Pathology (5) Cell Injury - Student Notes PDF

Sala Altamimi  Pathology (5) Cellular responses to stress (4) Presenter: Shifaa’ Al Qa’qa’, MD Assistant professor of pathology Renal and genitourinary pathologist Faculty of Medicine, Al-Balqa Applied University Ground floor Al-salt, Jo...

Sala Altamimi  Pathology (5) Cellular responses to stress (4) Presenter: Shifaa’ Al Qa’qa’, MD Assistant professor of pathology Renal and genitourinary pathologist Faculty of Medicine, Al-Balqa Applied University Ground floor Al-salt, Jordan Email: [email protected] Objectives: - Intracellular Accumulations (lipids, proteins, Hyaline changes, glycogen, and pigments) - Pathologic Calcification (Dystrophic calcification and metastatic calcification) - Cellular Aging  44191 =4/14/ accumulation of Intracellular Accumulations < abnormal or excessive material inside the cells Under some circumstances, cells may accumulate abnormal amounts of various substances, which may be harmless or may cause varying degrees of injury. Intracellular accumulation may be harmful * = = 8%1x. & harmful accumulation I ↳ or harmless to the tissue depends , on the type -& zigi4! & &95, of material accumulated in the cells. The substance may be located in the cytoplasm, within organelles (typically lysosomes), or in the nucleus. where does it ? I occur 3cellular accumulation%E The substance may be synthesized by the affected cells or it may be produced elsewhere. o 81 ! grig = 551 &i,p ;59 jes Tje's Three main causes of cellular accumulation : The main pathways (mechanism) of abnormal intracellular accumulations are: due to 2 1. Inadequate removal and degradation: Abnormal metabolism, defect in protein folding transport. 215 ! Big ! - 2. Excessive production of an endogenous substance. ils , les 3. Deposition of an abnormal exogenous material. -5 > is 1, Increased uptake of the material of decreased excetion of this material mainly due I zsi to metabolic abnormalities or hoss of transport systems responsible for excretion i of this material &j , /  abnormal metabolism of fat Steatosis 1 - 16) Selected examples: %inte ↳ jsl i 1 1. Fatty Change: lipid intracellular accumulation is fat - Also called steatosis, refers to any accumulation of triglycerides within parenchymal cells. - Resulting from excessive intake or defective transport (often because of defects in synthesis of transport proteins. transport J4 E - It is most often seen in the liver, since this is the major organ involved in fat metabolism, but also may occur in heart, skeletal muscle, kidney, and other organs. tissue kind where steatosis occurs - Steatosis may be caused by: & metabolism : 69 fat Liver organs / = ig 50 3:. 1. Toxins 1 eg. 2. Protein malnutrition ! Mis :& fat accumulation s sst fat 3. Diabetes mellitus -19 E.- : 4. Obesity - fat protien + lipoprotein complex responsible for transporting fats -. 5. Anoxia. absense doxygen =, : Mis& lipids , 6. Alcohol abuse. 11 ide ! · tissues 14 at& Eis fat Ji dig. Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver) in industrialized nations !541 &149s(5-7) 0, &! * on%d 01 used Fatty change 2. Cholesterol and Cholesteryl Esters: 3Types of lipids ? - Cellular cholesterol metabolism is tightly regulated to ensure normal generation of cell membranes (in which cholesterol is a key component) without significant intracellular accumulation. jets & 1 cholestrol Did , cell membrane * jon cholesterol membranes sin % metabolism cell - Phagocytic cells may become overloaded with lipid (triglycerides, cholesterol, and cholesteryl esters) in several different pathologic processes------Characterized by increased intake or decreased catabolism of lipids. [ E.g. : Atherosclerosis; lipid seen in macrophages and smooth muscle cells of vessel Cholestral 11 walls in atherosclerosis. that degradades dead gl a macrophages J4 accumulation * cells phagocytic cells - cell membrane of injured or dead cells $95- S Cholestrol Cholestral easters 111 84 + 1is macrophages 54 accumulation Cs macrophages excessive accumulation of cholestral cholestrol easters inside macrophages Ja ** excessive tissue injuryI s i Atherosclerosis o pathologic 15) Atherosclerosis blood flow J& 8. - ?! lipid 5 In atherosclerosis, abnormal hemodynamic changes occur in the blood vessel walls (regardless of whether the patient has hypertension). N & 1 Djopbo os ↳ 39i43 This leads to tissue injury in the vessel wall and an increased number of macrophages, which accumulate cholesterol. ~ 515 sid *This is