Pathology (Cell Adaption & Injury) Notes PDF 2024-2025 by Dr. Abeer Ali

3rd Stage Pathology Dr. Abeer Ali 2024-2025...

3rd Stage Pathology Dr. Abeer Ali 2024-2025 Lectures 1 and 2 Cellular adaptation, cell injury and cell death Cellular responses to stress and noxious stimuli Cells actively interact with their environment, constantly adjusting their structure and function to accommodate changing demands and stresses. The intracellular environment of cells is normally regulated such that it remains fairly constant, a steady state known as homeostasis (the ability of the cell to maintain a dynamically stable internal state). When cells are exposed to stress or pathological stimuli, cells may adapt, or become injured reversibly and recover, or irreversibly damaged and die. 1.Adaptation: Aims to achieve a new steady state preserving viability and function. 2.Cell injury: Develops if the adaptive capability of the cell is exceeded or the external stress is inherently harmful. If the stress is mild or transient, injury is reversible, and cells return to their stable baseline; however, if the stress is severe, persistent and rapid in onset, it results in irreversible injury and 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. 1.Physiologic adaptations (responses of cells to normal stimulation by hormones or endogenous chemical mediators or the demands of mechanical stress). 2.Pathologic adaptations (responses to stress that allow cells to modulate their structure and function and thus escape injury, but at the expense of normal function) *Physiologic and pathologic adaptations can take several distinct forms: (Hypertrophy, atrophy, hyperplasia and metaplasia) 1.Hypertrophy: is an increase in the size of cells resulting in an increase in the size of the organ. In pure hypertrophy there are no new cells, only larger cells with increased amounts of structural proteins and organelles. 1 Hypertrophy can be physiologic or pathologic and is caused by increased functional demand or growth factor or hormonal stimulation. *Physiologic hypertrophy E.g. Enlargement of the uterus during pregnancy due to estrogen stimulated smooth muscle hypertrophy and hyperplasia. E.g. Enlarged size of skeletal muscles in athletes in response to increased workload. *Pathologic hypertrophy E.g. Left ventricular hypertrophy in systemic hypertension or aortic stenosis (to generate the required higher contractile force as a result of persistently increased workload) 2. Hyperplasia: is an increase in the number of cells in an organ that results from increased proliferation, either of differentiated cells or progenitor cells. It occurs in tissues that contain cell populations capable of replication. In both physiologic and pathologic hyperplasia, cellular proliferation is stimulated by hormones or growth factors. *Physiologic hyperplasia: E.g. Hormonal hyperplasia of the female breast at puberty and pregnancy. E.g. compensatory hyperplasia (residual tissue grows after removal or loss of part of organ), e.g. if part of liver resected, it can return to normal size. *Pathologic hyperplasia: E.g. Endometrial hyperplasia due to increased estrogenic stimulation (common cause of abnormal menstrual bleeding). E.g. Benign prostatic hyperplasia 3. Atrophy: is shrinkage in the size of cells by the loss of cell substance. When a sufficient number of cells are involved, the entire tissue or organ is reduced in size. It results from decreased protein synthesis and increased protein degradation Causes of atrophy: 1. Decreased workload (e.g., immobilization of a limb to permit healing of a fracture) 2. Loss of innervation (e.g. poliomyelitis and spinal cord injury) 3. Diminished blood supply (e.g. arterial obstruction by atherosclerosis) 4. Inadequate nutrition (e.g. starvation) 5. Loss of endocrine stimulation (e.g. postmenopausal endometrial atrophy) 6. Aging (senile atrophy) 2 4. Metaplasia: is a change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type ( better able to withstand the adverse environment). It is thought to arise by the reprogramming of stem cells. *Epithelial metaplasia: E.g. that occurs in respiratory epithelium of habitual cigarette smokers ( normal ciliated columnar epithelial cells of the trachea and bronchi often are replaced by stratified squamous epithelium that may be able to survive chemicals in cigarette smoke). E.g. Bilharzial infection of urinary bladder can cause metaplasia of transitional epithelium into squamous epithelium. E.g. Metaplasia of stratified squamous epithelium of the lower esophagus to gastric or intestinal-type columnar epithelium, in case of chronic gastric reflux. *Mesenchymal metaplasia: e.g. bone is occasionally formed in soft tissues, particularly in foci of injury. Stimuli that induce epithelial metaplastic changes, if persistent, may predispose to malignant transformation. Cell injury Causes of cell injury 1. Hypoxia and ischemia: Hypoxia (oxygen deficiency) and ischemia (reduced blood supply) , are among the most common causes of cell injury. Hypoxia affects aerobic oxidative respiration and the generation of ATP. Causes of hypoxia: a. The most common cause of hypoxia is ischemia due to arterial obstruction. b. Inadequate oxygenation of the blood, as diseases of the lung c. Reduction in oxygen-carrying capacity of blood (e.g. anemia, carbon monoxide poisoning). 2. Chemical agents: E.g. air pollutants, insecticides, CO, cigarette smoke, ethanol, glucose, salt, water, oxygen and drugs. Many drugs in therapeutic doses can cause injury in a susceptible patient or if used excessively or inappropriately. 