Cellular Adaptation, Intracellular Accumulation, Pathological Calcification & Aging Lecture Notes PDF
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These notes cover different types of cellular adaptation, intracellular accumulation, pathological calcification, and aging. They include definitions, descriptions, and examples, suitable for an undergraduate-level biology course. The document is likely lecture notes, rather than a past exam paper.
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# Cellular Adaptation, Intracellular Accumulation, Pathological Calcification & Aging ## Specific Learning Outcomes - **Knowledge:** - Define hypertrophy, hyperplasia, atrophy and metaplasia. - Describe types, causes, mechanisms, morphology and sequelae of hypertrophy, hyperplasia, atrophy...
# Cellular Adaptation, Intracellular Accumulation, Pathological Calcification & Aging ## Specific Learning Outcomes - **Knowledge:** - Define hypertrophy, hyperplasia, atrophy and metaplasia. - Describe types, causes, mechanisms, morphology and sequelae of hypertrophy, hyperplasia, atrophy and metaplasia with their examples. - Describe abnormal intracellular accumulation (lipid, protein, glycogen and pigments). - Describe mechanisms of cellular aging and abnormalities of telomere maintenance. - Define and describe forms of pathological calcification (dystrophic vs. metastatic) with examples. - **Skills:** - Identify morphology (macroscopic and/or microscopic features) of different types of cellular adaptation and their examples. - Identify morphology (macroscopic and/or microscopic features) of different types of cellular accumulation and their examples. - Contents: - Definition of hypertrophy, hyperplasia, atrophy and metaplasia. - Types, causes, mechanisms, morphology and sequelae of hypertrophy, hyperplasia, atrophy and metaplasia with their examples. - Abnormal intracellular accumulation. - Mechanisms of cellular aging and abnormalities of telomere maintenance. - Definition and forms of pathologic calcification with examples. ## Cellular Adaptation - **What is cellular adaptation?** - Reversible changes in cells in response to changes in their environment (stress/stimulation) - size - number - phenotype - metabolic activity - function - **Why cells need to adapt?** - To achieve a new steady state (homeostasis) to preserve viability and function. ## Hyperplasia - Increase in cell number resulting in increase in organ size. - Adaptive response in cells capable of replication. - **WHY?** increased functional demand or hormonal stimulation. - Hyperplasia and hypertrophy can occur together in some organs. ### Physiologic - **Hormonal hyperplasia:** proliferation of glandular epithelium of the breast during puberty/pregnancy/lactation. - **Compensatory hyperplasia:** eg kidney/liver - When a liver is partially resected, there is increased proliferation of the remaining hepatocytes/connective tissues restoring the liver to its normal weight. - The stimuli are GFs produced by remnant hepatocytes and nonparenchymal cells in the liver. - After restoration of liver mass, cell proliferation is turned off by growth inhibitors. ### Pathologic - Caused by excessive/unregulated hormonal/growth factor stimulation. - Excessive hormonal stimulation (estrogen) to non-pregnant uterus: - endometrial hyperplasia - abnormal uterine bleeding - eg. PCOS, taking hormonal pills, traditional meds - Macroscopically, the endometrium is thickened. - Microscopically, there is increased number of the endometrial glands resulting in closely packed glands with minimal intervening stroma. - These process are still reversible if the stimulus returns to normal level. - Uncontrolled stimulus: can progress to dysplasia/cancer (endometrial carcinoma). ## Hypertrophy - Increase in cell size resulting in an increase in the organ size: - due to increased amount of structural proteins - due to increased amount of organelles - **WHY?** due to increased functional demand or hormonal stimulation. - In some organs/cells, hypertrophy and hyperplasia can occur together eg. smooth muscle cells of pregnant uterus. - **Pure hypertrophy:** - occur in cells incapable of dividing eg muscle cells in skeletal muscle and cardiac muscles. ### Physiologic - Weightlifter developed rippled physique due to hypertrophy of individual skeletal muscle cells induced by increased workload (exercise). - Hormone-induced enlargement of uterus during pregnancy: - hypertrophy of smooth muscle cells and also hyperplasia. ### Pathologic - **Sequelae of Cardiac Hypertrophy:** - Persistent stress reach limit of muscle cell can enlarge & compensate contractile burden. - Limited resource to vasculature. - Limited ATP in mitochondria to synthesise contractile proteins. - Myocardial fibers fragmentation. - Loss of myofibrillar elements. - Enlarged fibers. - Ventricular dilatation. - Heart failure. - Adaptations: response to increased load. - Adapted myocyte (hypertrophy). - **Gross:** - Organ/heart increase in