CELL INJURY: BASIC CONCEPTS Cell injury : Any disease taking place in the human body at a microscopic level is because tissues are not « functioning properly due to cell damage or not able to function properly Causes of cell injury: At the level of cells 1. Physical factor ~ eg. temperature -> too high temperature -» eg. burn injury less than normal ; sub zero temperature + eg. frostbite 2. Exposure to chemicals 3. Exposure to infections 4. Genetic ~ MC cause of cel! injury at the level of cells is Hypoxia ~ Hypoxia -+ (Hypo ~ less, Oxia~ oxygen) when a cell is having less oxygen with it for purpose of utilization, that is called as Hypoxia a LU ~ 0 diffuse from alveoli into blood. in blood, there are RECs which contains Hb inside them. Hb combines with O* available from diffusion process and forms oxyhaemoglobin. This oxyhaemoglobin goes into different cells or tissues and utilize this O°. ~ 4 coramon causes of Hypoxia ~ 4. Hypoxie type Hoh altitudes pulronary disease 2. Anemie Hp Anemia Non functional Hb Eg. (a) CO poisoning (COHb) (b) MetHe (Fe® Fe) 3. Stagnant hypoxia + Ischemia 7 Congestion 4. Histotoxie Hypoxia+ Cytochrome LO cyanide - MC Cause of hypoxia is ischemiainjurious agent = injurious agent x —_t —, Cell injury ft Reversible Irreversible ‘ Cell Death Severity of injury is affected by - . 1. Duration 2. Nature of cell Sensitivity of cell in body to any kind of injury : Neuron > Cardiac tissue > Skeletal Muscle (Most sensitive cell) Fibre Fibre > Fibroblast (most resistant cell) D vn souscueREVERSIBLE CELL INJURY = 10" + Mitochondria affected -+ 1ATP 4 : Affects ~ Parts or functions of the cells which are mainly energy consuming or energy dependent + 1. Cell membrane 2. Endoplasmic reticulum 3B. Nucleus 4 Cell membrane -+ 2x LATP = | Activity of pump + 1 Na’ inside cell @ 4 nat 1 water inside i ; v Cellular swelling z (£ microscopic feature) . cet Suells op - When cell swells up, additional changes seen are : + Loss of microvilli «Swelling up of organelles «Myelin figures - are small é spiral Fragments derivéd either from cell membrane or membrane of organelles. Myelin figures are made up of phospholipids. ~Sometimes cellular swelling is mentioned by the tera hydropie change 2. ER + Normally ribosomes on surface protein synthesis LATP energy Ribosomes break away ~ 1 protein synthesis accompanied by less formation of secondary and tertiary structure of proteins 3. Nucleus + 102 -» T Glycolysis +1 pyruvate 1 Acidosis 1 lactate- ne 6 + ome Curing, Appearance of Cpateng deposition Nudeus Of, eromatin makrial) = Clumping of chromatin is only nuclear change associated with reversible cell injury= More inside - More Na’ outside ~ More Ca” ~ Mechanism of irreversible cell injury ~ Hypoxia 4.402 + ATP + Energy dependent Ca pumps fats ie t1Ca’ 11. Ene ation Deposition a mitchondi ATPases / nucleases (mitochondrial densities) Phospholipase 4 Lysosomal enzymes Dysfunctional mitochondria Cell Death ~ Nucleases + Pyknosis ~ Karyorhexis a ~ Karyolysis e Figknosis Q-— @ Karyorhexis : ila & Karyolysis Necrosis CSmeor pattern) - Normal cell - single dark hand nucleic material is unbroken - Necrosed cell - diffuse staining nucleic material unbroken & pattern is given k/as smear patternae ~ Phospholipase activation = Phospholipase activation ‘ = Cell membrane damage 1g. Cardiac cell (intracellular enzyme i. Troponin) Reversible cell injury irreversible cell injury 4 ‘ ~ cell becomes bigger ~ cell becomes bigger = no membrane damage ~ membrane damage ~ enzymes won't leak out ——_- enzyme present in cardiac cell will leak out = enzyme level normal ~ increased enzyme level = Angina -Mi NECROSIS = Cell death - changes -» necrosis ~ subtypes 4. Coagulative necrosis ~ tissue will be having firm appearance + denaturation or inactivation of hydrolytic enzymes + most common subtype of necrosis that we observe in the tissue + most common cause of coagulative necrosis is ischemia