build up it head to Lissue Ischemia process , may i ;g & tissue Join in injury injury gylie fisshe jet 3. Proteins: - Occur when excesses are presented to the cells or if the cells synthesize excessive amounts. coupled with decreased of excretion or degradation a protein E.g. : - In the kidney, for example, trace amounts of albumin filtered through the glomerulus are normally reabsorbed by pinocytosis in the proximal convoluted tubules. However, in disorders with heavy protein leakage across the glomerular filter (e.g., nephrotic syndrome), much more of the protein is reabsorbed, and vesicles containing this protein accumulate, giving the histologic appearance of pink, hyaline cytoplasmic droplets. The process is reversible: if the proteinuria abates, the protein droplets are metabolized and disappear. & 561 protein droplets 11:55 1 1915 is. i so's. 1 * In Immunologic reactions - Marked accumulation of newly synthesized immunoglobulins that may occur in the RER of some plasma cells, forming rounded, eosinophilic Russell bodies. pinkish material Normal process it doesn't cause accumulation abnormalities in plasma cells - Alcoholic hyaline in the liver (Mallory bodies). protein in the liver - Neurofibrillary tangles in neurons (as in Alzheimer disease). L  Nephrotic Syndrome - - excretion of large amount of albumin which is normally not excreted from glomerular basement membrane (GBM) because it's a large protein. · % albumin 159 = excretion * & ,. ? Nephrotic is excretion && ·15841 Ni (GMB) sl 83 21"T" glomeruli st3 glomerular disorder · filtration Exce ‫وﺑﺎﻟﺘﺎﻟﻲ رح‬،urine ‫(ﻋﺎﻟﯿﺔ ﺑﺎل‬including albumin)‫ رح ﺗﺼﯿﺮ ﻋﻨﺎ ﻛﻤﯿﺔ اﻟﺒﺮوﺗﯿﻦ‬،urine ‫( رح ﯾﻄﻠﻊ ﻣﻊ ال‬filtration)‫ ﺗﺮﺷﯿﺢ‬albumin ‫ﺑﻌﺪ ﻣﺎ ﯾﺼﯿﺮ ﻟﻞ‬- proximal tubule‫ ﺑﻜﻤﯿﺔ اﻛﺒﺮ ﻣﻦ اﻟﻜﻤﯿﺔ اﻟﻲ ﺑﺴﺘﺤﻤﻠﮭﺎ ال‬increased intake of protein ‫ ورح ﯾﻨﺘﺞ‬proximal tubules ‫ﯾﺰﯾﺪ اﻟﺒﺮوﺗﯿﻦ اﻟﻮاﺻﻞ إﻟﻰ ال‬ glomerular disorder ‫ ﻟﻤﺎ ﻧﺸﻮﻓﮫ ﻻزم ﻧﺘﺄﻛﺪ اﻧﻮ ﻣﺎ ﻋﻨﺎ‬protein resorption droplets ‫ﻓﯿﺘﺠﻤﻊ ﻋﻠﻰ ﺷﻜﻞ‬ ↓ reabsorption 19is S In Glomerular disorder alhumin proteind ii. reabsorptionC we see proteins in other proteins in the proximal tubule * urine protein droplets the tubules in * proximal 4. Glycogen: cause glucoseemulation - Excessive intracellular deposits of glycogen are associated with abnormalities in the metabolism of either glucose or glycogen. Es is = - In poorly controlled diabetes mellitus, the prime example of abnormal glucose metabolism, glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of the islets of Langerhans.1..2409 - Glycogen also accumulates within cells in a group of related genetic disorders collectively referred to as glycogen storage diseases-----glycogen accumulation in marcophages due to defect in lysosomal enzymes that break down glycogen. 11. %s ( inde u enzymes ↓I glycogen & degradation 5% 2) inside the cell. glycogen accumulation lipids it also lead to accumulation of other substances like may  material accumulated inside 5. Pigments: Indigestable cells it can be the tissue or inside the endogenous or exogenous & Pigments are colored substances that are either exogenous, coming from outside the S body, such as carbon, or are endogenous, synthesized within the body itself, such as lipofuscin, melanin, and certain derivatives of hemoglobin. Indigestible pigments Exogenous pigments: -black pigment * harmless to the tissue. * accumulated in lung tissue. - The most common exogenous pigment is carbon, a ubiquitous air pollutant of urban life. When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes. Aggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis). E condition of accumulation of Carbon inside the lung tissue Endogenous pigment: By 1 ageing 119 8T of accumulation causes - 1. Lipofuscin “wear-and-tear pigment”: of this pigment - Is an insoluble brownish-yellow granular intracellular material that accumulates in a variety of tissues lipids &C L > damage St (particularly the heart, liver, and brain) with aging or atrophy. lipoprotein free radicals brand 155/. - Lipofuscin represents complexes of lipid and protein that are produced by the free radical–catalyzed 2 damage Illi. 7 _ is peroxidation of lipids peroxidation of polyunsaturated lipids of subcellular membranes. the fat gets oxidizeda broken down - It is not injurious to the cell but is a marker of past free radical injury. > This leads to accumulation of lipofuscin - The brown pigment when present in large amounts, imparts an appearance to the tissue that is called brown atrophy. !