Irreversible cellular injury.
Necrosis – types. Apoptosis.
Synopsis
 Irreversible cellular injury – cellular
death.
 Clinical - anatomical forms of
necrosis.
 Apoptosis- programm...
Morphology of cellular injury
 Subcellular alterations
 Related to biochemical changes
 Reversible cell injury
 2 grou...
Irreversible cell injury
 Two types of cell death, which differ in
their morphology, mechanisms, and
roles in disease and...
Necrosis
 A local death of cells, tissues, part of an organ,
and sometimes an entire organ.
 This term included the seri...
Causes of necrosis
 Hypoxia
 Ischemia
 Hypoxemia
 Loss of oxygen carrying capacity
 Free radical damage
 Chemicals, ...
Necrosis
 Development
 Immediately
 Slowly - necrobiosis
 Responses of the heart to
different types of stress:

Ische...
Necrosis
 Electron microscopy
 breakdown of plasma membrane and organellar membranes,
 marked dilation of mitochondria ...
Clinical - anatomical forms of necrosis
 Several morphologically distinct patterns of
tissue necrosis, which may provide ...
Coagulative necrosis
 It is a form of tissue necrosis in which the component cells
are dead but the basic tissue architec...
Coagulative necrosis
 Macroscopy
 Necrotic areas –whitish,
firm, protruding above
surrounding tissue
 Microscopy
 The ...
Coagulative necrosis (heart)
 the cellular appearance looks “cooked” and cell
structures and delineation is lost
Necrosis...
Coagulative necrosis (ren)
 the cellular appearance looks “cooked” and cell structures and
delineation is lost
Necrosis r...
Caseous necrosis
 Variant of coagulation
necrosis associated with
acellular, cheese-like
(caseous) material
 Tuberculosi...
Necrosis pulmonis
(Bronchopneumonia tbc caseosa)
Necrosis lymphonodi
(Tuberculosis lymphonodi)
Liquefactive necrosis
 = Necrotic degradation of tissue
that softens and becomes liquified
 Mechanisms
 Lysosomal enzym...
Liquefactive necrosis (brain)
Gangrenous necrosis
 Necrosis of tissues in contact with
outside environment
 It is not a distinctive pattern of cell
de...
Fat necrosis
 Pancreas - in acute pancreatitis
 Activation of pancreatic lipase causing
hydrolysis of triglyceride in fa...
Fibrinoid necrosis
 It is a special form of
necrosis limited to small
muscular arteries,
arterioles, venules, and
glomeru...
Decubitus ulcer
 =pressure sore
 Decumbere means "to lie down"
 Results from the prolong pressure,
that cuts off the bl...
Sequestrum
 A fragment of dead
tissue, that has separated
from healthy tissue as a
result of injury or disease
 Bone – o...
Outcome of necrosis
 Irreversible injury
 Inflammation – line of demarcation
 Phagocytosis – neutrophils (enzymes)
 Or...
Enzyme markers of cell death
 Tissues release certain enzymes that indicate
the type of tissue involved and extent of inj...
APOPTOSIS
 A cell death that is induced by a tightly regulated suicide
program
 When a cell is deprived of growth factor...
Microscopic appearance of
apoptosis
 Cell detachment from
neighboring cells
 Deeply eosinophilic-staining
cytoplasm
 Py...
Features of Necrosis and Apoptosis
Feature Necrosis Apoptosis
Cell size Enlarged
(swelling)
Reduced (shrinkage)
Nucleus Py...
APOPTOSIS
 Normal (preprogrammed)
 serves to eliminate potentially harmful cells
and cells that have outlived their
usef...
“NORMAL” APOPTOSIS
 Embryogenesis
 implantation, organogenesis, developmental involution, metamorphosis
 Hormonal “Invo...
“PATHOLOGIC” APOPTOSIS
 “Toxic” effect on cells, e.g., chemicals, pathogens
 Radiation, cytotoxic anticancer drugs, extr...
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  1. 1. Irreversible cellular injury. Necrosis – types. Apoptosis.
  2. 2. Synopsis  Irreversible cellular injury – cellular death.  Clinical - anatomical forms of necrosis.  Apoptosis- programmed cell death.
