Morpholgy of irreversible cell injury

Morphology of Irreversible Cell Injury

CELL DEATH
Autolysis
Necrosis
Apoptosis

CELL DEATH
Autolysis
Disintegration of cell by its own hydrolytic enzyme liberated from lysosomes
It can occur in living body surrounded by inflammatory reaction or postmortem change where complete absence of inflammatory response
It is rapid in some tissues e.g. Pancreas, gastric mucosa
Intermediate in tissues e.g. Heart, liver & kidney
It is slow in fibrous tissue

Necrosis Cell death / death of group of cells Denaturation of protein Lysosomal enzymes Host response Autolysis Immigrant leukocytes Lysosomal enzymes Necrosis

NECROSIS
It is focal death of cell along with degeneration of tissue by hydrolytic enzyme liberated by cells
There are 5 types of Necrosis-
1) Coagulative necrosis
2) liquification (colliquative) necrosis
3) Caseous necrosis
4) Fat necrosis
5) Fibrinoid necrosis
6) Gangrenous necrosis (gangrene)

Necrosis
Causes of Necrosis
Ischaemia (reduced / absent blood supply)
Bacterial toxins
Immune injury
Viral infections
Chemical poisons / drugs
Physical agents

Necrosis
Morphological features of necrosis
Cytoplasmic changes
Eosinophilia, glassy homogeneous
Vacuolated
Nuclear changes
Karyolysis
Pyknosis
Karyorrhexis
Ultrastructural changes

Coagulative Necrosis
It is most common type
Causes- mostly due to sudden cessation of blood flow & less often from bacterial & chemical agents. Organs affected are heart, kidney & spleen
Appearance of affected organ-
Grossly-:
In early stage pale firm & slightly swollen with progression becomes yellowish softer & shrunken
Microscopically-
Cells swollen more eosinophillic conversion of normal cell to tombstone i.e. outline retained but the nuclear details are lost. Those results from
Denaturation of proteins &
Enzymatic digestion of cell

Liquefaction (colliquative) Necrosis
Causes- It occurs due to ischemic & hypoxic injury & bacterial agents as well as degradation tissue by action of hydrolytic enzymes
Organs affected- infarcts of brain, Abscess cavity
Appearance-
Grossly-
Affected organ is soft with liquefied center containing necrotic debris
Microscopically-
Macrophages filled with phagocytosed material, cell wall formed by proliferating capillaries, inflammatory cells & gliosis in case of brain & proliferating fibroblast in case of abscess cavity

Caseous Necrosis
Found in the center of foci of tubercular infection it has combine features of both above necrosis
Appearance-
Grossly-
Dry cheese, soft granular & yellowish appearance
Microscopically-
Foci are eosinophilic, structure less & contain granular debris
Surrounding tissue shows inflammatory reaction consisting of epitheloid cells with interspersed giant cells of langerhans, foreign body & lymphocytes

Fat Necrosis
Occurs in two types-
1)Acute pancreatic necrosis-
there is liberation of pancreatic lipase from injured or inflammed tissue results in necrosis
2)Traumatic fat necrosis-
Damage adipose cells assume cloudy appearance when only free fatty acids complex with Ca+ to form calcium soaps
Appearance –
Grossly- Yellowish white & firm deposits
Chalky white appearance
Microscopically- Cloudy appearance & surrounded by inflammatory tissue
Formation of calcium soap as amorphous granular & basophilic material

Fibrinoid Necrosis
Characterised by deposition of fibrin like material which has staining properties of fibrin
It occurs in immunologic tissue injury
E.g. Immune complex vasculitis, Autoimmune diseases
Appearance –
Microscopically –
Identified by brightly eosinophilic hyaline like deposition in vessel wall or on luminal surface of peptic ulcer
Local hemorrhage occur due to rupture of these blood vessels

GANGRENE
It is form of necrosis of tissue with superadded putra function. There are 3 types of gangrene:
Dry gangrene
Wet gangrene
Gas gangrene
1) Dry gangrene-Begins in distal part of limb due to ischemia occurs in toes & feet of old patient
Causes - Atherosclerosis, trauma, ergot poisoning. Line of separation present between gangrenous & viable part
Pathologic changes- Dry, shrunken & dark black due to liberation of Hb from hemolysed RBCs acted by H 2 S produced by bacteria result in iron sulphied
Histologically- Line of separation consist of inflammatory tissue

Wet Gangrene
Occurs in moist tissues & organs such as mouth, bowel, lungs, cervix, vulva etc. diabetic foot is an another example of wet gangrene
It develops rapidly due to the blockage of venous & less commonly due to arterial flow from thrombosis & embolism
There is no line of demarcation between the gangrenous & viable part
Pathologic changes –
organ becomes soft, swollen, putrid, rotten, dark
Histologically-
Coagulative necrosis with shifting of affected part is with blood
There is ulceration of mucosa & intense inflammatory infiltration

Gas Gangrene
It is the special form of gangrene caused by gas forming clostridia which gain entry in tissues through open contaminated wound
Clostridia produces various toxins which produce necrosis, edema locally & also producing profound systemic manifestation
Pathologic changes-
Area is swollen edematous, painful & crepitant due to accumulation of gas bubbles within the tissues
Affected tissue become dark, black, & foul smelling

