Lec- 2 Cell Injury, Cell Death, and Adaptation.docx

Cell Injury, Cell Death, and Adaptation ======================================= Lec -- 2 *د. مصطفى السعدي* ========================== **[Cellular responses to stress and injurious stimuli:]** Cells are the active part in their environment, maintaining normal homeostasis (staying stable) and adjus...

Cell Injury, Cell Death, and Adaptation ======================================= Lec -- 2 *د. مصطفى السعدي* ========================== **[Cellular responses to stress and injurious stimuli:]** Cells are the active part in their environment, maintaining normal homeostasis (staying stable) and adjusting their structure and function to accommodate any changes or extracellular stresses. Any physiologic stresses or pathologic stimuli on the cells, they can undergo **[adaptation]**, achieving a new steady state and preserving viability and function. Types of adaptation are: **[Hypertrophy], [Hyperplasia], [Atrophy] and [Metaplasia*.*]** If the adaptive capability is exceeded or if the external stress is harmful, **[cell injury]** develops. **[Cell injury is of two type:]** 1. **Reversible injury:** The cells return to a stable state. 2. **Irreversible injury:** Severe or persistent stress results in **[cell death]**. **[Cellular adaptations to stress:]** **[Adaptations]** are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment. Adaptation could be: 1. **[Physiologic adaptations]**: Responses of cells to **[normal stimulation]** by hormones or endogenous chemical materials, e.g.: the hormone-induced enlargement of the breast and uterus during pregnancy. 2. **[Pathologic adaptations]**: Responses to **[stress]** that allow cells to modulate their structure and function and thus escape injury. **[Types of adaptations: ]** 1. **[​Hypertrophy]:** An increase in the size of cells resulting in increase in the size of the organ. There are no new cells, just bigger cells, enlarged by an increased amount of structural proteins and organelles. Hypertrophy occurs when cells are incapable of dividing. a. **Physiologic hypertrophy**: e.g.: in skeletal muscle cells of weight lifter. b. **Pathologic hypertrophy**: e.g.: cardiac enlargement that occurs with hypertension or aortic valve disease. 2. **[​Hyperplasia:]** An increase in number of cells that occur if the cell population is capable of dividing. c. **Hormonal hyperplasia**: e.g.: The proliferation of the glandular epithelium of the female breast at puberty and during pregnancy. d. **Compensatory hyperplasia**: occurs when a portion of the tissue is removed or diseased. e.g.: when a liver is partially resected, mitotic activity in the remaining cells begins to restore the liver to its normal weight. e. **Pathologic hyperplasia**: caused by excessive hormonal or growth factor stimulation. e.g, endometrial hyperplasia that occurs due to disturbances in the balance between estrogen and progesterone hormone causing abnormal menstrual bleeding. Another example is connective tissue hyperplasia in wound healing in which proliferating fibroblasts and blood vessels aid in repair. 3. **[​Atrophy:]** Shrinkage in the size of the cell by the loss of cell substance*.* Atrophic cells may have diminished function but they are not dead. Causes of atrophy include a decreased workload, e.g., immobilization of a limb to permit healing of a fracture, loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine stimulation, and aging (senile atrophy). 4. **[​Metaplasia:]** Change in which one adult cell type (epithelial or mesenchymal) by another adult cell type, e.g. in cigarette smokers, the normal ciliated columnar epithelial cells of the respiratory epithelium is replaced by stratified squamous epithelial cells. **[Overview of cell injury and cell death]** Cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents or suffer from intrinsic abnormalities. Injury may progress through a reversible stage and culminate in cell death. 1. **[​Reversible cell injury:]** In early stages or mild forms of injury the functional and morphologic changes are reversible if the damaging stimulus is removed. At this stage, although there may be significant structural and functional abnormalities, the injury has typically not progressed to severe membrane damage and nuclear dissolution. 2. **[Cell death]***:* With continuing damage, the injury becomes irreversible, at which time the cell cannot recover and it dies. **[Types of cell death:]** 1. **[Necrosis:]** Occur when the damage to membranes is severe, enzymes leak out of lysosomes, enter the cytoplasm, and digest the cell*.* Cellular contents also leak out through the damaged plasma membrane and result in a host reaction (inflammation). Necrosis results from ischemia, exposure to toxins, various infections, and trauma. 2. **[Apoptosis]** occurs when a cell is deprived of growth factors or the cell\'s DNA or proteins are damaged beyond repair, the cell kills itself by another type of death, called apoptosis*,* which is characterized by nuclear dissolution without complete loss of membrane integrity. Apoptosis is an active, energy-dependent, tightly regulated type of cell death that is seen in some specific situations. Whereas necrosis is always a pathologic process, apoptosis serves many normal functions and is not necessarily associated with pathologic cell injury. **[Causes of cell injury]** 1. **Hypoxia:** It is oxygen deficiency**,** caused by ischemia which is loss of blood supply in a tissue. 2. **Chemical Agents:** Include air pollutants, insecticides, CO, asbestos, alchohol and therapeutic drugs if used excessively or inappropriately. 3. **Infectious Agents:** Viruses, rickettsia, bacteria, fungi, protozoans and tapeworms. 4. **Immunologic Reactions:** Although the immune system defends the body against pathogenic microbes, immune reactions can also result in cell and tissue injury like autoimmune reactions against one\'s own tissues and allergic reactions against environmental substances. 