Necrosis and apoptosis

Necrosis and apoptosis

1. NECROSIS Necrosis( death,the stage of dying,the act of killing)is the premature death of cells in living tissues. (irreversible injury) changes produced by enzymetic digestion of dead cellular elements ,without chemical messege .

2. Types of necrosis Coagulative necrosis Liquefactive necrosis Caseous necrosis Fat necrosis Fibrinoid necrosis

3. Coagulative necrosis Preservation of general tissue architecture-tombstone appearance of the cell Affected tissue is firm Denaturation of structural protiens and enzymetic digestion of cells Example : Heart,kidney,Spleen

4. Liquifaction necrosis The tissue becomes liquid viscous mass Material is creamy yellow in colour Seen in brain,abscess

5. Caseous necrosis Type of coagulative necrosis Seen in tuberculous infections Tissue is cheesy white in appearance The tissue architecture is preserved Also seen in lungs

6. Fat necrosis Seen in pancreas, breast In acute pancreatitis, activated lipase causes fat necrosis Grossly visible chalky white area Presence of shadowy outline necrotic cells

7. Types of fat necrosis

8. Fibrinoid necrosis Deposition of fibrin like material Seen in immunologic cell injury,hypertension,peptic ulcer Affect blood vessel and the glomerulus infiltrated with fibrin Its colour is bright pink in artery

9. Causes of necrosis Ischemia Physical agents Chemical agents Immunological injury

10. Ischemia In medicine, ischemia,is a restriction in blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue . It also means local anemia in a given part of a body sometimes resulting from congestion (such as vasoconstriction, thrombosis or embolism)

11. Physical agents Physical agents such as heat or radiation can damage a cell by literally cooking or  coagulating  their contents. Impaired nutrient supply, such as lack of oxygen or  glucose , or the production of  adenosine triphosphate  (ATP) may deprive the cell of essential materials needed to survive .

12. Chemical agents Internal factors causing necrosis include  trophoneurotic   disorders; injury and paralysis of nerve cells . Pancreatic enzymes (lipases) are the major cause of fat necrosis .  Necrosis can be activated by components of the immune system, such as the  complement system ;  bacterial toxins ; activated natural killer cells ; and  peritoneal   macrophages .  Pathogen-induced necrosis programs in cells with immunological barriers ( intestinal mucosa ) may alleviate invasion of  pathogens  through surfaces affected by inflammation . Toxins and pathogens may cause necrosis; toxins such as  snake venoms may inhibit enzymes and cause cell death.

13. Pathogenesis of necrosis  There are two broad pathways in which necrosis may occur in an organism . The first of these two pathways initially involves  oncosis , where swelling of the cells occur .  The cell then proceeds to  blebbing , and this is followed by  pyknosis , in which nuclear shrinkage transpires .  In the final step of this pathway the nucleus is dissolved into the cytoplasm, which is referred to as  karyolysis . The second pathway is a secondary form of necrosis that is shown to occur after apoptosis and budding .  Cellular changes of necrosis occur in this secondary form of apoptosis, where the nucleus breaks into fragments, which is known as  karyorrhexis .

14. Cellular changes The nucleus changes in necrosis, and characteristics of this change are determined by manner in which its DNA breaks down : They are of three types Karyolysis : the  chromatin  of the nucleus fades due to the loss of the DNA by degradation . Pyknosis : the nucleus shrinks and the chromatin condenses . Karyorrhexis : the shrunken nucleus fragments to complete dispersal

15. Gangrene Gangrene  is a serious and potentially life-threatening condition that arises when a considerable mass of body tissue dies ( necrosis ). This may occur after an injury or infection, or in people suffering from any chronic health problem affecting  blood circulation . The primary cause of gangrene is reduced  blood supply  to the affected tissues, which results in  cell  death . Diabetes  and long-term smoking increase the risk of suffering from gangrene