APOPTOSIS
Programmed death of cell. In this process normal, abnormal or unwanted cells are eliminated. It is different from necrosis.
Apoptosis in health-
1) Metamorphosis of tadpole to frog
2) Loss of auto reactive response of T-cells in thymus preventing autoimmune attack
3) Atrophy & involution often in withdrawal of hormones
Apoptosis in disease-
1) Irradiation
2) Virus infection
3) Action of cytotoxic T cells e.g. in rejection of transplant organ
4) in tumour apoptosis & proliferation rate control the rate of tumour growth

Apoptosis is biological Phenomenon
Eliminate cells no longer needed
Embryogenesis
Hormone dependant involution in adults
Cell deletion in intestinal crypt epithelia
Death of cells that have served their purpose
Cell death induced by cytotoxic T cells
A) Physiologic Situations

B) Pathologic conditions
Cell death by injurious stimuli
Cell injury in viral diseases
Pathologic atrophy in parenchymal organs after duct obstruction
Cell death in tumours

Morphology
Cell shrinkage
Chromatin condensation
Cytoplasmic blebs & apoptotic bodies
Phagocytosis of apoptic bodies by the macrophages
No inflammatory reactions occurs

APOPTOSIS SIGNALS Mitochondria- dependent apoptosis Caspase- dependent apoptosis Death Receptor- dependent apoptosis Caspase- dependent apoptosis Caspase- in dependent apoptosis Caspase- in dependent necrosis

Figure: Mechanisms of apoptosis. Labeled (1) are some of the major inducers of apoptosis. These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand), withdrawal of growth factors or hormones, and injurious agents (e.g., radiation). Some stimuli (such as cytotoxic cells) directly activate execution caspases (right). Others act by way of adapter proteins and initiator caspases, or by mitochondrial events involving cytochrome c. (2) Control and regulation are influenced by members of the Bcl-2 family of proteins, which can either inhibit or promote the cell's death. (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins. This results in a cascade of intracellular degradation, including fragmentation of nuclear chromatin and breakdown of the cytoskeleton. (4) The end result is formation of apoptotic bodies containing intracellular organelles and other cytosolic components; these bodies also express new ligands for binding and uptake by phagocytic cells.

Figure The intrinsic (mitochondrial) pathway of apoptosis. Death agonists cause changes in the inner mitochondrial membrane, resulting in the mitochondrial permeability transition (MPT) and release of cytochrome c and other pro-apoptotic proteins into the cytosol, which activate caspases

Figure The extrinsic (death receptor-initiated) pathway of apoptosis, illustrated by the events following Fas engagement (see text).

Molecular mechanism of Apoptosis Initiators of apoptosis Regulators of apoptosis (BCl-2, others Programmed cell death FAS receptor activation (cytotoxic T-cell) DNA damage (radiation, chemotherapy, free radicals) Ceramide APOPTOSIS Mitochondrial Injury DNA damage Caspases TP53 (p53) BAX PHAGOCYTOSIS

Necrosis vs apoptosis Feature Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis Karyorrhexis karyolysis Fragmentation into nucleosome sized fragments Plasma membrane Disrupted Intact: altered structure esp. orientation of lipids

Necrosis vs apoptosis Feature Necrosis Apoptosis Cellular contents Enzymatic digestion: may leak out of cell Intact: may be released in apoptotic bodies Adjacent inflammation Frequent No Physiologic or pathologic role Invariably pathologic (culmination of irreversible cell injury) Often physiologic means of eliminating unwanted cells: may be pathologic after some forms of cell injury, esp. DNA damage

Dystrophic In dying/dead tissues Normal serum levels of calcium No alterations in calcium metabolism Examples – Psammoma bodies in papillary cancers, Asbestos bodies Can cause organ dysfunction (heart valves, Atherosclerosis) Metastatic In normal tissues Always results from hypercalcemia (in hyperparathyroidism, bone damage or diseases, William’s syndrome Disturbance in calcium metabolism
Morphology = Basophilic, amorphous or granular appearance intracellular, extracellular or both in H & E stained sections
P athologic Calcifications
Abnormal tissue deposition of calcium salts along with smaller amounts of iron, magnesium etc.
Two forms = 1. Metastatic calcification & 2. Dystrophic calcification
Morphology = Basophilic, amorphous or granular appearance intracellular, extracellular or both in H & E stained sections

HEALING
It is final stage of response to tissue injury
The capacity of tissue of regeneration depends upon its proliferative ability, on the type & on the severity of damage
3 broad groups of cell are considered in the cell cycle
1)Labile cells- Normally continues turnover
e.g. covering epithelium & bone marrow
Changes of regeneration are excellent
2)permanent cells- Not capable to proliferation
e.g. neuron in adult
Healing by scaring (no regeneration)
3)Stable cells- Normally little little proliferation but remain capable of more rapid cell division of following injury
e.g. liver, renal tubular epithelium

HEALING
Changes of regeneration are good
Regeneration involves 2 processes
a) Proliferation of surviving cells to replace the lost tissue
b) Migration of surviving cells into the vacant space
The factors which control the healing & repair are complex
They include variety of growth factors
e.g. epidermal growth factor in case of specialized cell regeneration
Transforming growth factor (TGF)- β in case of fibroblast
Vascular growth factor (VGF) in case of new capillary formation

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Morpholgy of irreversible cell injury

by Seema Thakur

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