Pathology: Cellular Adaptation Lecture Notes PDF

PATHOLOGY Lecture 72: Cellular adaptation  LEARNING OUTCOMES At the completion of this lecture students should be able to: 72.1 State the stages of the cellular response to stress and injurious stimuli. 72.2 Relate the nature of injurious stimuli to the cellular responses....

PATHOLOGY Lecture 72: Cellular adaptation  LEARNING OUTCOMES At the completion of this lecture students should be able to: 72.1 State the stages of the cellular response to stress and injurious stimuli. 72.2 Relate the nature of injurious stimuli to the cellular responses. 72.3 Define& discuss the types, causes, examples, mechanism, morphology & clinical significance of hyperplasia, hypertrophy, atrophy, and metaplasia. 72.4 List the role of autophagy in human diseases.  All diseases start with molecular or structural alterations in cells This concept of the cellular basis of disease was first put forth in the nineteenth century by Rudolf Virchow, father of modern pathology A German physician, anthropologist, pathologist, prehistorian, biologist, writer, editor, and politician Virchow emphasized the idea that individuals are sick because their cells are sick  Injury to cells & to the extracellular matrix ultimately leads to tissue & organ injury, which determines the morphologic & clinical patterns of disease  Cellular Responses to Stress and Noxious Stimuli  Cells normally maintain a steady state, called homeostasis  Adaptations: alterations that enable cells to cope with stresses without damage  Reversible injury refers to structural & functional abnormalities that can be corrected if the injurious agent is removed  Cell death : if the injury is persistent or severe, it can become irreversible & lead to cell death(the end result of injury)  Cellular Responses to Stress & Noxious Stimuli Cells actively interact with their environment constantly adjusting their structure & function to accommodate changing demands & extracellular stresses in order to maintain a steady state, a process called homeostasis As cells encounter physiologic stresses or injurious stimuli, they can undergo adaptation , achieving a new steady state & preserving viability & function adaptive capability is exceeded or if the external stress is inherently harmful, cell injury occurs  Adaptation, Reversible injury, & Cell death stages of progressive impairment following different types of insults ADAPTATIONS are reversible functional & structural responses to changes in  physiologic states (e.g., pregnancy) &  some pathologic stimuli during which new but altered steady states are achieved, allowing the cell to survive & continue to function 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  Cellular Responses to Injury Nature of Injurious Stimulus Cellular Response Altered physiologic stimuli; some nonlethal injurious stimuli Cellular adaptations  Increased demand, increased stimulation by growth factors, hormones  Hyperplasia, hypertrophy  Decreased nutrients, decreased stimulation  Atrophy  Chronic irritation (physical or chemical)  Metaplasia Reduced oxygen supply; chemical injury, microbial infection Cell injury  Acute and transient  Acute reversible injury Cellular  Progressive and severe (including DNA damage) swelling, fatty Change  Irreversible injury → cell death: Necrosis, Apoptosis Metabolic alterations, genetic or acquired; Intracellular accumulations; sub-lethal chronic injury Cumulative sub lethal injury over long life span Cellular aging  ADAPTATIONS Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment Hypertrophy: an increase in the size & functional activity of cells Adaptive Hyperplasia: an increase in cell number responses Atrophy: a decrease in the size & metabolic activity of cells  Metaplasia: a change in the phenotype of cells If the stress is eliminated, the cell can return to its original state without having suffered any harmful consequences  Hypertrophy  Hypertrophy is an increase in the size of cells that results in an increase in the size of the affected organ  increased size of the cells is due to the synthesis & assembly of additional intracellular structural components  can be caused by physiologic or pathologic stimuli  striated muscle cells in the heart & skeletal muscles have only a limited capacity for division, & respond to increased metabolic demands mainly by undergoing hypertrophy  The most common stimulus for hypertrophy of skeletal and cardiac muscle is increased workload  Hypertrophy  Hypertrophy is an increase in the size of cells that results in an increase in the size of the affected organ  