in solid organs leading to formation of localized area k/as infarcts sZenker's degeneration - enteric fever / typhoid Coagulative necrosis in skeletal muscle is is commonly followed by neutrophilic infiltration is is associated with "tombstone appearance” 2 Liquefactive necrosis / Colliquative necrosis ° Hydrolytic enzymes 4 Damage to tissue architecture = cause of ischemic injury to brain = pus formation DR. SPARSH GUPTA3. Caseous necrosis : Cheese like necrotic material - -™% = Systemic fungal infections (histoplasmosis) ~ coag necrosis + liquefactive necrosis 4. FAT necrosis = fat / lipases ~ injury to omentum tissue ~ injury to breast tissue - Acute pancreatitis 4 Gallstones / Alcohol ‘ Lipase activation Lipa fatty acids 4 Ca2+ Yellow like + saponification chalk like deposits 5. Fibrinoid necrosis = Vessel wall injury Immune complex (type 3 hypersensitivity reaction) 4 : . (42 Damage to plasma protein in the vessel wall o 4 Inside the vessel wall deposition of plasma protein ~ Malignant hypertension - Aschoff body = Ischemia + secondary infection = Ischemia = Lower limb involvement - Bowel ~ liquefactive necrosis ~ Coagulative necrosis = higher chances of bacterimia, purification ~ both dey & wet gangrene scan in diabetes mellitus=Programmed cell death 1 Controlled by genes = Single cell = Small group of cells ~ Physiological or pathological Genes a) Q ~ ps3 gene ~ BCL - 2 gene ~ bea-xs gene ~ BCL - XL gene * Glucocorticoid + 1 * Sex hormone — 1 PHYSIOLOGICAL embryogenesis F515 & f > uf +— k ThC-S000 TLE15009 —Tic-5000 endometrium P — estrogen S + Prog. MENSESPATHOLOGICAL Retinitis pigmentosa t t Rods cones 1 t Diva light Day light Apoptosis of rods + night blindness * Viral infection 1 Councilman body PATHWAYS OF APOPTOSIS Intrinsic pathway SH/ 1 GF +1 BCL 2 activity BCL 2 replaced by BAK /BAX 4 T mitochondrial permeability t 1 cyto 'C in the cytoplasm 1 1 activity of APAF - 2 1 LmownaenInitiator 1 activity of CASPASE 9/10 1 Executioner stimulate (CASPASES 3/6/7) 1 Activity of + Proteases + endonucleases 1 Cell death Extrinsic pathway Severe damage -+ FAS - L or TNE vey 7 TNF @/eAS FADD (ONY ange Caspase - -8 wl A ofa te 3.8 Death eSHmulate Apeptesi ‘Ckp \adder Nomal P a paton) ‘ell Apoptosis Neots mea pattern Flipping 2 Annexin V + 4 of apoptosis Annexin AZ ~ Hairy cell leukemia (oc eot apoptotic al No Inflammation Di orsursncumaNECROPTOSIS + Characteristics + Programmed cell death “. Carpase independent cell death Important for pathogenesis of conditions like free fo Caspase. Radicals ectvetion * Parkinsonism. { * Pancreatitis + Fighting infections like CMV -+ Carpase inhibitor so {O[tipds Gell dents PYROPTOSIS: Caupate, Ini eg cel dest + Pyro means pyrexia or fever + Caused by bacterial infection —» associated with formation of multi molecular complex inside WBC known as Inflammasome formation 4 Caspase 1 & 42 4 IL-1 formation 4 fever FREE RADICAL INJURY + Free radiedl injury :~ unpaired electron in its structure + Highly reactive molecules + Associated with - Radiation ~ Reperfusion injury ~ Heavy metal injury (Cu/Fe) ~ Infections Fe2+ Fe3+ Fenton's reaction $0, 0, + HO > On Hydrogen] (HYDROXYL RADICAL) L Peroxide 1 Free radical fp LaddJ causes Damage to DNA/P/lipids 1 Auto-catalytic reaction 4 Cell Death © Most dangerous free radical - hydroxyl radical © Damage from free radicals can be prevented by :- Antioxidants Antioxidants 2) Vitamin A/C/E 2) Plasma proteins Transferrin (Fe) Cerruloplasmin (cu) 3) Enzymes 0, ~ 0, ———*,,_H,0, + OH sop Glutathione /( gsh \ Catalase peroxidase — gs-sq HO HO 2) Superoxide dismutase 2) Catalase 3) Glutathione peroxidase f 5 DR. SPARSH GUPTASUBTYPES OF APAPTATION. 