as in necrosis
  49. 49. ABNORMAL INTRACELLULAR DEPOSITIONS Abnormal deposits of materials in cells and tissues are the result of excessive intake or defective transport or catabolism. ■ Deposition of lipids ■ Fatty change: Accumulation of free triglycerides in cells, resulting from excessive intake or defective transport (often because of defects in synthesis of transport proteins); manifestation of reversible cell injury ■ Cholesterol deposition: Result of defective catabolism and excessive intake; in macrophages and smooth muscle cells of vessel walls in atherosclerosis ■ Deposition of proteins: Reabsorbed proteins in kidney tubules; immunoglobulins in plasma cells
  50. 50. ■ PATHOLOGIC CALCIFICATIONS ■ Dystrophic calcification: Deposition of calcium at sites of cell injury and necrosis ■ Metastatic calcification: Deposition of calcium in normal tissues, caused by hypercalcemia (usually a consequence of parathyroid hormone excess ■ Deposition of glycogen: In macrophages of patients with defects in lysosomal enzymes that break down glycogen (glycogen storage diseases) ■ Deposition of pigments: Typically indigestible pigments, such as carbon, lipofuscin (breakdown product of lipid peroxidation), or iron (usually due to overload, as in hemosiderosis
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