MCOLEAA © BASIC PRINCIPLE OF CELL INJURY ¢ INFLAMMATION a> [mpeRFecl CINEa LLG } Comm 2 IMPERFECT) PHARMACY,PATHOPHYSIOLOGY e@ The word Pathophysiology is desived ot made ftom 3 words :- - Palhos- Disense = Physio - Nature / Biological function - Lay — ° Fathophystology can be simply defined ag Chango, that ocurs in biological functions — coused by a disease Some Other Common Definitions, Etiology | Tk Is: simply the study of cavses/ reasons of disease . Pathogenesis Tt is the Study of mode /mannes / mechanism of disease formationHomEOSTASIS Tt ts made yp of two words ‘Homes’ and ‘ stasis’ Homeo + Stasis (Sarme) (State) Homegstasis is defined as the ability of human body to maintain Q constant internal environment’ by maintaining. and bolancing a OH, temperature , acid- base level etc. The regulation / maintainance of the homeostasis is govern by the feedbac systems of the bedy. Feepgack SYSTEM When there are some changes fakes place in the intemal environment of body then body's feedback system works to take it back info 4he normol / equilibrium condition. A Seedtack aystem includes +hree basic components © Receptor . or Centre © Effector IweenrecTReceptor A teeptor is a body structure that monitors / detects changes in 4he intemal environment of body Control_Centre A control centre in the body ts receive the input from the receptors and generates output in the form of nerve impulse , hormones or other chemical signols. Effector Effector is a body structure thot teceives output from the control centte and respond to the commands of control Centre. “Types of Feedback Systems There are basicaly tuo types of feedback aystem © Positive Feedback System © Neqotive Feedback SystemNeGative FEEDBACK SYSTEM A nenabive Seedback system fesponses to reverse / decrease the changes in internal environment - example Regulation of blood pressure Stimulus. Increase in Heart rote { Blood Pressure Increceet t FT Receptor Baro receptor achates and sends input to Control centre in tne form of nerve impulse t Control Centre Brain collect input and sends output t Effector Blood vessel receives output € gets dilated 4 Blood Pressure decreased Blood Pressure back +o normal € body feturn +o homeostasisPositive FEEDBACK SYSTEM A positive feedback system responses to Increases the change in \otemal environment: example: Normal Child Birth. Contraction of uterus wall forces baby's body /head 40 cervix t t Receptor Stretch sensitive nerve cells Sends input to Control centre inthe form of nerve impulse t Control Centre Brain collects input and sends output by releasing. oxytocin bicubic t Effectow. Uterine muscles contract more forcefully t Stretching, of cervix | aT Baby's body stretch cervix more| [Increased stretching of cervix Causes felease of more oxytocin which resuts fn more stretching of cervixCec. INwury © Cells ore the basic unit of tissues , which forms organ € + systems In human body . © Cell Thy is defined as effect of variety of stresses that cause changes in cell's intemal ax well as extemal environment . © The cellular (esponses fo stress depends on variety of factors, and also the cell injury can be either reversible or freeversible . Normac Ceur Moderate Stress Atrophy Hypertrophy Hyperplasia Metoplosia Necross, Dysplasia Apoptosis Cellvlor_Adaptation (lve adaptation iso process of any cell fo sumive in any Opposite or adverse situation. These are the temporary Or permanent changes in the shape , size or type of cal. Pxample : Attophy, Hypertrophy , Hyperplasia etc. ? TwvenrecTReversible Cll Injun TF the stress omied on the ell is mild to moderate level then after somehme when applied stress is femoved cells recovered back fo its Normal state and this phenomenon is known a& Revesible cell Thjury Tneversible Cll Inju FF the stress applied on the cell tg very Severe level then it leads to cell death and cells never recovered back , then this type of phenomenon is known ax reversible cell injury .There are variety of causes! stress which can cause cell injury , they an be mainly classifiecl into two classes ® Grenetic Causes Acquired Causes Genetic_Guses © When cell injury occurs due to defect tn genes or chromosomes , then these type of cowses ore known as genetic Couses, © They are of following types © Developmental Defect ® Cytogenic Defect @ Single Gene Defect ® Mutifincional Inheritance Disorder [Developmental Defect]: These are the defects that ocurs