size. - Thickened ventricular wall. - Small ventricular space. - **Complications of hypertrophy:** - Enlargement of the organ - Decompensation of the enlarged cells/heart failure - Ischaemia of the enlarged cells. ## Atrophy - Shrinkage in cell size by loss of cell substance. - When a sufficient number of cells involved, the entire tissue/organ diminishes in size (atrophic). - Atrophic cells are not dead, but diminished function. ### Physiologic - Loss of endocrine stimulation (uterine atrophy in menopause). - Atrophy of lymphoid tissue with age. - Atrophy of thymus in adult life. - Atrophy of gonads after menopause. - Osteoporosis with reduction in size of bony trabeculae due to ageing. - Senile atrophy of the brain - aging. ### Pathologic - Decreased workload/demand eg. fractured limb -> muscle atrophy. - Loss of innervation eg. stroke/nerve disease -> no stimulation -> muscle atrophy. - Reduced blood supply eg. atherosclerosis (brain, kidney) -> inadequate nutrition/energy to function -> organ atrophy. - Inadequate nutrition. ## Metaplasia - A change of one mature (differentiated) cell type to another mature (differentiated) cell type. - An adaptive response to produce cells better equipped to withstand an environmental change. - Thought to arise by the reprogramming of stem cells to differentiate along a new pathway. ### Physiologic - Hormonal changes (beginning of reproductive age). - Squamous metaplasia in the cervix: - Replacement of ciliated columnar epithelium of endocervix by squamous epithelium. ### Pathologic - **LUNG** - Squamous metaplasia in the bronchi due to chronic cigarette smoking. - Bronchi (ciliated columnar epithelium) are replaced by squamous epithelium. - Although it can withstand the assault of cigarette smoke (survival advantage), but lost protective mechanisms: - mucus secretion - ciliary clearance of particulate - **ESOPHAGUS** - Barret esophagus caused by chronic gastric reflux. - Gross: salmon-pink patches. - Replacement of the normal distal stratified squamous mucosa of the esophagus by metaplastic columnar epithelium containing goblet cells. - Intestinal columnar cells able to withstand gastric juice irritation. - **CERVIX** - HPV infection - Chronic irritation of physical nature (chemical irritants, intrauterine contraceptive device, inflammation). ## Intracellular Accumulation - Accumulation of substances produced by synthesis by the cell itself or elsewhere. - Substances can collect in: - cytoplasm - organelles such as lysosomes - nucleus ### Lipids - 1) Cholesterol/cholesterol esters - 2) Glycerides: tri-, bi-, mono- - 3) Free fatty acids - Mainly stored in cells called adipocytes. - Transported in the blood circulation in a form called 'lipoprotein'. #### Fatty Change - Also called STEATOSIS. - Any accumulation of triglycerides within parenchymal cells. - Often seen in the liver -> the major organ for fat metabolism. - May occur in heart, skeletal muscle, kidney and other organs. - **Most common cause:** Alcohol abuse - ethanol metabolism enhances lipid biosynthesis - ethanol impairs lipid secretion leads to accumulation of lipid droplets in hepatocytes (liver cells). - Other causes: - Diabetes (insulin resistance) & obesity - Excess glucose -> stimulate free fatty acid production in hepatocytes. - Increase mobilisation of free fatty acids from adipose tissue and taken up by hepatocytes. - Toxins, protein malnutrition, anoxia. #### Cholesterol & Cholesterol Esters - Due to increased intake or decreased catabolism of lipids. - Eg: Foam cells in atherosclerosis. - Macrophages engulf LDL lipoprotein (high cholesterol & cholesterol esters content). - Increase uptake of LDL by smooth muscle cells in the blood vessel wall overloaded with lipids. - Accumulation of foam cells ->fatty streaks. ### Protein - Less common than lipid. - Occur when: - excess synthesis of protein in the cell - excess uptake of protein into cell - accumulation of misfolded protein - Eg: - Plasma cells: accumulation of immunoglobulins (Ab) in plasma cells. - Kidneys: nephrotic syndrome - Liver: alcoholic hyaline - Neuron: accumulation of neurofibrillary tangles ### Glycogen - Glycogen -> storage form of glucose. - Excessive intracellular deposits of glycogen. - Associated with abnormalities of glucose or glycogen metabolism. - **Poorly controlled diabetes mellitus** (large amount of glucose in body) -> glycogen accumulates in cells: - renal tubular epithelium - cardiac myocytes - cells of the islets of Langerhans (pancreas) - **Glycogen storage diseases (glycogenoses)** - inherited genetic disorder. - deficiency enzymes in glycogen synthesis or degradation. - result in excessive accumulation of glycogen or abnormal glycogen form. - stored in cytoplasm/nucleus. - any organs (mainly liver, skeletal muscles, heart). ### Pigments - Colored substances that are: - exogenous: derived from outside of the body - endogenous: synthesised by the body #### Carbon - Most common exogenous pigment. - From soot, diesel exhaust, coal, cigarette