Irreversible cellular injury. Necrosis – types. Apoptosis.

Synopsis

Irreversible cellular injury – cellular death.

Clinical - anatomical forms of necrosis.

Apoptosis- programmed cell death.

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

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 damagedbeyond repair, the cell kills

physiologic and pathologic

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.

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

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

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)

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

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

Coagulative necrosis

Macroscopy Necrotic areas –

whitish, firm, protruding above surrounding tissue

Microscopy The necrotic cells -

eosinophilia Shadows of structures

Ren -glomerules, tubules

Nuclear fragments

Coagulative necrosis (heart) the cellular appearance looks “cooked” and cell

structures and delineation is lost

Necrosis myocardii

Coagulative necrosis (ren) the cellular appearance looks “cooked” and cell

structures and delineation is lost

Necrosis renis

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

Necrosis pulmonis (Bronchopneumonia tbc

caseosa)

Necrosis lymphonodi (Tuberculosis lymphonodi)

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.

Liquefactive necrosis (brain)

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

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

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

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

Sequestrum A fragment of dead

tissue, that has separated from healthy tissue as a result of injury or disease Bone – osteomyelitis lung

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)

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

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

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

Features of Necrosis and Apoptosis

Feature Necrosis Apoptosis

Cell size Enlarged (swelling)

Reduced (shrinkage)

Nucleus Pyknosis → karyorrhexis → karyolysis

Fragmentation into nucleosome-size fragments

Plasmamembrane

Disrupted Intact; altered structure

Cellular contents

Enzymatic digestion; mayleak out of cell

Intact; may be released in apoptotic bodies

Adjacent inflammation

Frequent No

Physiologic/ Pathologicrole

Invariablypathologic

Often physiologic, may be pathologic after someforms of cell injury (DNA damage)

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

“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 corticosteroid destruction of lymphocytes

“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