in the starting of development of fetol life . [Gutogenic Defect]: These are the defets that occurs or reloted ath abnormalities of chromosomes . it can be eithes structural or fureHenal numerical . [Single Gene Defects]: Tt is also known as Mendelian Disordes and outs due to disorder in single specific gene. Mutiindional Inheritance Disorder]: These are the disorders that ocurs due fo multifunctional (ex) IwrenrecT [runacr)Acquired Causes © Giher than genetic ‘here cre many Other aquired couses thal are responsible “for cell injury : © Thay are as follows ~ © Hypoxia / Ischemia @® Physical Agents @ Chemical Agents @ Microbial Agents © Immunological Agents © Notional Dearrangements @ Poychogenic 2 Gils of different tissues require oxygen € blood to generate energy € perform different functions. Hyporia is defined as loss of oxygen supply while Ischemia is defined as loss of blood supply € both are one of the mayor causes fos cell Injury . [Physical Agents ]: There are many physical cefets that con casse Cell inqury @ Mechanical Trowma : Accidents © Thermal Trowma : Heat / Gld © Electoicity : Curent © Radiation : UV rmoys ©@ Rapid Change in AtmosphereChemical Agents |: Following chemical defects can couse cell injury © Chemical Poisoning : Cyanide , As etc. © Strong Acid/ Base + HaSou, Nao , HCI etc. @ Environmental Pollutants © Pesticides € Insectisides © Hypertonic Salt © Alcohol, Nicotine , Drugs Microbial Agents |: Various microbial agents like bacteria, Fongi » Virus Protozoa, Paracites etc Gon also cause defect in Cellular fonctions € responsible for cellular injury . [Gimmonotogical Agents | : The immune system works in the defence against foreiqn agents but sometime immune fesponse feactiona such as Hypersensitivity Teaciions , Autoimmune Disorders can cause Al injury . [Notional Dearrangements J+ Dificiency or excess of nutrients may lex to Nutritional Imbalance which uttimadely Gon couse Cell injury ° Dificiency 2 Anaemia © Excess : Obesity Peychogenic Defects |: Paychogenic defects ke Anxiety , Depression € Drug Addictness like alcohol, smoking a fo call injury. [runacr)© Tnyuy to cell may have many causes that con be either known or unknown but in most of fhe Cases oxygen plays a central role tn cell Injury © Pathogenesis of cell injury mainly include - © Cll Membrane Damage @ Mitochondrial Damage © Ribosome Damage @ Nedeor Damage ATP Formation | Nat/ kt Pump Failure Lactic Acid t € pnyPathogenesis of Reversible Cel Thjory © Hypoxia / Ischemia leads to decreased generatton of cellular ATP. ® Sodium - potassium pump clamage leads fo accumulation of sodiom € woler inside the cell which ultimately couse cel swelling. © Trcteasec| anaerobic qiycolysis leads to increased formation of © lactic acid which cause cong of chromatin . © Odtachment of ribosomes from endoplasmic reticulum leads fo decrease! formakon of parteins . enesis_of Tneversible_cell_tnju @ Increased calcium influx : Mitochondnal Da © Phospholipase Activation =. Membrane Damage © Protease Activation : frotetn Damage © Endonucease Activation * Nuclear Damage © Alpase Activation : ATP Damge © Bursting Of Lysosomal Enzymes: Cell DeathGeneral Steps | Pothogenesis of _@ll Dhow © Membrane of ceil can be easily damaged by any type of destructive physical agents like heat or radiation . © Loss of Oxygen supply cused by hypoxia decreases the ATP formation £ due to this supply of essentiol material that cll needs to survive Teduced . ® Also the membrane damage increases the infiox of (* fons inside the cell which oimately plays mojor fole in cell injury . @ Tragased! tn cytosolic calcium leads to increase in inoganic phosphate and certain fatty acids. © Thorgonic phosphate and fatty acids alone can rot damage the titochondria but along with Ca?! they can extremely damaged the mitochondria . © Even Calcium con alone damage the mitochondria , Ribosome Damage © Decreased ATP formation leads fo detachment of nitosomes from fough endoplasmic “seticulum which vlkimately leads to decreased} rotein synthesis / ° Pee In the proteth synthesis ultimately leacls to major — arecT oo© The decrease in ATP formation € loss of Orygen supply leads to Increased anaerobic glycolysis which results tn the increased formation of Lactic Acid . © This lactic acid leads to clumping of chromatin -€ fall in pH . © The fall tn pl leads fo bursting to lysasomal enzymes. which ullimotely couse cell death . Free