* 3 not harmfuls brown d tissue Sign 4 515 is innocent pigments. > Lipofuscin - &XB, previous injury 2. Melanin: S ageing of cell - Is an endogenous, brown-black pigment that is synthesized by melanocytes located in the epidermis and acts as a screen against harmful UV radiation. - Although melanocytes are the only source of melanin, adjacent basal keratinocytes in the skin can accumulate the pigment (e.g., in freckles), as can dermal macrophages. "Where can find melanin ? melanocytes E productions we - Sim % -Keratenocytestorage - excessive production of Melanin "pathologic 3 where accumulation occurs Sun exposure activates melanocytes by melanocytes eg. melanin accumulates in macrophages & Karatenocytes it appears clinically in the treckels form of or skin pigmentation  Heme part & 51 Hemoglobin d 3. Hemosiderin: ferritin/iron o homegroup hemosiderin%6 excretion in the liver% bilirubin pigment 6 Globin part - Is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron. - Iron is normally stored within cells in association with the protein apoferritin, forming ferritin micelles. - Hemosiderin pigment represents large aggregates of these ferritin micelles, readily visualized by light and electron microscopy; the iron can be unambiguously identified by the Prussian blue histochemical reaction. - Although hemosiderin accumulation is usually pathologic, small amounts of this pigment are normal in the mononuclear phagocytes of the bone marrow, spleen, and liver, where aging red cells are normally degraded. hemosiderin i& 53 ,. - Excessive deposition of hemosiderin due to iron overload, called hemosiderosis, and more extensive accumulations of iron seen in hereditary hemochromatosis. Giron overload "Ed - blood transfusion example of condition accumulation inside the tissue by caused excessive hemosiderinc - increased absorptionof iron -decreased secretion of iron  - when does hemosiderin become pathologic ? * it forms after bleeding (brusie)0/oi 80 1: 1 J & , (=) extravasation of RBCs e=& injured tissue& 1519. blood Vessel Ols s hemosiderin &159%9 (5) lysis S's o= 5 Sig 2 brusie that result from saccording to the type of the pigment RBCs the breakdown of as are hemoglobin in ,. degraded by the body 155W: 3 -i d! brusie s ii ↳ hemosiderin brusie 1155 Lipofuscin in cardiac muscle & yellow-brown pigment Helt stain * most seen in hereditary hemochromatosis overload" in the tissue "iron the fiver especially. Hemosiderin in liver. What is the stain???? prussian blue Stain Gistis iron 11  sign i1 * I Dystrophic calcification *Similarities* Metastatic calcification ~ -Both composed of Calcium phosphate Calcium metabolism is normal hypercalcemia + 55 are (2015 the same almost * histologically they , are the tissue ? to blue material in & deposition of purple at the site of cellular injury background tissue is normal , - but theCalcification is widespread. (Cellular necrosis , or site of cellular abnormal ? ageing 3 background tissue is  Pathologic calcification V intracellular or extracellular deposition of Calcium phosphate material - A common process in a wide variety of disease states, is the result of an abnormal deposition of calcium salts, together with smaller amounts of iron, magnesium, and other minerals. It can occur in two ways: harmful harmless be or < can to the amount according 1. Dystrophic calcification: & Location Injury JI's essen 2015 64. 15 , - In this form, calcium metabolism is normal but it deposits in injured or dead tissue, such as areas of necrosis of any type. - Dystrophic calcification is common in areas of caseous necrosis in tuberculosis. - It is virtually ubiquitous in the arterial lesions of advanced atherosclerosis. - Although dystrophic calcification may be an incidental finding indicating insignificant past cell injury, it also may be a cause of organ dysfunction. For example, calcification can develop in aging or damaged heart valves, resulting in severely compromised valve motion. Dystrophic calcification S of the aortic valves is an important cause of aortic stenosis in elderly persons. example of dystrophic calcification - Dystrophic calcification is initiated by the extracellular deposition of crystalline calcium phosphate in membrane-bound vesicles, which may be derived from injured cells, or the intracellular deposition of calcium in the mitochondria of dying cells. It is thought that the extracellular calcium is concentrated in vesicles by its affinity for membrane phospholipids, whereas phosphates accumulate as a result of the action of membrane-bound phosphatases. The crystals are then propagated, forming larger deposits.  