Lecture 2 _ Cellular Adaptations.pdf

Cellular Adaptations Lecture 2.  Introduction Pathology is the study of the structural and functional causes of human disease. Four aspects of a disease process: Etiology - causation Pathogenesis - biochemical and molecular mechanisms Morphologic changes - structural an...

Cellular Adaptations Lecture 2.  Introduction Pathology is the study of the structural and functional causes of human disease. Four aspects of a disease process: Etiology - causation Pathogenesis - biochemical and molecular mechanisms Morphologic changes - structural and functional alterations in cells and organs Clinical manifestations - clinical consequences  Learning objectives : A. Define and understand the concept of cellular adaptations. B. Identify and define the different types of cellular adaptations C. Understand the mechanisms and progression of events in the cell that leads to cellular injury and cell death D. Differentiate between reversible and irreversible cell injury E. Identify and differentiate the patterns of cell death  Overview Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment. Such adaptations may take several distinct forms. Adaptations occurs when physiologic or pathologic stressors induce a new state that changes the cell but otherwise preserves its viability in the face of the exogenous stimuli.  Cellular adaptations Hypertrophy Hyperplasia Atrophy Metaplasia  Hypertrophy Hypertrophy is an increase in the size of cells often in response to increased workload. – Induced by growth factors produced in response to mechanical stress or other stimuli; – results in an increase in the size of the affected organ. – hypertrophied organ has no new cells, just larger cells.  Mechanism of Hypertrophy The increased size of the cells is due to the synthesis and assembly of additional intracellular structural components.  Hypertrophy in Dividing vs Non-dividing Cells Cells capable of division may respond to stress by undergoing both hyperplasia and hypertrophy Whereas non-dividing cells (e.g., myocardial fibers) increase tissue mass due to hypertrophy.  Physiologic Hypertrophy Physiologic hypertrophy is caused by increased functional demand or stimulation by hormones and growth factors.  Examples of Physiologic Hypertrophy The massive physiologic growth of the uterus during pregnancy The bulging muscles of bodybuilders  Pathologic Hypertrophy Pathologic hypertrophy is the result of increased workload or disease. – Example : Cardiac hypertrophy due to hypertension or valvular disease.  Mechanisms of Pathologic Hypertrophy Increased workload leads to synthesis of more proteins and increasing the number of myofilaments per cell, enhancing the muscle's strength and work capacity.  Cardiac Hypertrophy Associated with a switch from adult-type to fetal-type contractile proteins – e.g., the α isoform of myosin heavy chain is replaced by the β isoform. Hypertrophy reaches a limit where enlargement is no longer able to cope with the increased burden – leads to regressive changes and potential cardiac failure.  Hyperplasia Hyperplasia is an increase in the number of cells in an organ or tissue – often secondary to hormones and other growth factors. – Occurs in tissues whose cells are able to divide or contain abundant tissue stem cells.  Physiologic Hyperplasia Occurs due to the action of hormones or growth factors – Example : the proliferation of glandular epithelium of the female breast at puberty and during pregnancy.  Compensatory Hyperplasia Occurs after damage or resection – such as liver regeneration after partial hepatectomy.  Pathologic Hyperplasia Caused by excessive or inappropriate actions of hormones or growth factors. – Examples include endometrial hyperplasia and benign prostatic hyperplasia.  Hyperplasia and Cancer Risk Pathologic hyperplasia elevates the risk of acquiring genetic aberrations that drive unrestrained proliferation and cancer.  Atrophy Atrophy is a represents decreased cell size, this will also diminish the overall organ or tissue size, which can be physiologic or pathologic. – Can occur secondary to disuse or decreased nutrient supply – associated with decreased synthesis of cellular building blocks and/or increased breakdown of cellular organelles, involving proteasome degradation or autophagy.  Physiologic Atrophy ❖ Common during normal development Example : the atrophy of embryonic structures during fetal development thyroglossal duct and notochord the decrease in size of the uterus after parturition.  Pathologic Atrophy Causes include : – decreased workload – loss of innervation – diminished blood supply – inadequate nutrition – loss of endocrine stimulation – pressure  Disuse Atrophy Occurs when a fractured bone is immobilized or a patient is restricted to complete bed rest, leading to skeletal muscle atrophy.  Denervation Atrophy Occurs when nerve supply to muscle is damaged, leading to atrophy of muscle fibers.  Ischemic Atrophy Chronic ischemia due to slowly developing arterial occlusive disease can result in tissue atrophy – example : senile atrophy of the brain  Nutritional Atrophy Profound protein-calorie malnutrition (marasmus) results in muscle wasting and cachexia.  Endocrine Atrophy Loss of endocrine stimulation, such as the atrophy of the endometrium, vaginal epithelium, and breast after menopause.  Pressure Atrophy Tissue compression due to enlarging tumors can cause atrophy in surrounding tissues. – 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.  Mechanisms of Atrophy Results from decreased protein synthesis and increased protein degradation, often via the ubiquitin-proteasome pathway. – Nutrient deficiency and disuse may activate ubiquitin ligases, which attach the small peptide ubiquitin to cellular proteins and target these proteins for degradation in proteasomes.  