3) Atrophy —e'A’ means absent “trophy. means growth = atrophy means | in number + 4 in size of cell or tissues = reasons for atrophy -+ protein degradation 4 Proteins are attached to ubiquitin 4 They get available for proteasome (a part of cell) 4 Proteasome destroy the proteins ~ in short, ubiquitin attached proteins are going to be destroyed by proteasome = Atrophy can be seen as a physiological as well as pathological change Example -» (A) PHYSIOLOGICAL () Atrophy of notochord (i) Atrophy of ductus arteriosus ~ it is a structure present in fetal life and not required after baby is born. So cells in this gets destroyed. (B) PATHOLOGICAL () Malnutrition -» babies suffering from this have lower weight as comparison to other age related babies (ii) Disuse Atrophy -+ patient suffering from the fracture of forearm bones, a plaster cast is tied to heal the bones but patient is asked to exercising his hand muscles to keep blood supply normal, No usage of thenar and hypothenar muscles of hand over a period of time will undergo shrinkage and decrease in size. To avoid this movement of muscles are advised to done and is a part of physiotherapy regimen (iil) Senile Atrophy -+ - Due to old age, gradual deposition of lipids on blood vessels ~ Cerebral artery in brain is going to develop atherosclerosis 4 Blood supply to brain is going to decrease causing deficiency of Ach.1 Meyernet Nucleus 4 — Loss of memory (reason) Neurons contain Senile Dementia Acteylcholine (Alzheimer’s Disease) “ 4 memory (iv) Pressure Atrophy- obstruction at urinary outflow level 4 More urine gets accumulated inside the kidney i Compression of the cortical part of the kidney 4 Cortical part undergoes atrophy So absence of growth of cells, either decrease in number or size of cells leads to atrophy New concept regarding atrophy -» Earlier it was considered as totally benign condition, but now it is considered that in some conditions, it is a premalignant condition. Premalignant condition 4 Endometrial cancer -+ (usually elder patients) Type 2 Type 2 4 4 t estrogen (females have endometrial (suffer from endometrial atrophy) hyperplasia) = patients have p53 gene mutation 4 Increases the risk of type 2 endometrial carcinoma 2Hypertrophy ——t"hyper" means excessive "Trophy" means growth DR. SPARSH GUPTA= It is an t in the size of individual cells 4 Over synthesis of structural proteins ~"This can be an example of physiological as well as pathological condition Example -» (A) PHYSIOLOGICAL (0) pregnancy -+ t in the size of cells of uterus and breast (ii) Puberty (ii) Bodybuilders + when they go to gym, pump iron or lift heavy weight 1 1 stress on the skeletal muscle fibres 4 Skeletal cell are permanent, do not multiply 4 That is why stress cause in t of size of cells (E_PATHOLOGICAL @ Cardiac patients + Particularly hypertension (i?) Stricture presence -» Narrowing of lumen and intestine : 4 Area prior to it undergo hypertrophy Heart pumps into aorta 4 Pressure in left ventricle is more than the pressure in the aorta 4 In case of HTN, LV have to exert more force 4 Over time, LV gets hypertrophy 4 Risk of cardiac failure B. Hyperplasia "hyper" means increase “*plasia’ means number ~ It means t no of cells = Can be a physiological change [BPrepLadderExample -» Physiological (D pregnancy (ii) puberty (involvement of uterus and breast tissue in both condition) (B) Pathologi¢al () Endometrial hyperplasia (pre-cancerous condition) 4 Females having this have high risk of endornetrial carcinoma She should be followed Up IF she develops it, To prevent endometrial it should be detected at earliest carcinoma i (i) Prostatic Hyperplasia (Benign prostatic hyperplasia) + Androgen dependent condition | ~ Testosterone is not responsible for BPH 1 Sa Reductase Di - hydro testosterone (DHT) . t in no of cells 4 Clinical syrnptoms of patient [elderly man presenting with delayed micturition, problems with starting the stream, stream is not |_of proper strength, he can not control it going washroom again & again 4 + in the size of prostate ~ This BPH takes place around the urethra zone ~ Periurethral zone enlarges 4 ~ If prostate in this area gets enlarged 4 it will compress the