HPCT_Prelim_Lec: Cell injury

Cell injury

The functional and biochemical abnormalities that occur when cells are exposed to injurious stimuli.

Cell death

One of the most crucial events in the evolution of disease in any tissue or organ.

Major organ responsible for homeostasis

Kidney.

Two types of cell injury

Reversible injury and irreversible injury.

Hypoxia

Oxygen deficiency that interferes with aerobic oxidative respiration and is a common cause of cell injury and death.

Ischemia

Loss of blood supply to a tissue due to impeded arterial flow or reduced venous drainage; the most common cause of hypoxia.

Pneumonia

A condition that can cause oxygen deficiency due to a problem involving the alveolar sacs, caused by viral or bacterial infection.

Anemia

A condition involving decreased hemoglobin that can result in inadequate oxygenation.

Carbon monoxide poisoning

A cause of inadequate oxygenation that can produce hypoxia.

Chemical/toxic agents

Agents commonly known as poisons that can cause severe cellular damage by altering membrane permeability.

Examples of toxic agents

Air pollutants, insecticides, carbon monoxide, asbestos, ethanol, and therapeutic drugs.

Infectious agents that cause cell injury

Viruses, parasites, bacteria, and fungi.

Immunologic reactions

Immune responses that can result in cell and tissue injury.

Autoimmune reaction

An immune reaction directed against the body's own tissues.

Allergic reaction

An immune reaction against environmental substances.

Immunodeficiency

A condition associated with impaired immune function that may contribute to cell injury.

Genetic defects

Congenital or inherited abnormalities that can cause cell injury.

Sickle cell anemia

A genetic disorder involving a single amino acid substitution in hemoglobin S.

Inborn errors of metabolism

Genetic defects involving deficiency or abnormality of functional proteins.

Nutritional imbalance

A cause of cell injury involving nutritional deficiencies such as protein-calorie insufficiency and vitamin deficiencies.

Physical agents that cause cell injury

Trauma, extremes of temperature, radiation, electric shock, and sudden changes in atmospheric pressure.

Aging

Leads to alterations in the replicative and repair abilities of cells and tissues and diminishes their ability to respond to damage.

Morphologic changes of cell injury

Structural alterations in damaged cells that may appear after cellular function has already been lost.

Reversible cell injury

Cell injury in which the cell can potentially recover if the injurious stimulus is removed.

Two consistent morphologic correlates of reversible cell injury

Cellular swelling and fatty change.

Cellular swelling

Result of failure of energy-dependent ion pumps in the plasma membrane, causing inability to maintain ionic and fluid homeostasis.

Hydropic change

Accumulation of water in the cell; also called vacuolar degeneration.

Vacuolar degeneration

Another name for hydropic change.

Cause of hydropic change

Decreased ATP production, often due to hypoxia and decreased aerobic respiration in mitochondria.

Fatty change

Appearance of small or large lipid vacuoles in the cytoplasm, occurring in hypoxic, toxic, or metabolic injury.

Cells commonly affected by fatty change

Cells participating in fat metabolism, particularly hepatocytes and myocardial cells.

Plasma membrane changes in reversible injury

Blebbing, blunting or distortion of microvilli, and loosening of intercellular attachments.

Mitochondrial changes in reversible injury

Swelling and appearance of phospholipid-rich amorphous densities.

Endoplasmic reticulum changes in reversible injury

Dilation of the ER with detachment of ribosomes and dissociation of polysomes.

Nuclear change in reversible injury

Clumping of chromatin.

Myelin figure

Phospholipid masses derived from damaged cellular membranes.

Factors determining cellular response to injury

Type, duration, and severity of the injury.

Factors determining consequences of an injurious stimulus

Type, status, adaptability, and genetic makeup of the injured cell.

Principal targets of cell injury

Mitochondria, calcium homeostasis, cellular and lysosomal membranes, DNA, and proteins.

Mitochondria in cell injury

Important because of their ability to generate ATP and reactive oxygen species under pathological conditions.

ATP depletion

Major mechanism of cell injury caused by reduced oxygen/nutrient supply, mitochondrial damage, or some toxins.

Major causes of ATP depletion

Reduced oxygen and nutrient supply, mitochondrial damage, and actions of some toxins.

Calcium influx

Increased cytosolic Ca2+ that activates enzymes capable of causing cellular damage.

Phospholipases

Enzymes activated by increased Ca2+ that cause membrane damage.

Proteases

Enzymes activated by increased Ca2+ that break down membrane and cytoskeletal proteins.

Endonucleases

Enzymes activated by increased Ca2+ that cause DNA and chromatin fragmentation.

ATPases

Enzymes activated by increased Ca2+ that hasten ATP depletion.

Effect of increased intracellular Ca2+ on apoptosis

May induce apoptosis by directly activating caspases and increasing mitochondrial permeability.

Necrosis

Cell death associated with loss of membrane integrity and leakage of cellular contents.

Cytoplasmic changes in necrosis

Increased eosinophilia, homogeneous appearance, prominent myelin figures, and vacuolated “moth-eaten” cytoplasm.

