L 29 - Cell Adaptations to Stress PDF

29 CELL ADAPTATIONS TO STRESS ILOs By the end of this lecture, students will be able to 1. Compare adaptive responses as regards Etiology, pathogenesis, and morphology. 2. Classify adaptive responses into physiological or pathological and reversible or irreversible....

29 CELL ADAPTATIONS TO STRESS ILOs By the end of this lecture, students will be able to 1. Compare adaptive responses as regards Etiology, pathogenesis, and morphology. 2. Classify adaptive responses into physiological or pathological and reversible or irreversible. 3. Relate adaptive responses to most common corresponding clinical conditions. Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment. Adaptations may take several distinct forms; hypertrophy, hyperplasia, atrophy and metaplasia. 1. Cells capable of division may respond to stress by undergoing both hyperplasia and hypertrophy, whereas nondividing cells as myocardial fibers increase tissue mass due to hypertrophy only. Hypertrophy and hyperplasia may coexist, occur due to the same triggers and both contributing to increased organ size. 2. If the limits of adaptive responses are exceeded or if cells are exposed to damaging insults, deprived of critical nutrients, or compromised by mutations that affect essential cellular functions, a sequence of events follows that is termed cell injury, whether reversible or irreversible. 1. Hypertrophy: Hypertrophy is an increase in the size of cells that results in an increase in the size of the affected organ. The hypertrophied organ has no new cells, just larger cells. Pathogenesis: The most common stimulus for hypertrophy of skeletal and cardiac muscle is increased workload. Muscle cells respond by synthesizing more protein, increasing production of growth factors and genetic modulation of some muscle proteins, leading to increasing the number of myofilaments per cell and increasing the amount of force each myocyte can generate and thus the strength and work capacity of the muscle as a whole. Hypertrophy can be classified into; physiologic (due to increased functional demand) or pathologic (due to stimulation by hormones and growth factors). Physiologic hypertrophy. Example; Uterine hypertrophy during pregnancy: The massive physiologic growth of the uterus during pregnancy; is stimulated by estrogenic hormone signalling through oestrogen receptors that eventually result in increased synthesis of smooth muscle proteins and an increased cell size. The bulging muscles of bodybuilders engaged in “pumping iron” result from enlargement of individual skeletal muscle fibers in response to increased workload and increased cellular demand. Page 1 of 3  Pathologic hypertrophy. The striated muscle cells in the heart and skeletal muscles have only a limited capacity for division and respond to increased metabolic demands mainly by undergoing hypertrophy. Example; Concentric left ventricular hypertrophy of heart in response to pressure overload due to increased peripheral resistance to cardiac pumping of blood. this occurs in case of systemic hypertension, or aortic valve disease. 2- Hyperplasia Hyperplasia is an increase in the number of cells in an organ or tissue in response to a stimulus. Hyperplasia can only take place if the tissue contains cells capable of dividing, thus increasing the number of cells. It can be physiologic or pathologic. Mechanism of Hyperplasia Hyperplasia is the result of growth factor–driven proliferation of mature cells and activation of signalling pathways that stimulate cell proliferation by increasing output of new cells from stem cells. Physiologic hyperplasia occurs whenever there is a need to increase functional capacity of hormone sensitive organs, or when there is need for compensatory increase after damage or resection. 1. Hormonal hyperplasia: the proliferation of the glandular epithelium of the female breast at puberty and during pregnancy, and lactation usually accompanied by enlargement (hypertrophy) of the glandular epithelial cells. 2. Compensatory hyperplasia: liver regeneration usually occurs in individuals who donate one lobe of the liver for transplantation, the remaining cells proliferate so that the organ soon grows back to its original size. 3. The bone marrow hyperplasia: in response to a deficiency of mature blood cells in the setting of blood donation, chronic bleeding, acute blood loss, haemolysis or high altitudes. Pathologic hyperplasia. Most forms of pathologic hyperplasia are caused by excessive or inappropriate actions of hormones or growth factors acting on target cells. Endometrial and Breast hyperplasia, under the effect of increased estrogen [whether due to excessive hormone production by a tumor of due to exogenous drug intake], a common cause of abnormal uterine bleeding and breast mass, respectively. NOTE; both may turn malignant. Benign prostatic hyperplasia: in response to hormonal stimulation by imbalanced estrogen and androgens in old aged males. 1. Atrophy Atrophy is a reduction in the size of an organ or tissue due to a decrease in cell size and number. Atrophy can be physiologic or pathologic. Mechanisms of Atrophy 1- Decreased protein synthesis Page 2 of 3  2- Increased protein degradation 3- Increased autophagy with presence of intracytoplasmic autophagic granules, containing debris from degraded organelles. Physiologic atrophy occurs during normal development as atrophy of embryonic structures, as notochord and thyroglossal duct during fetal development and uterine atrophy after menopause or reduction of uterine size after delivery. Pathologic atrophy may be local or generalized. Example; 1. Disuse atrophy; caused by decreased workload, e.g., following complete bed rest due to fractured bone with prolonged immobilization. It is reversible once activity is resumed. 