5. **Genetic Defects:** Genetic defects can result in pathologic changes like congenital malformations associated with Down syndrome and sickle cell anemia. 6. **Nutritional Imbalances:** Like protein-calorie insufficiency and specific vitamin deficiencies. Excesses of nutrition are also important causes of cell injury, e.g., obesity increases the risk for type 2 diabetes mellitus, and diets rich in animal fat lead to the development of atherosclerosis. 7. **Physical Agents:** Trauma, extremes of temperatures, radiation, electric shock, and sudden changes in atmospheric pressure all have wide-ranging effects on cells. 8. **Aging:** Cellular senescence leads to alterations in replicative and repair abilities of individual cells and tissues. All of these changes result in a diminished ability to respond to damage and, death of cells and of the organism. **[The morphology of cell injury: ]** **[A- Morphology of reversible Injury:]** 1. **[Cellular swelling]** due to failure of energy-dependent ion pumps in the plasma membrane, leading to an inability to maintain ionic and fluid homeostasis. Microscopic examination may reveal small, clear vacuoles within the cytoplasm; these represent distended and pinched-off segments of the endoplasmic reticulum. This pattern of nonlethal injury is sometimes called **hydropic change** or **vacuolar degeneration.** 2. **[Fatty change]** occurs in hypoxic injury and various forms of toxic or metabolic injury. It is manifested by the appearance of small or large lipid vacuoles in the cytoplasm. It occurs mainly in cells involved in and dependent on fat metabolism, such as Hepatocytes in the liver and myocardial cells in the heart. **[B- Morphology of irreversible Injury: Necrosis]** **[Necrosis]** is a series of changes that accompany cell death, resulting from the digestive action of enzymes on injured cells. Necrotic cells are unable to maintain membrane integrity, and their contents often leak out. **[Morphology]** 1. Increased eosinophilia**:** i.e., pink staining from the eosin dye, the \"E\" in \"H&E\" due to increased binding of eosin to denatured cytoplasmic proteins and to loss of the basophilia that is normally imparted by the ribonucleic acid (RNA) in the cytoplasm (basophilia is the blue staining from the hematoxylin dye, the \"H\" in \"H&E\"). 2. The cell may have a more glassy homogeneous appearance than viable cells, because of the loss of glycogen particles. 3. When enzymes have digested the cytoplasmic organelles, the cytoplasm becomes vacuolated and appears motheaten. 4. Dead cells may be replaced by large, whorled phospholipid masses which then either phagocytized by other cells or degraded into fatty acids which will be calcified resulting in the appearance of calcified dead cells. 5. Nuclear changes occur due to breakdown of DNA and chromatin and it include: a. K**aryolysis:** The basophilia of the chromatin may fade, secondary to deoxyribonuclease (DNase) activity. b. **Pyknosis: N**uclear shrinkage and increased basophilia; the DNA condenses into a solid shrunken mass. c. K**aryorrhexis:** The pyknotic nucleus undergoes fragmentation and then completely disappears.  Morphologic changes in reversible and irreversible cell injury (necrosis). **A,** Normal kidney tubules with viable epithelial cells. **B,** Early (reversible) ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells. **C,** Necrotic (irreversible) injury of epithelial cells, with loss of nuclei and fragmentation of cells and leakage of contents. **[Patterns of Tissue Necrosis]** 1. **Coagulative necrosis**: The component cells are dead but the basic tissue architecture is preserved for at least several days. Coagulative necrosis is characteristic of **infarcts** (areas of ischemic necrosis) in all solid organs except the brain. 2. **Liquefactive necrosis: S**een in focal bacterial or, occasionally, fungal infections, because microbes stimulate the accumulation of inflammatory cells and the enzymes of leukocytes will digest (\"liquefy\") the tissue and it occur within the dead cells of the central nervous system. Liquefaction completely digests the dead cells, resulting in transformation of the tissue into a liquid viscous mass. If the process was initiated by acute inflammation, the material is frequently creamy yellow and is called **pus**. 3. G**angrenous necrosis:** Applied to a limb, generally the lower leg, that has lost its blood supply and has undergone coagulative necrosis involving multiple tissue layers. When bacterial infection is superimposed, coagulative necrosis is modified by the liquefactive action of the bacteria and the attracted leukocytes, so-called **wet gangrene**. 4. **Caseous necrosis:** The term \"caseous\" (cheese-like) is derived from the friable yellow-white appearance of the area of necrosis. The necrotic focus appears as a collection of fragmented or lysed cells with an amorphous granular appearance. Unlike coagulative necrosis, the tissue architecture is completely lost and cellular outlines cannot be seen. Caseous necrosis is often enclosed within a distinctive inflammatory border; this appearance is characteristic of a focus of inflammation known as a **granuloma**. It is seen most often in foci of tuberculous infection. 5. **Fat necrosis**: Focal areas of fat destruction, resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. Histologically, the foci of necrosis contain shadowy outlines of necrotic fat cells with basophilic calcium deposits, surrounded by an inflammatory reaction. 6. **Fibrinoid necrosis:** Seen in immune reactions involving blood vessels. This pattern of necrosis is prominent when complexes of antigens-antibodies are deposited in the walls of arteries together with fibrin that has leaked out of vessels; result in a bright pink and amorphous appearance in H&E stains, called \"fibrinoid\" (fibrin-like).