Radicle_Mediahon of -@ll Tnory © Free adicols are chemical species that have single unpaired eleckon in their outer orbit . © Th biological system the term fee radicals mainly fefer to feadive “Oxygen species CROS) . © Free fadicles ore exteremely unstable and reacts with cell membrne € Nudeic acid tn the cd. © There ase some ‘radicals like Superoxide radical » Peforide rane, ete that Are very destructive to lls thal cause lipid damage oxidation of piotein, DNA damage etc. coMorenovogy Or Ceu Iniury - Adaptive CuanGes © Adaptive changes are the adjustments which the cell make in fesponse +0 skesses @ These changes can be physiological as wel ax pathological . Adaptive changes are generally telale! to change tn Stee, shope ot type of ll. @ These are the following adoptations a cell moke in response to various type of stresses . © Atrophy @ Hypertrophy @ Hyperplasia @ Metaplasia © Dysplasia Attoy Atrophy ts defined as decrease in size of the cell. TF atrophy takes place in enough number of an organ's cell the complete organ gets smalles, Atrophy 1s mainly found in heart , skeletal musdes , brain etc. Tt can be either Physiological or palholagical . oucalHypertroph © Hypertrophy is defined as increase tn size of the cell. © TF hypertrophy occured in enough number of calls of @ particular Organ then it leads fo increase in Complete organ size. © Te generaty occured due fo increased funcional demand © Hypertrophy can be elther physiological or pathotog’cal : — CLED Of Hyperplasia © Hyperplasia is defined as an increase in number of cells. © TF hyperplasia continues then finally it results in the enlargement ans . © TF aan be either physiological or pathological — EB Hyperplasia,Metaplasia © Metaplasia ts simply defined ag directly change in type of the cell. © Th metaplasia function of one call is Completely change into. function of another cal. ot an be either Physiological or pothelagicel . COCO > CLO Cm © Dysplasia © Dysplasia Is defined a8 abnormal or stoppage of growth. © When the growth of @lt is stop and its shape € size femain Constant ds per germ cel then it 1s called dysplasia © Tt can be ether physiological or pathological . ©-0-0-O ©-0-@-©CELLULAR SWELLING © (ell Swelling 1s simply defined as accumulation of water. © Cell Swelling 1s generally acured due fo dlisbalance in the function of Nat/k pump . © Cell swelling Is generally caused by high fever , Buma or dve to any chemical or bacterial agent © Grenerally cell swelling results in the incrense of Sze € weight of the organ . @ The Swelling of cell Is reversible . ATP ¥ 4 4 $ tTntracellular Accumulation © Intracellular accumulation 1s simply define! aa accumslation of abnormal substanes that can ‘emporaily or pesrnanenty lomage a ell. © Ti con be cer due fo cuerproducion , abnormal metabolism or disbalance in normal physidoay . Tt Gn be either feversible Or imeversible . —Galatfication _ © Calcification is’ defined as accumulation of calcium in body tissues © Th Mormally occurs in the formation of bone but abnormal cleposition Of buildup of calcium can disrupt body's natural process . © Calcification can be occur almost in every part of body - eventoally leads +0 health problems, . © TF can be ocur due to hypercalcemia , Calcium metoboltic disorders , Qolcium fich diets etc. Leakage € Gl! Death © The \ysosomes inside the cell is fulftled with hydtoly tic enzymes , © These enzymes are 80 much destrucive that it can instonti destroy the whole cell hence they are safely packed inside lysosomal membranes . © Disbalance in normal body function € acid- base balance con leads 4o breokage of lysosomal membranes ond leakage of these emymes that eventually leads to elt death. ws ayAcidosis € Alkolosis _ © Most of the body's organs funcions ot a cettain pH © Disbalonce in thés pH can cause distutbahce tn findioning. Tdeotly ph of blood ts 44. © TT this pH goes below 74 then jt ts defined aa acidosis . otf the es above %4 then it ts defined ag alkalosis . © Now this acidosis | alkalosis are of ly two © Respiratory oe OF decreases ee o. “icin? @ Metabolic —C Other than respiratory ) Electrolyte Imbalance © Bloodstream contains many chemicals thal are very essential for Tormol body functions . Electrolytes are one of them. © Gilcium, Magnesium, Sodium , fotascivm are some examples of eledrolytes . © Now Disbalance in these electrolytes (an cause vari of disturbanes . fe Elecrotyte Imbalance can become