harmless unless > - accumulated 2. Metastatic calcification: it is in Large amounts - This form is associated with hypercalcemia and can occur in normal tissues. - The major causes of hypercalcemia are: (1) increased secretion of parathyroid hormone, due to either primary parathyroid tumors or production of parathyroid hormone–related protein by other malignant Conditions ** tumors. · resorption & parathyroid Secretion effect)M bone &25 hermone & J% serumis osteoclast (2) destruction of bone due to the effects of accelerated turnover (e.g., Paget disease), immobilization, or tumors (increased bone catabolism associated with multiple myeloma, leukemia, or diffuse skeletal metastases). (3) vitamin D–related disorders including vitamin D intoxication and sarcoidosis (in which macrophages activate a vitamin D precursor). (4) renal failure, in which phosphate retention leads to secondary hyperparathyroidism. failure is Li ( lowlevelsfaciumda Venal lossal calcium in urine 9 hormone & activation & S i parathyroid breabsorption of Phosphate secondary hyperparathyroidism a condition of Ehyperphosphatemia3  =/ & + / = v Morphology of calcifications: calcification J · tissued 8 histologically the two types of calcification Dystrophic calcification: , almost the are same. Is common in areas of caseous necrosis in tuberculosis. Sometimes a tuberculous lymph node is essentially converted to radiopaque stone. On histologic examination, calcification appears as intracellular and/or extracellular basophilic deposits. With time, heterotopic bone may form in foci of calcification. Metastatic calcification: Can occur widely throughout the body but principally affects the interstitial tissues of the vasculature, kidneys, lungs, and gastric mucosa. The calcium deposits morphologically resemble those described in dystrophic calcification. Although they generally do not cause clinical dysfunction, extensive calcifications in the lungs may be evident on radiographs and may produce respiratory deficits, and massive deposits in the kidney (nephrocalcinosis) can lead to renal damage.  Cellular aging Chronic diseases 14.11515 1551 , 1 j& Aging has important health consequences because age is one of the strongest independent risk factors for many chronic diseases, such as cancer, Alzheimer disease, and ischemic heart disease. Cellular aging is the result of a progressive decline in the lifespan and functional activity of cells.  /198 =v/ * Several abnormalities (mechanisms) contribute to the aging of cells: 1. Accumulation of mutations in DNA: - - With aging, metabolic insults, ROS-induced by toxins, and radiation may result in damage to nuclear and mitochondrial DNA. - Although most DNA damage is repaired by DNA repair enzymes, some persists and accumulates as cells age, especially if repair mechanisms become inefficient over time. Accumulation of mutations in nuclear and mitochondrial DNA ultimately compromise the functional activities and survival of cells. Ana sn=81 pid , ii, repair ! DNA 1451 s s repair d. As ~ &90 > It's Basi is repair entyme 2. Decreased cellular replication: - Normal cells (other than stem cells) have a limited capacity for replication, and after a fixed number of divisions, they become arrested in a terminally nondividing state, known as replicative senescence. Aging is associated with progressive replicative senescence of cells. Cells from children have the capacity to undergo more rounds of replication than do cells from older people. - In contrast, cells from patients with Werner syndrome, a rare disease characterized by premature replications (19 161 < replication - aging, have a markedly reduced in vitro life span. 11&, jet telomeres J. , chromosomes nucleotides is edges of chromosomes & protection%s S,m abnormality during replication & mis fusion s duplication or breaks & 20 i5 - Replicative senescence occurs in aging cells because of progressive shortening of telomeres, which S - ultimately results in cell cycle arrest. telomere 1100 replication (1501 & & ; #5 is - Telomeres are short repeated sequences of DNA present at the ends of chromosomes that are important for ensuring the complete replication of chromosome ends and for protecting the ends from fusion and degradation. Telomeric DNA also binds proteins that shield it, preventing activation of a DNA damage response. When somatic cells replicate, a small section of the telomere is not duplicated, and telomeres become progressively shortened. As they shorten, the ends of chromosomes cannot be protected and are sensed in cells as broken DNA, which signals cell cycle arrest.  