3. Infectious agents: All infectious pathogens ( viruses, bacteria, fungi and parasites) can injure cells by e.g. producing toxins or stimulating harmful immune response. 3 4. Immunologic reactions: E.g. autoimmune reactions against individual’s own tissues and allergic reactions against environmental substances. 5. Genetic abnormalities: Such as chromosomal abnormalities and specific gene mutations. E.g. *congenital malformations in Down syndrome or *single amino acid substitution of hemoglobin in sickle cell anemia, *deficiency of functional proteins, such as enzymes in inborn errors of metabolism. 6. Nutritional imbalances: Excess or deficiency e.g. *Protein–calorie insufficiency, *specific vitamin deficiencies, *excessive dietary fat intake (may result in obesity and e.g. type 2 diabetes mellitus and atherosclerosis). 7. Physical agents: Trauma, extremes of temperature, radiation, electric shock and sudden changes in atmospheric pressure. 8. Aging: Aging results in impairment of replicative and repair abilities of individual cells that will diminish ability to respond to damage and end in cell death. Reversible and irreversible cell injury Cell injury results when cells are exposed to stress that exceeds the adaptative capability of the cell or the stimulus is inherently damaging. Cell injury could be reversible or irreversible cell injury (cell death) *Reversible injury: is the stage of cell injury at which the deranged function and morphology of the injured cells can return to normal if the damaging stimulus is removed (injury has not progressed to severe membrane damage and nuclear dissolution). Morphology: The 2 most consistent forms of reversible cell injury are cellular swelling and fatty change 1. Cellular swelling (hydropic change or vacuolar degeneration): is commonly seen in cell injury (cells {and intracellular organelles} become swollen because of sodium and water influx due to failure of energy-dependent ion pumps in the plasma membrane i.e. inability to maintain ionic and fluid homeostasis). Gross (macroscopical examination): When it affects many cells, it causes pallor (due to compression of capillaries) and increase in organ weight. 4 Microscopic examination: Small, clear vacuoles within the cytoplasm; these represent distended and pinched-off segments of the endoplasmic reticulum. 2. Fatty change: It is manifested by the appearance of cytoplasmic lipid vacuoles. It is principally seen in organs that are involved in lipid metabolism. Other ultrastructural changes of reversible cell injury (seen by electron microscopy): (1)Plasma membrane changes like blebbing (2) Mitochondrial swelling with phospholipid-rich amorphous densities (3) Dilation of the ER with detachment of ribosomes (4) Nuclear changes (clumping of chromatin) (5) Myelin figures (collections of phospholipids resembling myelin sheaths, that are derived from damaged cellular membranes). *Irreversible cell injury (cell death): With persistent or excessive harmful exposures, irreversible cell injury and cell death develop. Irreversible cell injury is consistently characterized by three phenomena: *the inability to restore mitochondrial function (oxidative phosphorylation and ATP generation) even after resolution of the original injury; *the loss of structure and functions of the plasma membrane and intracellular membranes; and *loss of DNA and chromatin structural integrity. Necrosis and apoptosis are the two main forms of cell death that differ in causes, mechanisms, morphology and functional consequences. Necrosis refers to the morphological changes that accompany cell death in living tissue due to loss of membrane integrity and leakage of cellular enzymes that ultimately digest the cell (effects group of cells). Necrosis stimulates local host response called inflammation, due to leakage of cell contents through damaged plasma membrane. The inflammatory response serves to eliminate the debris and start the subsequent repair process. The enzymes responsible for digestion of the cell are derived from lysosomes of the dying cells themselves or from leukocytes recruited as part of the inflammatory reaction. Morphology: Necrosis is characterized by changes in the cytoplasm and nuclei of the injured cells. 5 *Cytoplasmic changes: By light microscope, necrotic cells show 1. Increased eosinophilia (due *to increased binding of eosin to denatured cytoplasmic proteins and *to loss of basophilic ribonucleic acid (RNA) in the cytoplasm). 2. The cell may have a glassy, homogeneous appearance, mostly due to the loss of glycogen particles. 3. Vacuolated cytoplasm (moth-eaten) By electron microscopy, necrotic cells are characterized by discontinuities in plasma and organelle membranes, marked dilation of mitochondria with large amorphous densities, disruption of lysosomes, and intracytoplasmic myelin figures (that are more prominent in necrotic cells than in reversibly injured cells). *Nuclear changes: Nuclear changes assume one of three patterns, all resulting from a breakdown of DNA and chromatin (pyknosis, karyorrhexis and karyolysis). Pyknosis: is characterized by nuclear shrinkage and increased basophilia; the DNA condenses into a dark shrunken mass. Karyorrhexis: When the pyknotic nucleus undergoes fragmentation Karyolysis: Nucleus undergoes dissolution (basophilia fades due to DNase activity) In 1 to 2 days, the nucleus in a dead cell may completely disappear. Fates of necrotic cells: Necrotic cells may persist for some time or may be digested and disappear. Dead cells may be replaced by myelin figures, which are either phagocytosed or degraded into fatty acids that bind to calcium salts resulting in calcified dead cells. THANK YOU 6