result into Vomiting , Diarthoet, sweating , High fever etc.INFLAMMATION © Infiammation cin be simply defined as a protective response of body's immune system against injory . Th aan also be defined as a process by which our body's white blocd cells protect us from infection with foreign patties. © Inflammation ts body's natural reaction ogainst injury -¢ infection Causes Of Infiammation There are varius causes of inflammation a8 ‘follows * © Physical Agents + Heat , Gld, Radiation , Mechanical Trauma © Chemical Agents ° Add, Base, Toxic Gases . © Biological Agents + Niral bacteria, fungal Tnfecions, . © Metabolic Products * Une Acid, Urea . © Circulation Disorders: Thrombosis, Infarction . Clinical Signs OF Inflammation _ © Redness —C Rubor) © Swelling (Tumor) © Heat C Calor ) © Pain ( Dolor ) © Loss of Function (Fundto Laesa )Types _of _Tnfiammation Depending on the time of durahon , inflammation are of two types : © Acute Inflammation © Chronic Inflammation © Tt oaurs for a short time period and on tapid onset. © The characteristics of acute inflammation, are: = Accumulation of fluid € plasma proteins on affected side . — Activation of platelets € nevtrophills © Tr occurs for a long time perio -€ remain for longer dlmation e@ The characteristics of chronic inflammations are : — Mononuclear Infiltration — Activation of Lymphogtes € Macrophages .Mecuanism OF INFLAMMATION © Inflammation is a process by which body's white blood cells protect the body from foreign substances. such ag, baceria @ viruses , © The mechanism of infiammation can be understand in two major steps © Vascular Events @ Gllular Events © Tr is the exutiest response fowards tissue {njury . © Tt is further divided into two steps, (1) Haemodynamic Chan (2) Alteration in vascular permeability Haemodynamic Chan The following haemodynamic changes occulta during an tnflammatory ise: © Transient vasoconstriction ( 3-S second ) \ © Pasistent Progressive Vasodilation ( Ocurs in half an hour Blood Flow t — Redness € Warn) © Thaeased Hydrostatic Pressure Ctransudation of fivid — Suelling ) © Slowing ] Stasis Fluid Volume 4 - lelons => Red Blood Gils t JupenrecT Areteriolor : End Nee Fluid LossAlteration in Vascular Rermeobit © Due to tnciease in hydtastahe pressure there is a excessive fuid escape ot fluid loss seen in the vessels . © Now if this fluid loss ts without Increased vascular Pameabilty then it Is called “Transudation . © But in case of inflammation vascular permeability get increased € due to this there is large amount of proteins also comes out with this, fluid € this process Is .called Exudalion . © And this protein tich fluid thot is lost from vessels is known ax Fluid Exudote © Loss of fivid from blood vessels and accumulation in interstitial spare is known as Edema , it can be either ttansudate or exudate.Cetwiar Events After the completion of voscular events here is a quick start of @llular events @ Migration of wBCs / Exudation of Leukocytes © Phagocytosis Migration of w8¢s | Erudation_of _levkocytes © Migration of w8cs or Exudation of levkoaytes is defined as escape Of white blood cals from blood vessel to injured fssue . © Now this mieten 1s further divided nfo some steps : oO Changes In Formed elements of blood ® Rolling 4 Adhesion @ Emigration ® Chemotaxis Changes in formed Elements : As we already see in Vascular events that due fo increased blood flow , loss OF fivid increased which leads to slowing of blood stream . Now due fo this : © Central * Stream — © Petiphetal Zone } Magiation © WBG comes Close to + R ng vessels wall fuk ec coRolling € Adhesion + The levkocytes Cmainly nevtophills) Starts rolling 2 adheres on endothelial wall of blood vessels. Selectins responsible for rolling @ Integrins responsible for adhesion . @ Weak Attachment @ Strong Attachment @ Mediated by Selectins e@ Mediated by ntegting. E Selecin fe They are of tuo types > edean } Endobcion Tey, Thin L Selectin } Meottophills [@ Ba Integrins Emigration © Once the leukocytes reaches on _endotheliom surface it starts secreting Collagenases which destroy the basement Membrane and after that kukacyles started moving fowards Injured cell / tiswe € this process is known as Emigration Chemotaxis: The ‘tansmigration of leukocytes afler cfassing several barrier 40 teach the site of injury ts known a6Pha sis © The process of killing or enguifiment of foreign patticles C bacteria ,vivg by WBCs