16. Gangrenous necrosis Wet gangrene Dry gangrene Gas gangrene

17. Wet gangrene Occurs in moist tissue like mouth,bowel,lung,cervix . Bed sores. Diabetic foot.

18. Dry gangrene Toes and feet due to arteriosclerosis Thromboangitis obliterans trauma

19. Comparison of wet and dry gangrene Wet gangrene Bowel Venous obstruction Moist, swollen, dark No clear line of demarcation Bacteria present Dry gangrene Limb Arterial obstruction Dry, black Presence of line of demarcation no bacteria

20. Gas gangrene: Gas gangrene:  (also known as " Clostridial myonecrosis “,  and " Myonecrosis ") is a  bacterial   infection  that produces gas in  tissues  in  gangrene . It is a deadly form of gangrene usually caused by  Clostridium perfringens  bacteria. It is a  medical emergency Seen in muscle. Seen in colon.

21. Gangrene in foot muscle:

22. Treatment from gangrene Treatment is usually  debridement  and  excision , with  amputation  necessary in many cases .   Antibiotics  alone are not effective because they do not penetrate  ischaemic   muscles  sufficiently to be effective . penicillin is given as an  adjuvant treatment  to surgery . In addition to surgery and antibiotics,  hyperbaric oxygen therapy  (HBOT) is used and acts to inhibit the growth of and kill the anaerobic   C. perfringens .

23. Necrosis cell processes Formation of small blebs Changes in nuclear structure The various blebs fused and become larger No organelles in the blebs Rupture of cell membrane releasing content of cells Organelle are non functional Induction of inflammation Tissue damage

24. Consequences of necrosis Acute or chronic inflammation Immunological reactions subcellular components released by dead tissue Lysis and absorption Isolation and discharge: ulceration and cavity formation Organization Encapsulation, calcification

25. Treatment of necrosis There are many causes of necrosis . Treatment of necrosis typically involves two distinct processes : Debridement , referring to the removal of dead tissue by surgical or non-surgical means, is the standard therapy for necrosis. Depending on the severity of the necrosis, this may range from removal of small patches of skin, to complete  amputation  of affected limbs or organs . Chemical removal of necrotic tissue is another option in which enzymatic debriding agents, categorised as proteolytic ,  fibrinolytic  or  collagenases , are used to target the various components of dead tissue

26. Apoptosis Named after Greek designation for “falling off” Pathway of cell death induced by a tight regulated intracellular program in which cells destined to die activate enzymes that degrade the cells own nuclear and cytoplasmic protein Programed cell death Evolutionary conserved Occurs in all animals and plant too Stages and genes conserved from nematodes and flies to humans

27. Induction of apoptosis Extrinsic or cell surface death receptor mediated pathway. Mitochondrial-initiated pathway(intrinsic). Endoplasmic reticulus (intrinsic).

28. Morphology Cell shrinkage Chromatin condensation-most characteristic feature Formation of cytoplasmic blebs and apoptotic bodies Phagocytosis of apoptotic cells or cell bodies by macrophages Plasma membrane remain intact during apoptosis until the last stage Apoptosis doesn,t illicitt inflammation

29. Causes of apoptosis: Physiological situations Pathological conditions

30. Apoptosis in physiological situations Programmed destruction of cell during embryogenesis and development Hormone-dependent tissue involution-endometrial cells (menstrual cycle) Cell deletion in proliferating cell population e.g skin Post-inflammatory clean up-neutrophils Cell death induced by cytotoxic T-cells to eliminate harmful cells-viral infected or tumor cells

31. Apoptosis in pathologic conditions Cell death produced by injurious stimuli-radiation , cytotoxic drug. Cell injury in certain viral diseases-viral hepatitis. Cell death in tumors

32. Apoptosis biochemistry Protein digestion ( caspases ) DNA breakdown (endonucleases) Phagocytic recognition

33. Mechanism of apoptosis The intrinsic or internal pathways External molecules binding to cell surface receptors. Due to reactive oxygen species.