  3. 3. Morphology of cellular injury  Subcellular alterations  Related to biochemical changes  Reversible cell injury  2 groups  Irreversible cell injury  =cell death  2 types  Necrosis  Apoptosis  The concequences of an pathologic factor depend on the cell type, status and adaptability of the injured cell
  4. 4. Irreversible cell injury  Two types of cell death, which differ in their morphology, mechanisms, and roles in disease and physiology  necrosis  “premature” or “untimely” death due to “causes”  always pathologic  ischemia, toxins, various infections, trauma.  apoptosis  “normal” death  When a cell is deprived of growth factors or the cell's DNA or proteins are damaged beyond repair, the cell kills  physiologic and pathologic
  5. 5. Necrosis  A local death of cells, tissues, part of an organ, and sometimes an entire organ.  This term included the series of changes that accompany cell death, largely resulting from the degradative action of enzymes on lethally injured cells.  Necrotic cells are unable to maintain membrane integrity, and their contents often leak out.  The enzymes responsible for digestion of the cell are derived either from the lysosomes of the dying cells themselves or from the lysosomes of leukocytes that are recruited as part of the inflammatory reaction to the dead cells.
  6. 6. Causes of necrosis  Hypoxia  Ischemia  Hypoxemia  Loss of oxygen carrying capacity  Free radical damage  Chemicals, drugs, toxins  Infections  Physical agents  Immunologic reactions  Genetic abnormalities  Nutritional imbalance
  7. 7. Necrosis  Development  Immediately  Slowly - necrobiosis  Responses of the heart to different types of stress:  Ischemia  incomplete occluded coronary artery – hypoxia, reversible cell injury  complete or prolonged occlusion – cell death
  8. 8. Necrosis  Electron microscopy  breakdown of plasma membrane and organellar membranes,  marked dilation of mitochondria with the appearance of large amorphous densities  disruption of lysosomes,  intracytoplasmic myelin figures  Nuclear changes, culminating in nuclear dissolution.  Pyknosis (nuclear shrinkage)  Karyorrhexis (nuclear memmbrane ruptured)  Karyolysis (complete dissolution of of nucleus, loss of chromatin)
  9. 9. Clinical - anatomical forms of necrosis  Several morphologically distinct patterns of tissue necrosis, which may provide clues about the underlying cause  Coagulative (parenchymal organs)  Liquefactive (brain)  Gangrenous (Extremities, Bowel, non-specific)  wet  dry  Caseous (cheese) (Tuberculosis)  Fat necrosis (pancreas, breast)  Fibrinoid (Rheumatoid, non-specific)  Decubitus ulcer  Sequestrum
  10. 10. 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  Dry necrosis - tissues rich in proteins, less water  Denaturation and coagulations of proteins due to inactivation of enzymes  Characteristic of infarcts (areas of ischemic necrosis) in all solid organs except the brain  Heart  Ren  spleen
  11. 11. Coagulative necrosis  Macroscopy  Necrotic areas –whitish, firm, protruding above surrounding tissue  Microscopy  The necrotic cells - ↑ eosinophilia  Shadows of structures  Ren -glomerules, tubules  Nuclear fragments
  12. 12. Coagulative necrosis (heart)  the cellular appearance looks “cooked” and cell structures and delineation is lost Necrosis myocardii
  13. 13. Coagulative necrosis (ren)  the cellular appearance looks “cooked” and cell structures and delineation is lost Necrosis renis
  14. 14. Caseous necrosis  Variant of coagulation necrosis associated with acellular, cheese-like (caseous) material  Tuberculosis  Lues  brucelosis  Microscopic features  The acellular material in the center of a granuloma - multinucleated giant cells  No shadows
  15. 15. Necrosis pulmonis (Bronchopneumonia tbc caseosa)
  16. 16. Necrosis lymphonodi (Tuberculosis lymphonodi)
  17. 17. Liquefactive necrosis  = Necrotic degradation of tissue that softens and becomes liquified  Mechanisms  Lysosomal enzymes released by necrotic cells or neutrophils cause liquefaction of tissue  Pseudocysts, containing liquid.  Brain  CNS infarction  Autocatalytic effect of hydrolytic enzymes generated by neuroglial cells produces a cystic space  Abscess in a bacterial infection  Hydrolytic enzymes generated by neutrophils liquefy dead tissue.