increased size of the cells is due to the synthesis & assembly of additional intracellular structural components  can be caused by physiologic or pathologic stimuli  striated muscle cells in the heart & skeletal muscles have only a limited capacity for division, & respond to increased metabolic demands mainly by undergoing hypertrophy  The most common stimulus for hypertrophy of skeletal and cardiac muscle is increased workload  Physiologic hypertrophy  massive physiologic growth of the uterus during pregnancy is a good example of hormone-induced enlargement of an organ that results mainly from hypertrophy of smooth muscle fibers  Uterine hypertrophy during pregnancy is stimulated by oestrogenic hormone signaling through estrogen receptors that eventually result in increased synthesis of smooth muscle proteins and an increased cell size  The bulging muscles of bodybuilders result from enlargement of individual skeletal muscle fibers in response to increased demand normal uterus normal uterus  Pathologic hypertrophy  A classic example of pathologic hypertrophy is enlargement of the heart in response to pressure overload, usually resulting from either hypertension or valvular disease  muscle cells respond by synthesizing more protein & increasing the number of myofilaments per cell. This in turn increases the amount of force each myocyte can generate and thus the strength & work capacity of the muscle as a whole  Initially, cardiac hypertrophy improves function, but over time this adaptation often fails, setting the stage for heart failure & other significant forms of heart disease  Mechanisms of Hypertrophy Hypertrophy results from the action of growth factors & direct effects on cellular proteins Mechanical sensors in the cell detect the increased load activate signaling pathways phosphoinositide 3-kinase (PI3K)/AKT signaling pathway G-protein–coupled receptor–initiated signaling pathways  Mechanisms of Hypertrophy  Some of the signaling pathways stimulate increased production of growth factors (e.g. TGF-β, insulin-like growth factor 1 [IGF1], fibroblast growth factor) & vasoactive agents (e.g., α-adrenergic agonists, endothelin-1, and angiotensin II)  These & other pathways activate transcription factors, including GATA4, nuclear factor of activated T cells (NFAT), & myocyte enhancer factor 2 (MEF2), which increase the expression of genes that encode muscle proteins Mechanisms of Hypertrophy  Mechanisms of Hypertrophy  Cardiac hypertrophy is associated with a switch in gene expression from genes that encode adult-type contractile proteins to genes that encode functionally distinct fetal isoforms of the same proteins  cardiac hypertrophy is associated with increased atrial natriuretic factor gene expression. Atrial natriuretic factor is a peptide hormone that causes salt secretion by the kidney, decreases blood volume and pressure, and therefore serves to reduce hemodynamic load.  Hyperplasia  Hyperplasia is an increase in the number of cells in an organ or tissue in response to a stimulus  hyperplasia & hypertrophy are distinct processes, they frequently occur together, and may be triggered by the same external stimuli  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  Physiologic hyperplasia  due to the action of hormones or growth factors occurs when there is a need to increase functional capacity of hormone sensitive organs, or when there is need for compensatory increase after damage or resection  bone marrow is also remarkable in its capacity to undergo rapid hyperplasia in response to a deficiency of mature blood cells. For example, in the setting of an acute bleeding or premature breakdown of red blood cells (hemolysis)  Pathologic hyperplasia inappropriate & excessive stimulation by hormones & caused by growth factors Abnormal hormone-  Endometrial hyperplasia resulting from a disturbed estrogen–progesterone balance induced hyperplasia  Benign prostatic hyperplasia as response to hormonal stimulation by androgens Hyperplasia is a characteristic response to certain viral infections, such as papillomaviruses, which cause skin warts and several mucosal lesions composed of masses of hyperplastic epithelium  Mechanisms of Hyperplasia  Hyperplasia is the result of growth factor–driven proliferation of mature cells and, in some cases, by increased output of new cells from tissue stem cells  growth factors are produced in the liver that engage receptors on the surviving cells and activate signaling pathways that stimulate cell proliferation  Metaplasia  Metaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type  It represents