Cellular Adaptation & Aging PDF

Cellular adaptation Dr –Mai inbiek 2024-2025  Cellular adaptation Objectives: - Definition of cellular adaptation. - Types of cellular adaptation. - Recognize the causes of each type of adaptation. - Mechanisms of cellular adaptation. - The clinical significance of cellular ad...

Cellular adaptation Dr –Mai inbiek 2024-2025  Cellular adaptation Objectives: - Definition of cellular adaptation. - Types of cellular adaptation. - Recognize the causes of each type of adaptation. - Mechanisms of cellular adaptation. - The clinical significance of cellular adaptation. Adaptation: - New ,steady altered state. - Allows them to survive. - Continue to function. -In abnormal environments.  CELLULAR ADAPTATONS TO STRESS Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment. +stress Normal cell Adapted cell - Stress  Types of cellular adaptation 1) Atrophy. 2)Hypertrophy. 3)Hyperplasia. 4)Metaplasia..  Atrophy ▪ Atrophy is reduced size of an organ or tissue resulting from a decrease in cell size and |or number. Shrinkage in the size of the cell by the loss of cell substance. Atrophic cells may have diminished function, they are not dead, but if the stimulus continues, die, often by apoptosis Mechanisms of atrophy Atrophy results from 1- Decreased protein synthesis because of reduced metabolic activity. 2- Increased protein degradation in cells. The degradation of cellular proteins occurs mainly by the ubiquitin-proteasome pathway.  Nutrient deficiency and disuse activate ubiquitin ligases which attach multiple copies of the small peptide ubiquitin to cellular proteins and target these proteins for degradation in proteasomes. This pathway is also thought to be responsible for the accelerated proteolysis seen in a variety of catabolic conditions, including cancer cachexia.  -Atrophy represents a reduction in the structural components of the cell. The cell contains fewer mitochondria, myofilaments, a lesser amount of endoplasmic reticulum. ▪ atrophy is also accompanied by increased autophagy, with resulting increases in the number of autophagic vacuoles. ▪ Autophagy ("self-eating") is the process in which the starved cell eats its own components in an attempt to find nutrients and survive. ▪ Some of the cell debris within the autophagic vacuole may resist digestion and persist as membrane bound residual bodies that may remain as a sarcophagus in the cytoplasm. ▪ An example of such residual bodies is the lipofuscin granules. ▪ When lipofuscin present in sufficient amounts, they impart a brown discoloration to the tissue (brown atrophy). (It is due to aging patients or patients with severe malnutrition and cancer cachexia.) A B Although atrophic cells may have diminished function, they are not dead. Common causes of atrophy ❖Reduced workload ❖Inadequate nutrition ❖Ageing ❖Loss of innervation ❖Reduced blood supply ❖Loss of endocrine stimulation  Types Of Atrophy 1- Physiologic Atrophy. 2- Pathologic Atrophy 1) Physiologic Atrophy: Examples: -Atrophy of ductus arteriosus in infants. -Atrophy of thymus in adults. -Atrophy of gonads in old age. 2) pathologic Atrophy: a- Generalized atrophy. b- Localized atrophy a)Generalized atrophy : Atrophy due to starvation. Chronic inflammatory disease and cancer b)Localized atrophy : 1- Ischaemic atrophy. 2- Disuse atrophy. 3- Neuropathic atrophy. 4- Endocrine atrophy. 5- Pressure atrophy. , localized pathologic atrophy : 1-Ischaemic atrophy. Gradual diminution of blood supply due to atherosclerosis may result in shrinkage of the affected organ e.g. i) Small atrophic kidney in atherosclerosis of renal artery. ii) Atrophy of brain in cerebral atherosclerosis. ,localized pathologic Atrophy: 2- Disuse atrophy. Prolonged diminished functional activity is associated with disuse atrophy of the organ e.g. - Wasting of muscles of limb immobilized in cast. , localized pathologic atrophy: 3-Neuropathic atrophy. Interruption in nerve supply leads to wasting of muscles e.g. i) Poliomyelitis iii) Nerve dissection. ,localized pathologic atrophy: 4-Endocrine atrophy. Loss of endocrine regulatory mechanism results in reduced metabolic activity of tissues and hence atrophy e.g: i) Hypopituitarism may lead to atrophy of thyroid, adrenal and gonads. ii) Hypothyroidism may cause atrophy of the skin and its adnexal structures. L,ocalized pathologic atrophy: 5- Pressure atrophy. Prolonged pressure from benign tumours or cyst or aneurysm may cause compression and atrophy of the tissues e.g. i) Erosion of skull by meningioma arising from pia-arachnoid. ii) Erosion of sternum by aneurysm of arch of aorta. A B Other causes of a small organ other than atrophy Hypertrophy - Hypertrophy an increase in the size of cells resulting in increase in the size of the organ. - In pure hypertrophy there are no new cells, just bigger cells containing increased amounts of structural proteins and organelles. -Cells capable of