smoke, air pollution. - Causes antharocosis: blackening of lung parenchyma and draining lymph nodes. - When inhaled -> phagocytosed by alveolar macrophages -> transported through lymphatic channels -> to the tracheobronchial lymph nodes -> blackening of lymph nodes and pulmonary parenchyma. #### Lipofuscin - "wear-and-tear pigment,” - An insoluble brownish-yellow granular intracellular material. - Accumulates in a variety of tissues (particularly the heart, liver, and brain). - Due to aging or atrophy. - Composed of complexes of lipid & protein produced by the free radical-catalyzed peroxidation of polyunsaturated lipids of subcellular membranes. - A marker of past free-radical injury. - Brown pigment -> when present in large amounts, imparts an appearance to the tissue called 'brown atrophy'. #### Melanin - An endogenous, brown-black pigment. - Synthesized by melanocytes in the epidermis. - Acts as a screen against harmful UV radiation. - Melanin pigments also accumulate in basal keratinocytes and in dermal macrophages. #### Haemosiderin - Hemoglobin-derived granular pigment (iron). - Golden yellow to brown. - Accumulates in tissues when there is a local or systemic excess of iron. - Normally iron is stored within cells with apoferritin protein -> ferritin. - Large aggregates of ferritin -> haemosiderin. - There can be small amounts of haemosiderin in the mononuclear phagocytes of the bone marrow, spleen, and liver, where aging red cells are normally degraded. - Hereditary hemochromatosis -> Extensive deposition of hemosiderin (haemosiderosis). ## Pathological Calcification - A common process in a wide variety of disease states. - A result of an abnormal deposition: - calcium salts - smaller amounts of iron - magnesium and other minerals. ### Dystrophic Calcification - Occurs at normal calcium level/metabolism. - Calcium deposition occurs in: - injured/degenerated tissues - dead/necrotic tissues. - May cause organ dysfunction. - If developed in aging/damaged heart valves -> severely compromise valve motion -> eg. calcification of the aortic valves -> aortic stenosis in elderly persons. - **Gross:** - fine white granules or clumps - gritty deposits. - **Microscopy:** - intracellular and/or extracellular basophilic deposits. - With time, heterotopic bone may form in foci of calcification. ### Metastatic Calcification - Associated with hypercalcemia. - Can occur in any tissues and also normal tissues. - **Causes of hypercalcemia:** - Excessive mobilisation of calcium from the bone. - Excessive absorption of Ca from gut. - **Common sites:** - Kidneys: basement membrane of tubular epithelium and in the tubular lumina causing nephrocalcinosis. - Lungs: alveolar walls. - Stomach: acid-secreting fundal glands. - Blood vessels: internal elastic lamina. - Cornea. - Synovium of the joint causing pain and dysfunction. - **Reversible when Ca level goes to normal.** - **Morphology same with dystrophic calcification.** - **May cause organ dysfunction:** - reduced lung capacity - kidney damage. ## Cellular Aging - We age because our cells age. - It is as a result of a progressive decline in the life span and functional activity of cells. - Adaptive response of cells to stress becomes slower. ### Accumulation of DNA Mutations - Over time, cells accumulate mutation in nuclear and mitochondrial DNA by reactive oxygen species (ROS). - ROS induced by: - toxins - radiation exposure. - DNA mutations can be repaired but DNA repair mechanisms become increasingly inefficient with increasing age -> mutations persist & accumulate. - Severe damage to DNA -> compromise the functional activities and survival of cells. - More cells die and decreasing regeneration of new cells. ### Decreased Cellular Replication - Normal cells (except stem cells) have a limited capacity for replication/divisions -> become arrested in a nondividing state = Replicative Senescence = Aging. - Replicative senescence is due to progressive shortening of telomeres after each cell division -> ultimately causing cell cycle arrest. ### Abnormal Protein Homeostasis - With time, cells unable to maintain normal protein homeostasis due to: - increased protein turnover - decreased protein synthesis (reduced translation) - accumulation of misfolded proteins - d/t defective activity of normal protein folding - d/t defective activity of proteasomes (which destroy misfolded proteins). - Decrease intracellular proteins -> cell cannot survive/replicate/abnormal functions -> trigger apoptosis. - The concomitant accumulation of misfolded proteins. ### Persistent Inflammation - With time -> accumulation of damaged cells/lipids/endogenous substances. - Activate the 'inflammasome pathway'. - Major inflammation pathway that involves protein complexes. - Result in persistent low-level inflammation. - Cytokines produced during inflammatory reactions -> induce cellular alterations -> exacerbate aging. - Chronic metabolic disorders may accelerate the aging process (eg. Type 2 diabetes, obesity).