an adaptive response in which one cell type that is sensitive to a particular stress is replaced by another cell type that is better able to withstand the adverse environment  influences that predispose to metaplasia, if persistent, can initiate malignant transformation in metaplastic epithelium Metaplasia of columnar to squamous epithelium in a bronchus (occurs with smoking)  Squamous Metaplasia  The most common epithelial metaplasia is columnar to squamous as occurs in the respiratory tract in response to chronic irritation  Cigarette smoking: normal ciliated columnar epithelial cells of the trachea & bronchi are often replaced by stratified squamous epithelial cells  Vitamin A (retinoic acid) deficiency: induce squamous metaplasia in the respiratory epithelium & in the cornea, the latter with highly deleterious effects on vision  Stones in the excretory ducts of the salivary glands, pancreas, or bile ducts: normally lined by secretory columnar epithelium, may also lead to squamous metaplasia Squamous to Columnar Metaplasia Barrett esophagus, in which the esophageal squamous epithelium is replaced by intestinal-like columnar cells under the influence of refluxed gastric acid The cancers that arise in these areas are typically glandular (adenocarcinomas)  Connective tissue metaplasia  formation of cartilage, bone, or adipose cells (mesenchymal tissues) in tissues that normally do not contain these elements  bone formation in muscle, designated myositis ossificans, occasionally occurs after intramuscular hemorrhage  result of cell or tissue injury  Not associated with increased cancer risk  Mechanisms of Metaplasia  results from reprogramming of local tissue stem cells or,  colonization by differentiated cell populations from adjacent sites  metaplastic change is stimulated by signals generated by cytokines, growth factors, & extracellular matrix components in the cells’ environment  In the case of stem cell reprogramming, these external stimuli promote the expression of genes that drive cells toward a specific differentiation pathway  A direct link between transcription factor dysregulation & metaplasia is seen with vitamin A (retinoic acid) deficiency or excess, both of which may cause metaplasia  Retinoic acid regulates gene transcription directly through nuclear retinoid receptors ( Chapter 9 ), which can influence the differentiation of progenitors derived from tissue stem cells  Atrophy  Atrophy is a reduction in the size of an organ or tissue due to a decrease in cell size & number  caused by decreased protein synthesis (due to reduced metabolic activity) and increased protein breakdown  can be physiologic or pathologic  postmenopausal atrophy of uterus due to loss of hormone stimulation  decrease in the size of the uterus that occurs shortly after parturition  occurs at times from very early embryological life, as part of the process Physiologic Causes of morphogenesis, some embryonic structures branchial clefts, of Atrophy thyroglossal ducts, & notochord all undergo involution during fetal development  physiological involution of organs such as the thymus gland in early adult life  Pathologic Causes of Atrophy  Decreased workload (disuse atrophy) When a fractured bone is immobilized in a plaster cast or when a patient is restricted to complete bed rest, skeletal muscle atrophy rapidly ensues  Loss of innervation (denervation atrophy): The normal metabolism and function of skeletal muscle are dependent on its nerve supply. Damage to the nerves leads to atrophy of the muscle fibers supplied by those nerves  Diminished blood supply: A gradual decrease in blood supply (chronic ischemia) to a tissue as a result of slowly developing arterial occlusive disease results in tissue atrophy. In late adult life, the brain may undergo progressive atrophy, mainly because of reduced blood supply as a result of atherosclerosis. This is called senile atrophy  Pathologic Causes of Atrophy  Loss of endocrine stimulation: Many hormone-responsive tissues, such as the breast and reproductive organs, are dependent on endocrine stimulation for normal metabolism and function. The loss of estrogen stimulation after menopause results in atrophy of the endometrium, vaginal epithelium, & breast. the prostrate atrophies following chemical or surgical castration  Pressure: Tissue compression for any length of time can cause atrophy. An enlarging benign tumor can cause atrophy in the surrounding uninvolved tissues. Atrophy in this setting is probably the result of ischemic changes caused by compromise of the blood supply by the pressure exerted by the expanding mass.  