34. Hyperactive APOPTOSIS: On the other hand, loss of control of cell death (resulting in excess apoptosis) can lead to neurodegenerative diseases, hematologic diseases, and tissue damage. The progression of HIV is directly linked to excess, unregulated apoptosis. In a healthy individual, the number of CD4+ lymphocytes is in balance with the cells generated by the bone morrow; however in HIV, this balance is lost due to an inability of the bone morrow to regenerate CD4+ cells. And CD4+ lymphocytes die at accelerated rate through uncontrolled apoptosis.

35. How does APOPTOSIS takes place? Steps involved in the programmed cell death; When the unnecessary enzymes starts activating in the cell, they eat up the proteins due to which cell starts becoming round. DNA present inside the nucleus starts separating and eventually it shrinks down. There is a nuclear membrane around the nucleus, when the apoptosis starts, it degrades and cells nucleus become without the outer layer.

36. Due to the absence of nuclear membrane, the DNA molecules starts rupturing into small fragments. As nucleus is no longer protected that is why it breaks down into many pieces along with the uneven pieces of DNA molecules. Due to the breakage inside the cell, cell itself starts degrading through the process of blebbing .

37. Types of apoptosis Internal apoptosis External apoptosis

38. Intrinsic pathway: Intrinsic: The intrinsic pathway of apoptosis is activated upon cellular stresses such as decreased oxygen, increased reactive oxygen species and DNA damage. Stressors cause initiator caspases within the mitochondria and endoplasmic reticulum to be cleaved. This then activates downstream effector caspases , ultimately leading to cell death. The intrinsic pathway is governed by the Bcl-2 family of proteins. These proteins are either pro-apoptotic or anti-apoptotic. Apoptotic Bcl-2 proteins, such as Bad, interact and activate the release of cytochrome C from the mitochrondria which eventually inititates the caspase cascade. Effector caspases are activated and these eventually cause cell death.

39. Exrinsic pathway: Extrinsic: The extrinsic pathway of apoptosis is activated upon the binding of a death ligand to a death receptor on the cell membrane. Death receptors are FAS and TNF receptors and activated by FAS or TNF ligands. Activation of these receptors causes the cleavage of initiator caspases within the cytoplasm. This then activates downstream effector caspases , ultimately leading to cell death.

40. Caspases : Caspases Caspases play the central role in the transduction of DR apoptotic signals . Caspases are proteins that are highly conserved, cysteine-dependent aspartate-specific proteases . There are two types of caspases : initiator caspases , caspase 8,10,9,2, and effector caspases , caspase 3,7,6. The activation of initiator caspases requires binding to specific oligomeric adaptor protein. Effector caspases are then activated by these active initiator caspases through proteolytic cleavage. The active effector caspases then proteolytically degrade a host of intracellular proteins to carry out the cell death program .

41. Why Is Apoptosis Important? Apoptosis is important in every day of our lives, as many processes rely on apoptosis to occur. Furthermore, research has shown that the inhibition or hyperactivity of apoptosis can cause disease. Below is a short overview of the importance of apoptosis: Apoptosis is vital for the formation of digits, organs and limbs in embryogenesis Apoptosis is needed in the strict process of tissue homeostasis in the developed animal Increased apoptosis causes the vascular calcification seen in end-stage kidney failure, sadly little can be done for this and many patients die from the effects of arterial calcification Increased apoptosis can lead to larger plaque formation in coronary heart disease Decreased apoptosis is seen in many aggressive cancers, chemotherapy targets cancer cells and induces them to die In arthrtitis , the increased levels of inflammation cause continual activation of cell death leading to the degradation and damage of affected joints

42. During development many cells are produced in excess which eventually undergo programmed cell death and thereby contribute to sculpturing many organs and tissue. In human body about one lakh cells are produced every second by mitosis and similar number die by apoptosis. Between 50 to 60 billion cells each day due to apoptosis in average human adult .

43. Comparison of apoptosis and necrosis A poptosis Role for mitochondria and cytochrome c No leak of lysosomal enzyme Nuclear changes Apoptotic bodies form DNA cleavage Activation of specific proteases Regulatable process Necrosis No role for mitochondria Leak of lysosomal enzymes Nuclei lost Do not form No DNAcleavage No activation Not regulated