Cell Death Pathways In Irreversible Injury

Morphology Of Irreversible Cell Injury (Cell Death):

Cell death is a state of irreversible cell injury. It may occur in the living tissues as a local or focal change caused by external factors (i.e. necrosis), or mediated by intracellular genetic programmes (i.e. programmed cell death).

Necrosis is distinct from autolysis (i.e. self-digestion), a term used for disintegration of the cell by its own hydrolytic enzymes liberated from lysosomes as a postmortem change in tissues, and is therefore unaccompanied with inflammatory response in the surrounding tissue.

Read And Learn More: General Pathology Notes

Autolysis 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 compact mesenchymal tissues such as fibrous tissue, cartilage and bones.

Necrosis may be superimposed by some pathologic changes (for example,Gangrene), while pathologic (or heterotopic) calcification may occur in normal tissues as well as following degenerations and necrosis.

C, Cytoplasm is more pink and the nucleus is fragmented (karyorrhexis). D, The cytoplasm is intensely pink and nuclear material has disappeared (karyolysis).

Classical form of programmed cell death is apoptosis; a few other types are necroptosis (programmed necrosis), pyroptosis (associated with fever-producing cytokine IL-1), ferroptosis (iron-dependent reactive oxygen species) and autophagy (self-eating). These topics are discussed below.

Necrosis:

Necrosis is defined as a localised area of death of tissue followed later by degradation of tissue by hydrolytic enzymes liberated from dead cells; it is invariably accompanied by inflammatory reaction. Necrosis can be caused by various agents such as hypoxia, chemical and physical agents, microbial agents, immunological injury, etc.

Based on etiology and morphologic appearance, there are 5 types of necrosis:

1. Coagulative
2. Liquefactive (colliquative)
3. Caseous,
4. Fat and
5. Fibrinoid necrosis.

1. Coagulative Necrosis:

This is the most common type of necrosis caused by irreversible focal injury, mostly from sudden cessation of blood flow (ischaemic necrosis), and less often from bacterial and chemical agents. The organs commonly affected are the heart, kidney, and spleen.

• Grossly:  Focus of coagulative necrosis in the early stage is pale, firm, and slightly swollen and is called infarct. With progression, the affected area becomes more yellowish, softer, and shrunken.
• Microscopically:  The hallmark of coagulative necrosis is the conversion of normal cells into their ‘tombstones’ i.e. outlines of the cells are retained and the cell type can still be recognised but their cytoplasmic and nuclear details are lost.

The necrosed cells are swollen and have more eosinophilic cytoplasm than the normal. These cells show nuclear changes of pyknosis, karyorrhexis and karyolysis. However, cell digestion and liquefaction fail to occur (c.f. liquefaction necrosis). Eventually, the necrosed focus is infiltrated by inflammatory cells and the dead cells are phagocytosed leaving granular debris and fragments of cells .

2. Liquefactive (Colliquative) Necrosis:

Liquefactive or colliquative necrosis also occurs commonly due to ischaemic injury and bacterial or fungal infections but hydrolytic enzymes in tissue degradation have a dominant role in causing semi-fluid material. The common examples are infarct brain and abscess cavity.

• Grossly:  The affected area is soft with liquefied centre containing necrotic debris. Later, a cyst wall is formed.
• Microscopically: The cystic space contains necrotic cell debris and macrophages filled with phagocytosed material. The cyst wall is formed by proliferating capillaries, inflammatory cells, and gliosis (proliferating glial cells) in the case of brain and proliferating fibroblasts in the case of abscess cavity .

3. Caseous Necrosis:

Caseous (caseous= cheese-like) necrosis is found in the centre of foci of tuberculous infections. It combines features of both coagulative and liquefactive necrosiThe interface between viable and non-viable area shows non-specific chronic inflammation and proliferating vessels.

• Grossly: Foci of caseous necrosis resemble dry cheese and are soft, granular and yellowish.
  • This appearance is partly attributed to the histotoxic effects of lipopolysaccharides present in the capsule of the tubercle bacilli, Mycobacterium tuberculosis.
• Microscopically: Centre of the necrosed focus contain structureless, eosinophilic material having scattered granular debris of disintegrated nuclei
  • The surrounding tissue shows characteristic granulomatous inflammatory reaction consisting of epithelioid cells (modified macrophages having slipper-shaped vesicular nuclei), interspersed giant cells of
  • Langhans’ and foreign body type and peripheral mantle of lymphocytes.

Contrasting features of three major forms of necrosis— coagulative, liquefactive and caseous, are given ingivrn in below.

4. Fat Necrosis:

Fat necrosis is a special form of cell death occurring at mainly fat-rich anatomic locations in the body. The examples are: traumatic fat necrosis of the breast, especially in heavy and pendulous breasts, and mesenteric fat necrosis due to acute pancreatitis.

• In the case of acute pancreatitis, there is liberation of pancreatic lipases from injured or inflamed tissue that results in necrosis of the pancreas as well as of the fat depots throughout the peritoneal cavity, and sometimes, even affecting the extra-abdominal adipose tissue.
• In fat necrosis, there is hydrolysis and rupture of adipocytes, causing release of neutral fat which changes into glycerol and free fatty acids. The leaked out free fatty acids complex with calcium to form calcium soaps (saponification) discussed later under dystrophic calcification.
• Grossly:  Fat necrosis appears as yellowish-white and firm deposits. Formation of calcium soaps imparts the necrosed foci firmer and chalky white appearance.
• Microscopically: The necrosed fat cells have cloudy appearance and are surrounded by an inflammatory reaction. Formation of calcium soaps is identified in the tissue sections as amorphous, granular and basophilic material

Contrasting features of three major forms of necrosis:

5. Fibrinoid Necrosis:

Fibrinoid necrosis is characterised by deposition of fibrin-like material which has the staining properties of fibrin such as phosphotungstic acid haematoxylin (PTAH) stain. It is encountered in various examples of immunologic tissue injury (for example,In autoimmune vasculitis, autoimmune diseases,

Arthus reaction etc), arterioles in hypertension, peptic ulcer etc.

Microscopically:

Fibrinoid necrosis is identified by brightly eosinophilic, hyaline-like deposition in the vessel wall. Necrotic focus is surrounded by nuclear debris of neutrophils (leucocytoclasis). Local haemorrhage may occur due to rupture of the blood vessel.

Morphology of Irreversible Cell Injury:

Necrosis Cell death is a state of irreversible cell injury. Examples are autolysis, necrosis and apoptosis.

• Term autolysis or self-digestion is generally used for post-mortem changes in tissues.
• Prototype of cell death is necrosis; it is defined as a localised area of death in living tissue and is accompanied by inflammatory reaction (vital reaction).
• Coagulative necrosis is caused by sudden cessation of blood flow (ischaemic necrosis) for example,Infarcts of the heart, kidney, and spleen, or occurs by reduced supply of blood from
  other causes.
• Liquefactive necrosis also occurs due to ischaemic injury and bacterial or fungal infections but the hydrolytic enzymes in tissue degradation have a dominant role in causing semifluid materialfor example, Infarct brain and abscess cavity.
• Caseous necrosis combines features of both coagulative and liquefactive necrosis.
• It is found in the centres of foci of tuberculous infections and is accompanied by granulomatous inflammation.
• Fat necrosis is seen in the breast and acute pancreatitis.
• Fibrinoid necrosis occurs due to immunologic tissue injury for example,Hypersensitivity vasculitis