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. This results in marked muscle wasting ( cachexia). Cachexia is also seen in patients with chronic inflammatory diseases and cancer.  Narrowing of the gyri widens the sulci Atrophy of the brain in an 82-year-old man with atherosclerotic cerebrovascular disease, resulting in reduced blood supply. Note that loss of brain substance narrows the gyri & widens the sulci.  Atrophy  fundamental cellular changes associated with atrophy are similar in all of these settings  initial response is a decrease in cell size & organelles, which may reduce the metabolic needs of the cell sufficiently to permit its survival  Early in the process, atrophic cells & tissues have diminished function, but cell death is minimal  atrophy caused by gradually reduced blood supply progress to the point at which cells are irreversibly injured & die, often by apoptosis  Mechanisms of Atrophy  Atrophy results from decreased protein synthesis & increased protein degradation in cells  Protein synthesis decreases because of reduced trophic signals (e.g., those produced by growth receptors), which enhance uptake of nutrients and increase mRNA translation  degradation of cellular proteins occurs by the ubiquitin-proteasome pathway  atrophy is accompanied by increased autophagy, marked by the appearance of increased numbers of autophagic vacuoles  Ubiquitin-proteasome pathway Nutrient deficiency & disuse may activate ubiquitin ligases, which attach the small peptide ubiquitin to cellular proteins and target these proteins for degradation in proteasomes Autophagy  is a process in which a cell eats its own contents (Greek: auto, self; phagy, eating)  involves the delivery of cytoplasmic materials to the lysosome for degradation  is an evolutionarily conserved survival mechanism whereby, in states of nutrient deprivation, starved cells live by cannibalizing themselves & recycling the digested contents  Autophagy functions as a survival mechanism under various stress conditions, maintaining the integrity of cells by recycling essential metabolites & clearing intracellular debris  Autophagy proceeds through several steps  Nucleation & formation of an isolation membrane, called a phagophore; the isolation membrane is believed to be derived from the ER, though other membrane sources such as the plasma membrane and mitochondria may contribute  Formation of a vesicle, called the autophagosome, from the isolation membrane, inside which intracellular organelles and cytosolic structures are sequestered  Maturation of the autophagosome by fusion with lysosomes, to deliver digestive enzymes that degrade the contents of the autophagosome  Atgs (autophagy-related genes) have been identified whose products are required for the creation of the autophagosome Autophagy. Cellular stresses, such as nutrient deprivation, activate an autophagy pathway that proceeds through several phases (initiation, nucleation, and elongation of isolation membrane) & eventually creates double-membrane-bound vacuoles (autophagosome) in which cytoplasmic materials, including organelles, are sequestered and then degraded after fusion of the vesicles with lysosomes. In the final stage, the digested materials are released for recycling of metabolites. Autophagy. Cellular stresses, such as nutrient deprivation, activate autophagy genes (Atgs) , whose products initiate the formation of membrane-bound vesicles in which cellular organelles are sequestered. These vesicles fuse with lysosomes, in which the organelles are digested, and the products are used to provide nutrients for the cell. The same process can trigger apoptosis by mechanisms that are not well defined.  Evidences that autophagy plays a role in human diseases  Cancer: Autophagy can both promote cancer growth and act as a defense against cancers, an area of active investigation  Neurodegenerative disorders: associated with dysregulation of autophagy. Alzheimer disease is characterized by impaired autophagosome maturation.  Infectious diseases: Many pathogens are degraded by autophagy; these include mycobacteria, Shigella spp., & HSV-1. This is one way by which microbial proteins are digested and delivered to antigen presentation pathways. Macrophage-specific deletion of Atg5 increases susceptibility to tuberculosis  Inflammatory bowel diseases: Genome-wide association studies have linked both Crohn disease & ulcerative colitis to single-nucleotide polymorphisms (SNPs) in the autophagy-related gene ATG16L1 https://www.clinicalkey.com/#!/content/book/3-s2.0- B9780323531139000029?scrollTo=%23top