2. Loss of innervation (denervation atrophy). Damage to the nerves leads to atrophy of the muscle fibers supplied by those nerves since metabolism and function of skeletal muscle are dependent on its nerve supply. (Irreversible) 3. Diminished blood supply. chronic ischemia as a result of slowly developing arterial occlusion results in tissue atrophy. Example is senile atrophy of brain, and renal atrophy mainly because of reduced blood supply as a result of atherosclerosis. (Irreversible) 4. Inadequate nutrition. Profound protein-calorie malnutrition (marasmus) is associated with the utilization of skeletal muscle proteins as a source of energy after other reserves such as adipose stores have been depleted: Cachexia. 5. Loss of endocrine stimulation. Postmenopausal loss of estrogen stimulation results in atrophy of the endometrium, vagina, and breast. The prostate atrophies following chemical or surgical castration (e.g., for treatment of prostate cancer). 6. Pressure atrophy. Prolonged tissue compression causes atrophy. 2. Metaplasia Metaplasia is a reversible change in which one differentiated\mature cell type (epithelial or mesenchymal) is replaced by another mature cell type. It occurs often in response to chronic irritation, or when one cell type is sensitive to a particular stress. These cells are replaced by another resistant cell type that is better able to withstand the adverse environment. Mechanisms of Metaplasia, it results from stimulation and reprogramming of local tissue stem cells or colonization by differentiated cell populations from adjacent sites. Examples; Squamous metaplasia of respiratory bronchial epithelium, gall bladder \ gland duct epithelium under chronic irritation by smoking or stones or due to Vit A deficiency. Squamous metaplasia of transitional epithelium of urinary bladder under chronic irritation by stone or bilharziasis eggs. Columnar cell \intestinal metaplasia of squamous esophageal epithelium under irritation by acidic gastric juice Page 3 of 3  L28 TYPES AND MECHANISMS OF CELL INJURY ILOs By the end of this lecture, students will be able to 1. Relate noxious physical, chemical, biological, genetic, and immunological agents to cellular changes. 2. Explore the pathogenesis of cell injury and its impact on disease development especially in a case of hypoxia, oxidative stress, toxins, DNA damage and other factors. Introduction: Normal cells are in a state of homeostasis (A healthy state that is maintained by the constant adjustment of biochemical and physiological pathways). Injury is defined as a set of biochemical and/or morphologic changes that occur when the state of homeostasis is disturbed by adverse influences. Cells react against various noxious endogenous or exogenous agents through different stages of progressive cellular impairment responses, including: Adaptation Reversible cell injury; Abnormal intracellular accumulation Irreversible cell injury; (cell death; necrosis, apoptosis and autophagy) So, we may consider adaptation, intracellular accumulation and cell death as stages of progressive cellular impairment following different types of insults. Causes of Cell Injury 1- Oxygen Deprivation: Hypoxia is a deficiency of oxygen, which causes cell injury by reducing aerobic oxidative respiration. Depending on the severity of the hypoxic state, cells may adapt, undergo injury, or die. Causes of hypoxia: It occurs due to inadequate oxygenation of the blood due to: 1  A. Ischemia; due to reduced arterial blood flow. B. Cardiorespiratory failure and inadequate oxygenation of blood. C. Reduced oxygen-carrying capacity of the blood; as in anemia or carbon monoxide poisoning. D. Severe blood loss. 2- Physical Agents: as mechanical trauma, extremes of temperature (burns and frostbite), sudden changes in atmospheric pressure, radiation or electric shock. 3- Chemical Agents and Drugs: Hypertonic chemicals, high oxygen concentrations, trace amounts of poisons, and environmental pollutants as insecticides, and herbicides; industrial and occupational hazards as well as cigarettes, alcohols and some drugs. 4- Infectious, biological, Agents: Range from sub microscopic viruses to tapeworms. 5- Immunologic Reactions: Immune reactions to many external or endogenous agents. 6- Genetic Abnormalities: leads to deficient protein function and accumulation of damaged DNA which trigger cell death by apoptosis when they are beyond repair. 7- Nutritional Imbalances: Deficiencies of protein, vitamins, obesity and high lipids diets. 8- Aging: Cellular aging or senescence leads to impaired ability of the cells to undergo replication and repair. Some principles of cell injury: The biochemical pathways in cell injury can be organized around a few general principles: The cellular response to injury depends on its nature, duration, and severity. The consequences of injury depend on the type, state, and adaptability of the injured cell. Any injurious stimulus may simultaneously trigger multiple interconnected mechanisms that damage cells. The consequences of injury of each of these cellular components are distinct but overlapping. All stresses and noxious influences exert their effects within minutes and hours at the molecular / biochemical and ultrastructural level, but it takes hours to days to appear at light microscopy and more to become visible by naked eye examination. Reversible injury: is a condition which is capable of being reversed with restoration of previous state of cells following the removal of the adverse influences. Irreversible injury: occurs where injurious stimulus is persistent or severe and cellular changes are not able to be undone or return back to normal status, and ultimately undergo cell death. Intracellular Targets of Injurious Stimuli: Cell injury results from disturbance in any of five essential cellular elements: 1- ATP production (mostly through effects on mitochondrial aerobic respiration) 2- Mitochondrial integrity independent of ATP production 3- Plasma membrane integrity, responsible for ionic and osmotic homeostasis 4- Protein synthesis, folding, degradation, and refolding 5- Integrity of the genetic apparatus General Mechanisms of Cell Injury; 1- Depletion of Adenosine Triphosphate 2  ATP is required for membrane transport, protein synthesis, lipogenesis, and the deacylation- reacylation reactions necessary for phospholipid turnover. Decreased ATP synthesis and ATP depletion are common consequences of both ischemic, chemical \toxic injury and mitochondrial damage. Depletion of ATP to