Pyknosis

Nuclear shrinkage with increased basophilia caused by DNA condensation into a solid, shrunken mass.

Karyorrhexis

Fragmentation of the pyknotic nucleus/chromatin.

Karyolysis

Fading or dissolution of nuclear chromatin due to DNase activity.

Typical sequence of nuclear changes in necrosis

Pyknosis → karyorrhexis → karyolysis.

Fate of necrotic cells

They may be digested by enzymes, disappear, form myelin figures, be phagocytosed, degraded into fatty acids, or become calcified.

Coagulative necrosis

Usually results from sudden interruption of blood supply to an organ, especially the heart; necrotic cell outlines are preserved but nuclei are lost.

Liquefactive necrosis

Characterized by digestion, softening, and liquefaction of tissue.

Liquefactive necrosis in the CNS

Characteristically results from ischemic injury to the central nervous system.

Liquefactive necrosis in infection

Can occur in suppurative infections associated with pus formation.

Fat necrosis

Necrosis caused by trauma to tissue with high fat content.

Saponification

Formation of calcium soaps from fatty acids released during fat necrosis.

Dystrophic calcification

Calcification occurring in nonliving tissue.

Metastatic calcification

Calcification occurring in living tissue.

Caseous necrosis

A type of necrosis with a cheese-like, white appearance; typical of tuberculosis.

Microscopic appearance of caseous necrosis

Amorphous eosinophilic material.

Gangrenous necrosis

Necrosis due to vascular occlusion.

Wet gangrene

Gangrene complicated by bacterial infection, resulting in superimposed liquefactive necrosis.

Dry gangrene

Gangrene consisting of coagulative necrosis without liquefactive necrosis.

Fibrinoid necrosis

A special form of necrosis, usually associated with immune reactions involving antigen-antibody complexes deposited in arterial walls.

Microscopic appearance of fibrinoid necrosis

Bright pink, amorphous appearance on H&E due to immune complexes and leaked fibrin.

Apoptosis

A pathway of cell death in which cells activate enzymes that degrade their own nuclear DNA and nuclear/cytoplasmic proteins.

Physiologic apoptosis

Elimination of cells that are no longer needed to maintain a constant number of cells in tissues.

Apoptosis during embryogenesis

Programmed destruction of cells during development.

Apoptosis of neutrophils

Elimination of neutrophils after they have served their useful purpose in an acute inflammatory response.

Apoptosis of self-reactive lymphocytes

Eliminates potentially harmful lymphocytes to prevent reactions against the body's own tissues.

Cytotoxic T-cell-induced apoptosis

A defense mechanism against viruses and tumors that kills virus-infected and neoplastic cells.

Pathologic apoptosis

Eliminates cells that are genetically altered or injured beyond repair.

DNA damage causing apoptosis

Can result from radiation, cytotoxic anticancer drugs, extreme temperatures, and hypoxia.

Misfolded proteins and apoptosis

Excessive accumulation of misfolded proteins in the ER causes ER stress and can lead to apoptosis.

Apoptosis in certain infections

Can occur in viral infections such as adenovirus and HIV infections and through host immune responses such as viral hepatitis.

Pathologic atrophy and apoptosis

Can occur in parenchymal organs after duct obstruction, including the pancreas, parotid gland, and kidney.

Mitochondrial/intrinsic pathway

An apoptosis pathway responsible for apoptosis in most physiologic and pathologic situations.

Death receptor/extrinsic pathway

An apoptosis pathway responsible for elimination of self-reactive lymphocytes and damage by cytotoxic T lymphocytes.

Autopsy

External and internal examination of the body after death.

Main purpose of autopsy

To ascertain the cause of death.

Manner of death categories

Natural, accident, suicide, homicide, and undetermined.

Natural death

Death resulting from body function failure due to age, illness, or disease.

Accidental death

Death that is unintentional.

Homicide

One individual takes the life of another intentionally or through a negligent or reckless act.

Undetermined death

Death in which the pathologist cannot determine the manner even after examinations and toxicological tests.

Clinical autopsy purposes

Confirm diagnosis, discover findings, academic interest, teaching, and research.

Medico-legal autopsy purposes

Identify the body, ascertain cause of death, determine injuries, determine presence of poison, estimate expectation of life for insurance, and interpret injuries.

Virchow autopsy technique

Organs are removed one by one from the cranial cavity down to the abdominal organs.

Virchow technique advantage

Good for demonstrating pathological changes in individual organs.

Virchow technique limitation

Relationships between various organs may be difficult to interpret.

Letulle autopsy technique

Organs are removed en masse and subsequently dissected into organ blocks.

Letulle technique advantage

Preserves vascular supply and relationships between organs and is fast.

Gohn autopsy technique

Thoracic/cervical organs, abdominal organs, and urogenital organs are removed in functionally related blocks.

Gohn technique advantage

Preserves anatomical relationships and is useful for academic or research purposes.

Rokitansky autopsy technique

In situ dissection combined with en bloc removal.