Mechanisms of Atrophy Atrophy is also accompanied by increased autophagy, marked by the appearance of increased numbers of autophagic vacuoles. An example of residual bodies is lipofuscin granules – impart a brown discoloration to the tissue (brown atrophy)  Metaplasia Metaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. – often secondary to chronic inflammation or irritation – This occurs through an altered differentiation pathway of tissue stem cells and can adversely affect tissue function and/or predispose to malignant transformation.  Mechanisms of metaplasia Metaplasia results from either reprogramming of local tissue stem cells or, alternatively, colonization by differentiated cell populations from adjacent sites. – it does not result from a change in the phenotype of an already differentiated cell type – In either case, the metaplastic change is stimulated by signals generated by cytokines, growth factors, and extracellular matrix components in the cells’ environment. The most common epithelial metaplasia is columnar to squamous  Squamous to columnar metaplasia – Example : Barrett’s esophagus in which the esophageal squamous epithelium is replaced by intestinal-like columnar cells under the influence of refluxed gastric acid Cell injury  Cell injury referring to sequence of events that follows when 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  Cell injury Cell injury is reversible up to a point, but if the injurious stimulus is persistent or severe, the cell suffers irreversible injury and ultimately undergoes cell death.  Types of cell injury : Reversible cell injury Irreversible cell injury  Causes of cell injury : Oxygen deprivation – Hypoxia : deficiency of oxygen, which causes cell injury by reducing aerobic oxidative respiration – Ischemia : reduced blood flow – Examples : inadequate oxygenation of the blood due to cardiorespiratory failure decreased oxygen-carrying capacity of the blood - anemia or carbon monoxide poisoning and severe blood loss.  Causes of cell injury : Physical agents – mechanical trauma – extremes of temperature (burns and deep cold), – sudden changes in atmospheric pressure – radiation – electric shock  Causes of cell injury : Chemical agents and drugs Infectious agents Immunologic reactions Genetic abnormalities Nutritional imbalances  Mechanisms of cell injury : ATP depletion Mitochondrial damage Increased permeability of cellular membranes Accumulation of damaged DNA and misfolded proteins Accumulation of reactive oxygen species (ROS) Influx of calcium Unfolded protein response and ER stress  Reversible cell injury Reversible cell injury is characterized by functional and structural alterations in early stages or mild forms of injury, which are correctable if the damaging stimulus is removed.  Morphologic features of cell injury : Cellular swelling Fatty change  Cellular swelling - also known as hydropic change or vacuolar degeneration. - earliest manifestation of almost all forms of injury to cells - small clear vacuoles may be seen within the cytoplasm; these represent distended and pinched-off segments of the ER  Fatty change - results when toxic injury disrupts metabolic pathways and leads to rapid accumulation of triglyceride-filled lipid vacuoles Ultrastructural changes of reversible cell injury : 1. Plasma membrane alterations, such as blebbing, blunting, and loss of microvilli 2. Mitochondrial changes, including swelling and the appearance of small amorphous densities 3. Accumulation of “myelin figures” in the cytosol composed of phospholipids derived from damaged cellular membranes 4. Dilation of the ER, with detachment of polysomes 5. Nuclear alterations, with disaggregation of granular and fibrillar elements  Irreversible cell injury Irreversible cell injury occurs when stressors exceed the capacity of the cell to adapt (beyond a point of no return) and denotes permanent pathologic changes that cause cell death. Cell Death  Cell death Necrosis Apoptosis  Necrosis Necrosis is a pathologic process that is the consequence of severe injury. The main causes of necrosis include: ○ loss of oxygen supply (ischemia) ○ exposure to microbial toxins, burns and other forms of chemical and physical injury ○ unusual situations in which active proteases leak out of cells and damage surrounding tissues (as in pancreatitis).  Necrosis Necrosis is characterized by : ○ denaturation of cellular proteins ○ leakage of cellular contents through damaged membranes ○ local inflammation ○ enzymatic digestion of the lethally injured cell.  How do you characterize the irreversibility of cell injury? “Point of no return” Two phenomena consistently characterize irreversibility : ○ the inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury ○ profound disturbances in membrane function.  Morphologic changes in Necrosis : Necrotic cells show increased eosinophilia in H&E stains The necrotic cell may have a glassy homogeneous appearance relative to normal cells, mainly as a result of the loss of glycogen particles When enzymes have digested the cell’s organelles, the cytoplasm becomes vacuolated and appears moth-eaten. Dead cells may be replaced by large whorled phospholipid precipitates called myelin figures, which are either phagocytosed by other cells or further degraded into fatty acids calcification of such fatty acid residues results in deposition of calcium-rich precipitates.  