division may responds to stress by undergoing both hypertrophy and hyperplasia. - Pure hypertrophy i,e hypertrophy without accompanying hyperplasia affected mainly straited muscles (heart, skeletal muscle ) permanent, nondividing cells. (Labile cells Epithelial cell Stable cells liver ,kidney) Causes: Hypertrophy may be physiologic or pathologic. In both cases, it is caused either by increased functional demand or by hormonal stimulation. Types of hypertrophy: A) Physiologic hypertrophy: Examples: The massive enlargement of the uterus during pregnancy occurs as a consequence of estrogen stimulated smooth muscle hypertrophy and smooth muscle hyperplasia. Breast enlargement during pregnancy. Skeletal muscle hypertrophy due to increased workload in exercise.  A, Gross appearance of a normal uterus (right) and a gravid uterus (left) that was removed for postpartum bleeding. B, Small spindle-shaped uterine smooth muscle cells from a normal uterus, compared with C, large plump cells from the gravid uterus B) Pathological hypertrophy Examples: Hypertrophy of uterine smooth muscles under the influence of estrogen secreted by ovarian tumor. Left ventricular hypertrophy due to systemic hypertension. Right ventricular hypertrophy due to pulmonary hypertension.  Pathological hypertrophy Myocardium in hypertensive heart disease  Pathological hypertrophy Myocardium in hypertensive heart disease Histology of cardiac muscle from a Histology of cardiac muscle from a normal heart hypertrophied heart An adaptation to stress can progress to functionally significant cell injury if the stress is not relieved. Ex. In extreme cases of cardiac hypertrophy in sever hypertension, myocardial fibers lysis and loss of myofibril contractile elements myocyte death can occur by either apoptosis or necrosis lead to cardiac failure. Mechanism of hypertrophy - Hypertrophy is the result of increased production of cellular proteins induced by mechanical sensors, growth factors and vasoactive agents. - Signal transduction occurs via 2 ways: 1-P13K- Akt pathway (physiological hypertrophy) 2- GPCR pathway (pathological hypertrophy) -Gene expression.  HYPERPLASIA It refers to increase in number of cells in an organ or tissue. Hyperplasia is characterized by an increase in cell number from increased proliferation, either of differentiated cells or, in some instances, less differentiated progenitor cells. Causes of hyperplasia: 1)Hormonal stimulation 2)Tissue loss (remaining tissue undergo hyperplasia to compensate for tissue loss). Labile cells and stable cells (e.g. parenchymal cells of the liver, pancreas, kidney, adrenal, and thyroid) can under go hyperplasia, while permanent cells (e.g. neurons, cardiac and skeletal muscle) have no capacity for regenerative hyperplastic growth.  Types of hyperplasia : a)Physiologic hyperplasia: Hormonal hyperplasia Compensatory hyperplasia 1)Hormonal hyperplasia : Examples : Proliferation of epithelium of female breast at puberty & during pregnancy due to estrogenic stimulation. Proliferation of uterine smooth muscle during pregnancy due to estrogenic stimulation.  Hyperplasia & hypertrophy of myometrium in pregnancy Hypertrophy and hyperplasia can also occur together, and obviously both result in an enlarged (hypertrophic) organ. Thus, the massive physiologic enlargement of the uterus during pregnancy occurs as a consequence of estrogen-stimulated smooth muscle hypertrophy and smooth muscle hyperplasia ,physiologic hyperplasia: 2)Compensatory hyperplasia : It refers to hyperplasia that occurs when a portion of tissue is removed or diseased. Examples : ❑ Compensatory hyperplasia of remaining liver after hepatectomy under influence of TGF- α-&-β and hepatopoietin produced by remnant hepatic cells. ❑ Hyperplasia of remaining kidney when one kidney is removed or destroyed. (hyperplasia and hypertrophy). B )Pathologic hyperplasia: Examples : 1- Adenomatous hyperplasia of endometrium : In some cases ,after menestrual period disturbed balance between estrogen and progesterone increased estrogen/progesteron ratio hyperplasia of the endometrial glands abnormal menstrual bleeding. 2- Hyperplasia of thyroid follicles in primary hyperthyroidism (Grave’s disease). Normal thyroid Grave’s disease. 3) Hyperplasia that is associated with certain viral infections for example, papilloma viruses HPV cause skin warts and mucosal lesions composed of masses of hyperplastic epithelium. In papillomatous epidermal hyperplasia , growth factors produced by viral genes or by infected cells may stimulate cellular proliferation 4) Hyperplasia of prostatic gland (BPH). (Benign prostatic hyperplasia) 5)Hyperplasia is also an important response of connective tissue cells in wound healing, In which proliferating fibroblast and blood vessels aid in repair. Under these circumstances, growth factors is also involved in the hyperplasia. Mechanism of hyperplasia The roles of growth factors and stem cells in cellular replication. This is seen after partial hepatectomy growth factors are produced in the remaining liver activate signaling pathways stimulate cell proliferation. But in case of hepatitis causing cell injury ,intrahepatic stem cells can instead regenerate hepatocytes.  