urethraIt is important to know because of two reasons: (il) BPH is not @ risk Factor (0 if patients symptoms are seen for the development of Ca with the help of DHT 4 Relief can be provided’ to patient by Decreasing the concentration of DHT By giving Finasteride to inhibit enzyme Sa reductase prostate as this is a benign condition 4 Reduces size of prostate in elderly male patients and provide symptomatic relief ~ So hyperplasia may or may not be a precancerous condition like atrophy which may or may not be a precancerous condition (4) Metaplasia concentration & hemosiderin = Prussian Blue-> Purple granules Perls Reaction = Hemochromatosis~ more presence of hemosiderin granules = tron deficiency anemia- concentration of hemosiderin in bone marrow reduces LIPOFUSCIN / LIPO CHROME/ FREE RADICAL INJURY PIGMENT = Brown Colored Pigment ~ Perinuclear = Shows lipid peroxidation with free radical injury \ conditions associated with intracellular deposition of lipofuscin: | Ke Protein energy malnutrition Cancer Aging ~ Wear and tear pigment = Brown in atrophy Various theories of aging: 2) Collagen eross linking 2). Free Radial injury- most accepted theory 3). DNA damage / defect in enzyme DNA helicase 4), Telomere shortening Certain disorders in aging:~ D Werner syndrome- DNA helicase defect (:. OF pre- mature aging) 4 DNA damage Sirturins- new set of modecules 1 Alter DNA ‘ ASe free radial damage 4 4Se in insulin resistance (in diabetes) 4 15es lifespan [Bppreptadder2). factors to increase sirtuins in body +12). {Calorie intake 2). Red wine consumption regularly CALCIFICATION Deposition of calcium Calcification Dasivophds Tak 7 Metastatic People with normal calcemia Hyper calcernia Ca deposited in dead /degenerated tissue 1 Deposited. in living tissue Egs:- (R/A/T) gs: 2) Tubereulosis of lymph node 2) Parathyroid Horvacne 2) Cardiac valves in condition Rheumatic 2) Vitarain D Heart disease 2) Parathyroid Horraone t p. Adenoma 3) Atherosclerosis cRE 4). Tumors 2) Vitamin D intoxication m— Meningioma 1 O-) Papilary Cancer Ovaries Granulomatous Disease s-\ salivary glands 1 1/ Thyroid {-€ OH enzyme 4 increased calcitriol Psammoma bodies 3) Milk Alkali <———> Syndrome 4) Metastasis { Osteolysis eas Ca” intracellulary -> Mitochondria * Ca deposit in organs eee, Lungs aatr soma Sage Blood Vessels (Cormonest) (Systemic arteries and pulmonary Veins) "Cas deposition directly will not affect Parathyroid gland PHARMOLOGICAL RELATION WITH CALCIUM Ca* -> Tetracycline (Radio- Labeled) Bone remodeling [ipPrepLadderBASIC CONCEPTS AND VASCULAR CHANGES OF ACTE INFLAMMATION INJURY, 4 RESPONSE OF BODY CHANGES IN BLOOD VESSELS CHANGES IN CELLS CLASSIFICATION INFLAMMATION Aarte Inflammation Chronic Inflammation + at Short Duration Long Duration -Neutrophils = Monornuclear W8Cs Lymphocytes and monocytes. ACUTE INFLAMMATION VASCULAR CHANGES 2) Vasoconstriction -> 1% changes 2) Vasodilation 4 Hyperemia -> Redness (Rubor) increased temperature (Color) 3) Inereased vascular permeability Seo ermal C&ndethekah = eens, Ffisa 4 tnloncn isthe Na) | “Inuessed ” cons | Permeability= Increased Permeability of [- Fluids ExUpATE —{ - Cells 4 |___ - Proteins SWELLING (Tumor) = Most common mechanism associated with increased vascular permeability is endothelial cell contraction. = M/C -» endothelial cell contraction. 4 Arteriole/ capillary / post Capillary Verules (Commonest vessel involved) = In Normal Vessels ~ Extravascular fluid in extra vascular space 4 Drained by Lymphaties 4 Injury increased permeability of cells, proteins. 4 Increased in lymphatic Flow 4 Sometimes bacteria and toxins also going to enter inside lymphatic + Lymphangitis ’) EC Contraction 4 Immediate transient response ii) EC DAMAGE -> Delayed prolonged response / leakage | 4) STASIS Dilated vessel 4 Leakage of fluid rich in protein de cells to outside Y brewed yous —? | : Concentration of blood inside the vessel increases 1 OR, SPARSH GUPTA