Patterns of Tissue necrosis : Coagulative necrosis Liquefactive necrosis Gangrenous necrosis Caseous necrosis Fat necrosis Fibrinoid necrosis  Coagulative necrosis A form of necrosis in which the architecture of dead tissue is preserved for a span of at least some days The affected tissue has a firm texture. Ischemia caused by obstruction in a vessel may lead to coagulative necrosis of the supplied tissue in all organs except the brain Infarct - a localized area of coagulative necrosis  Liquefactive necrosis A form of necrosis characterized by digestion of the dead cells, resulting in transformation of the tissue into a viscous liquid. It is seen in focal bacterial or, occasionally, fungal infections, because microbes stimulate the accumulation of leukocytes and the liberation of enzymes from these cells. Pus - necrotic material appearing as frequently creamy yellow because of the presence of leukocytes Hypoxic death of cells within the central nervous system often manifests as liquefactive necrosis  Gangrenous necrosis is not a specific pattern of cell death It is usually applied to a limb, generally the lower leg, that has lost its blood supply and has undergone necrosis (typically coagulative necrosis) involving multiple tissue planes. Wet gangrene - when bacterial infection is superimposed, there is more liquefactive necrosis because of the actions of degradative enzymes in the bacteria and the attracted leukocytes  Caseous necrosis The term caseous (cheeselike) is derived from the friable white appearance of the area of necrosis This form of necrosis encountered most often in foci of tuberculous infection On microscopic examination, the necrotic area appears as a structureless collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border- this appearance is characteristic of a focus of inflammation known as a granuloma  Fat necrosis A form of necrosis that refers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. Fat saponification - fatty acids are generated that combine with calcium to produce grossly visible chalky-white areas On histologic examination, the necrotic areas contain the shadowy outlines of necrotic fat cells, basophilic calcium deposits, and an inflammatory reaction.  Fibrinoid necrosis A special form of vascular damage usually seen in immune reactions involving blood vessels. It typically occurs when complexes of antigens and antibodies are deposited in the walls of arteries. “fibrinoid” (fibrin-like) - deposits of these immune complexes, together with plasma proteins that has leaked out of vessels, result in a bright pink and amorphous appearance in H&E stains  Nuclear changes in Necrosis : Karyolysis - faint, dissolved nucleus Pyknosis - nuclear shrinkage and increased basophilia Karyorrhexis - nuclear fragmentation  Apoptosis Apoptosis is a type of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade the cells’ genomic DNA and nuclear and cytoplasmic proteins.  Apoptosis Apoptotic bodies - apoptotic cells break up into plasma membrane–bound fragments, which contain portions of the cytoplasm and nucleus. ○ While the plasma membrane remains intact, its surface components are altered so as to produce “find me” and “eat me” signals for phagocytes. Efferocytosis - process of apoptotic cell phagocytosis Autophagy - process in which a cell eats its own contents ○ involves sequestration of cellular organelles into cytoplasmic autophagic vacuoles (autophagosomes) that fuse with lysosomes and digest enclosed material.  Morphologic and Biochemical Changes in Apoptosis Cell shrinkage. ○ Cell size is reduced, the cytoplasm is dense and eosinophilic and the organelles, although relatively normal, are more tightly packed. Chromatin condensation. ○ This is the most characteristic feature of apoptosis. ○ The chromatin aggregates peripherally, under the nuclear membrane, into dense masses of various shapes and sizes. The nucleus itself may break up into two or more fragments.  Morphologic and Biochemical Changes in Apoptosis Formation of cytoplasmic blebs and apoptotic bodies. ○ The apoptotic cell first shows extensive surface membrane blebbing, which is followed by fragmentation of the dead cells into membrane- bound apoptotic bodies composed of cytoplasm and tightly packed organelles, with or without nuclear fragments Phagocytosis of apoptotic cells or cell bodies, usually by macrophages. ○ The apoptotic bodies are rapidly ingested by phagocytes and degraded by the phagocyte’s lysosomal enzymes.  Mechanisms of Apoptosis Caspases - enzymes that when activated is a marker for cells undergoing apoptosis Two major pathways in apoptosis : ○ Mitochondrial (intrinsic) pathway ○ Death receptor (extrinsic) pathway  Other forms of Apoptosis Necroptosis is a form of cell death that shares aspects of both necrosis and apoptosis. ○ Morphologically, it resembles necrosis but mechanically is triggered by signal transduction pathways that culminate in cell death. Because of these features, it is sometimes called programmed necrosis.  Other forms of Apoptosis Pyroptosis is a form of apoptosis that is accompanied by the release of the fever-inducing cytokine Interleukin-1 (IL-1) ○ It is thought to be the mechanism by which some microbes cause the death of infected cells and at the same time, trigger local inflammation. ○ Microbial products that enter infected cells are recognized by cytoplasmic innate immune receptors and can activate the multiprotein complex called the inflammasome  Other forms of Apoptosis Ferroptosis is a distinct form of cell death that is triggered when excessive levels of intracellular iron or reactive oxygen species overwhelm antioxidant defenses to cause unchecked membrane lipid peroxidation. ○ This disrupts membrane function and loss of cell membrane permeability.  Pathologic calcifications : Dystrophic calcification - Deposition of calcium at sites of cell injury and necrosis Metastatic calcification - Deposition of calcium in normal tissues,caused by hypercalcemia (usually a consequence of parathyroid hormone excess)  Cellular Aging Cellular aging is the result of a progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences Reference book : ROBBINS & COTRAN PATHOLOGIC BASIS OF DISEASE, TENTH EDITION, Chapter 2