  18. 18. Liquefactive necrosis (brain)
  19. 19. Gangrenous necrosis  Necrosis of tissues in contact with outside environment  It is not a distinctive pattern of cell death, but the term is still commonly used in clinical practice  generally the lower leg - ishemia  Dry gangrene  Macroscopy – grey -black colour  Wet gangrene  When bacterial infection is superimposed - liquefactive action of the bacteria and the attracted leukocytes  Durty green colour, smell  Noma  wet gangrene of lips and cheeks in exhausted children
  20. 20. Fat necrosis  Pancreas - in acute pancreatitis  Activation of pancreatic lipase causing hydrolysis of triglyceride in fat cells  And conversion of fatty acids into soap (saponification)  Combination of fatty acids and calcium  Gross appearance  Chalky yellow-white deposits in peripancreatic and omental adipose tissue  Microscopy  Pale outlines of fat cells filled with basophilic-staining calcified areas  Traumatic fat necrosis  Occurs in fatty tissue (e.g., female breast tissue) as a result of trauma  Not enzyme-mediated
  21. 21. Fibrinoid necrosis  It is a special form of necrosis limited to small muscular arteries, arterioles, venules, and glomerular capillaries  In connective tissue diseases  Immune vasculitis (e.g., polyarteritis nodosa )  malignant hypertension
  22. 22. Decubitus ulcer  =pressure sore  Decumbere means "to lie down"  Results from the prolong pressure, that cuts off the blood supply to the skin, causing the skin and other tissue to die  Older people -70 y, hea  Severe illness (people who cannot move themselves)  Back, knees, elbows, ankles
  23. 23. Sequestrum  A fragment of dead tissue, that has separated from healthy tissue as a result of injury or disease  Bone – osteomyelitis  lung
  24. 24. Outcome of necrosis  Irreversible injury  Inflammation – line of demarcation  Phagocytosis – neutrophils (enzymes)  Organisation  Granulation tissue⇒ cicatrix (connective tissue), calcification  liquefactive necrosis (brain) – pseudocyst (glial capsule)
  25. 25. Enzyme markers of cell death  Tissues release certain enzymes that indicate the type of tissue involved and extent of injury.  Aspartate aminotransferase (AST), Alanine aminotransferase (ALT)- – markers of diffuse liver cell necrosis (e.g., viral hepatitis)  Creatine kinase MB (CK-MB) - isoenzyme increased in acute myocardial infarction or myocarditis  Amylase and lipase - marker enzymes for acute pancreatitis
  26. 26. APOPTOSIS  A cell death that is induced by a tightly regulated suicide program  When a cell is deprived of growth factors  or the cell's DNA or proteins are damaged beyond repair  Kerr and Wyllie, 1972  "falling off“ (fragments of the apoptotic cells break off)  Apoptosis is an active enzymatic process in which nucleoproteins are broken down and then the cell is fragmented  caspases  mitochondrial pathway - most often  the death receptor pathway - cytotoxic T lymphocytes
  27. 27. Microscopic appearance of apoptosis  Cell detachment from neighboring cells  Deeply eosinophilic-staining cytoplasm  Pyknotic, fragmented, or absent nucleus-apoptotic bodies  No inflammatory infiltrate surrounding the cell
  28. 28. Features of Necrosis and Apoptosis Feature Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis → karyorrhexis → karyolysis Fragmentation into nucleosome-size fragments Plasma membrane Disrupted Intact; altered structure Cellular contents Enzymatic digestion; may leak out of cell Intact; may be released in apoptotic bodies Adjacent inflammation Frequent No Physiologic/ Pathologic role Invariably pathologic Often physiologic, may be pathologic after some forms of cell injury (DNA damage)
  29. 29. APOPTOSIS  Normal (preprogrammed)  serves to eliminate potentially harmful cells and cells that have outlived their usefulness  Pathologic (associated with necrosis)  when cells are damaged beyond repair, especially when the damage affects the cell's DNA or proteins
  30. 30. “NORMAL” APOPTOSIS  Embryogenesis  implantation, organogenesis, developmental involution, metamorphosis  Hormonal “Involution”  such as endometrial cell breakdown during the menstrual cycle, and regression of the lactating breast  Cell loss in proliferating cell populations  such as intestinal crypt epithelia, -to maintain a constant number  Post Inflammatory “Clean-up”  neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response  Elimination of potentially harmful self-reactive lymphocytes  in order to prevent reactions against one's own tissues  Cytotoxic T-Cells cleaning up 
  31. 31. “PATHOLOGIC” APOPTOSIS  “Toxic” effect on cells, e.g., chemicals, pathogens  Radiation, cytotoxic anticancer drugs, extremes of temperature, and even hypoxia  damage DNA - directly or via production of free radicals.  After duct obstruction  Pathologic atrophy - in the pancreas, parotid gland, and kidney  Cell injury in certain infections  particularly viral infections, in which loss of infected cells is largely due to apoptotic death  Tumors – delayed apoptosis, slow cell death  Anti-tumor therapy

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