Ptelomere 11 - Telomere length is maintained by nucleotide addition mediated by an enzyme called telomerase. Telomerase is a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes. Telomerase is expressed in germ cells and is present at low levels in stem cells, but absent in most somatic cells. Therefore, as mature somatic cells age, their telomeres become shorter and they exit the cell cycle, resulting in an inability to generate new cells to replace damaged ones. Conversely, in immortalized cancer cells, telomerase is usually reactivated and telomere length is stabilized, allowing the cells to proliferate indefinitely. In cancer cells telomerase activity increases (3 E Cancer cells aplastic anemia the telomerase activity decreases Telomere shortening also may decrease the regenerative capacity of stem cells, further contributing to cellular aging. Despite such alluring observations, however, the relationship of telomerase activity and telomere length to aging has yet to be fully established. Abnormalities in telomere maintenance have been implicated in many diseases, such as aplastic anemia and other cytopenias (thought to be caused by a failure of hematopoietic stem cells), premature greying of hair, skin pigment and nail abnormalities, pulmonary and liver fibrosis, and others.------These disorders are sometimes considered the prototypic “telomeropathies” 55 Cell cycle # telomerase 81. & bites ! telomere a nucleotides decreased activity of telomerase 11 , replications 11 254 15512. 3 telomeres) 59 is cell sl:155 2 Cell death 11 d. · Telomere and telomerase in aging  /198 =v/ * 3. Defective protein homeostasis: > - imbalance body in how proteins are managedof produced in the > more down proteinsmade are broken than Increased protein turnover and decreased protein synthesis caused by reduced translation of proteins and defective activity of chaperones (which promote normal protein folding) and proteasomes (which destroy misfolded proteins). The resultant decrease in intracellular proteins------many deleterious effects on cell survival, replication, and functions. The concomitant accumulation of misfolded proteins----- exacerbates the loss of functional proteins and can trigger apoptosis.  due to > - causes cellular ageing 4. Persistent inflammation: increased cytokines. As individuals age, the accumulation of damaged cells, lipids, and other endogenous substances may activate the inflammasome pathway, resulting in persistent low-level inflammation. Inflammation in turn induces chronic diseases, such as atherosclerosis and type 2 diabetes. Cytokines produced during inflammatory reactions may themselves induce cellular alterations that exacerbate aging, and chronic metabolic disorders may accelerate the aging process.  that help the body response to stress hormones > - 5. Stresses, perhaps acting via increased production of glucocorticoids, accelerate aging. Alas, the precise mechanisms underlying these effects remain to be defined. high Levels of glucocorticoids over time effects can have negative on of to the the body contribute ageing process Biochemical signaling pathways that counteract the aging process: fewer Calories than usual > eating while still getting all the important nutrients your body needs. Calorie restriction has been found to slow down aging and prolong life in every species tested from flies to mice. It is now thought that calorie restriction alters signaling pathways that influence aging. Among the biochemical alterations associated with calorie restriction that have been described as playing a role in counteracting the aging process is reduced activation of insulin-like growth factor receptor signaling, which involves a downstream network of kinases and transcription factors. Reduced IGF-1 signaling leads to lower rates of cell growth and metabolism and possibly reduced errors in DNA replication, better DNA repair and improve protein homeostasis. Calorie restriction also serves to improve immunity. All of these inhibit aging. Clinical observations and epidemiologic studies have shown that physical activity and calorie restriction slow the aging process. physical activity restriction 51 , Calorie J* ! -4 vs -1995&6 I cellular ageing Mechanisms of cellular aging Thank you