Clinical significance of hyperplasia:  Hyperplasia can be reversed after removal of the stimulus.  Hyperplasia may produce clinical disease (eg: endometrial bleeding, thyroid hyperfunction).  Hyperplasia increases the risk of neoplasia (eg: endometrial hyperplasia, HPV). Adaptations – Hyperplasia Endometrial Carcinoma 39  Metaplasia Metaplasia is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type. Causes of Metaplasia : 1)Chronic irritation (cigarette smokers, stone) 2)Chronic inflammation 3)Vit. A deficiency (vitamin A is essential for normal epithelial differentiation) Types of Metaplasia: a) Epithelial Metaplasia:: 1) Squamous metaplasia. 2) Columnar metaplasia. b) Mesenchymal Metaplasia.  Types of Metaplasia a)Epithelial Metaplasia: 1).Squamous metaplasia: ❖ Replacement of columnar epithelium by stratified squamous epithelium in Gallbladder, trachea, bronchi, bronchioles, endocervical glands,& excretory ducts of glands, in response to irritation or inflammation.  Schematic diagram of columnar to squamous metaplasia ❖ Metaplasia of epithelial in respiratory passages & renal calyces & pelvis into keratinizing stratified squamous epithelium in response to vit. A deficiency. 2). Columnar metaplasia: Metaplasia from squamous to columnar type may also occur; e.g.in chronic gastric reflux, the normal stratified squamous epithelium of the lower esophagus may undergo metaplastic transformation to gastric or intestinal-type columnar epithelium called (Barrett esophagus). Influence of refluxed gastric acid, and cancers may arise in these areas adenocarcinoma. Barrett esophagus. Microscopic view showing squamous mucosa (left) and intestinal-type columnar epithelial cells in glandular mucosa (right). Advantage of epithelial metaplasia: It is protective response and the metaplastic cells are capable of surviving against injurious agent. Disadvantage of epithelial metaplasia: -The protective mechanism of the epithelium is lost (epithelium resulting from squamous metaplasia leads to loss of mucus secretion). - Fertile soil for malignant transformation. For this it is called two edged sword. Ex. Squamous metaplasia of the respiratory epithelium often coexists with lung cancers. b)Mesenchymal Metaplasia: ( in these situations it is generally a reaction to some pathologic alteration and not an adaptive response to stress) Examples: 1) Metaplasia of fibroblast into chondroblast to produce cartilage. 2)Metaplasia of fibroblast into osteoblast to produce bone in traumatic injury to muscle causing “myositis ossificans” which occurs after intramuscular hemorrhage Summary  CELLULAR AGING Definition: - Cellular aging is the result of a progressive decline in the life span and functional activity of cells. - Caused by genatic abnormalities and, -Accumulation of cellular and molecular damage. -Due to continuous exposure to exogenous factors. (We age because cells of our body age). Mechanisms of cellular aging ▪ Several abnormalities contribute to the aging of cells : 1-Accumulation of DNA damage and mutations: Defects in DNA repair enzymes Enhanced by: -endogenous agents (free radical injury -exogenous agents ) Physical, chemical, biologic) cause Accumulation of mutations in nuclear and mitochondrial DNA -A rare disease characterized by premature aging e.g. Werner syndrome (defective DNA helicase) ,they have defective in DNA replication and have a markedly reduced capacity to divide. 2-Decreased Cellular Replication: -All normal cells have a limited capacity for replication (Replicative Senescence reduced capacity of cells to divide , non dividing state cell cycle arrest) ❖Aging is associated with progressive replicative senescence of cells: -Telomere is short repeated sequence of DNA present at the linear ends of chromosomes – ensures complete replication of chromosomes and protect chromosome endings from fusion and destruction. -Telomere shorten each time the DNA replicate at chromosome ends and no longer divide and aging. - Telomerase maintain the normal length of telomeres in immortal cell by adding (TTAGGG) repeates onto the telomeric ends. -Telomerase activity is increased in some cancer cells. In humans, telomerase (cellular immortalizing enzyme)is active in germ cells, in vitro, immortalized cells , the vast majority of cancer cells and , possibly in some stem cell, 3- Defective protein homeostasis: loss of normal proteins and accumulation of misfolded proteins. 4-Persistent inflammation : Aging is exacerbated by chronic diseases, especially those associated with prolonged inflammation, and by stress, and is slowed down by calorie restriction and exercise. Mai