Cleukocytes) ts known as Phagocytosis . © Th is further divided into three steps 0 Recognition € Attachment ® Enquifiment ® killing € Degradation Recognition € Altadiment + The release of chemotactic factors by bacterial products helps the phagocytic cells CwBG) fo recognise bacteria € altach with them Enquifinent + The psudopads present on the surface of leukocytes, wap the foreign patticles € enguif them € the New strudure formed is known as Phagosome . killing € dation : The Phagosome fuses with lysosome & forms Phagolysasame © afer that lysosomal enzymes feleased inside phagolysosome which Kills digest the baceiaMeoiators OF INFLLAMMATION @ Factors or chemicals that mediate the process of inflammation by vascular and Cellular events are known aa Mediotors of Tnflammatton . © These mediators (an be either cell derived or plasma derived . —Propetties_of Mediatora_of nflammolton_ © These mediators are released either from cells or ftom plasma proteins. © Mediators are (leased in tesponse to certain stimuli’. © Mediators act on differnt targets . may hove similar action on different forget cells or diferent action on different target cells. © They moy act on cells which itself produced them or on ther body alls. © The common actions of mediolors ore : Thereased vascular permeabitty Vasodilation , fever , pain ec. © Mediators have short life span . Mepiators OF INFLAMMATION Cell Derived Mediators Vasoactive Amines The Kinin System Arachidonic Acid Metabolites The Clotting System Lysosomal Components The Fibrinclytic System Plotelet Activoting Factor Complement Systern Cytokines Free Radicals Plasma Derived MediatorsThe various ll derived mediators are given as follows : © Vasoactive Amines _ © They give eatliest inflammatory Tesponse © They are of mainly 3 types 1- Histamine 2 Sewotonine ( S- Hydrorytryptamine 3- Neuropeptides HISTAMINE SEROTONIN NeuroPePTiIDES e[Tt is stored in grandes} TF is present in cells [TF is another class of mast cells, basophills] of GIT , splen , mast [Of vasoactive amines and platelets . @lls ac. but rarely activates @|Released due to heat, | Release dve to Or farely seen , cold, ietitotion etc. injury . ©] Acton : Vasodilation | Acton > Same ax histam Vescular Permeability ft Ine but less Potent Tiching , fain etc. @ Arachidonic Acid Metabolites ( Eicosanoids ) © Aradnidonic acid Is 0 fatty acd . © Tt is @ constituent of phospholipid cell membrane. @ Tt is tdease fom cll membrane by phospholipases . ° Prostaglandin 's mayor arachidonic acid metabolite . ? lwenrecT@_Lysosomal Components © The inflammatory els - nevtrophills and monocytes contains lysosomal granules which ads as inflammatory mectialors, . © They are tesponsible for chemotaxis, degradation of bacteria , teense of collagenase etc. ® Plotetet Activating Factor © Tits teleased from basophills , mast cells, endothelium 4 platelets . © TH shows following action, = - Thereased vascular Permeability - Vasodilation - Adhesion - Chemotaxis © Gytokines © Cytokines cre polypeptide substances produced by activated lymphocytes and activated monoaytes © Ths mojor fonctions are adhesion -€ vasodilation . © Oxygen Metabolites and Nitric Oxide © Oxygen derived metabolites ore teleased from activated neutrophils and Mactophages ¢ Plays Mayor (ole In Increeaing vascular Permeability. © Nittic acid is tesponsible for vasodilation.Prasma Dertve MeoiATors These mediators are derived from ackvation and jnteradion of 4 interlinked system Ckinin , Clotting , Fibrinalyhrc € Gmplement ) as follows ° The_kinin System © The system is activated by Xia factor that generates bradykinin © Brodykinin shows following actions: — Smocth muscle contracion ~ Vosoditation ~ Thoeased Voxcular Fermeabilty —The_clotting System _ © This system is also activated by factor Xia that generates fibrinogen which further forma Fibrin . © They shows following adions * ~ Tnceased vascular permeability =. Chemotaxis The Fibrinolytic System © This system is activated by Plasminogen activator. © shows following adiony, : - Adivates factor IL ~ Thoeased voscular permeability ? lweenrecTComplement System © The complement system gets ddivated either b @ The classic pathway of forming antigen-antibody complex ar Gi) The alternate pathway Involve fon- Immunologic agents . © Affer activation it shows Fotowing action, ~ Release Histamine - Thoeas voacvlar permeability ~ Tncrease — Phagoaytosis ooLBasic_Princiere OF Wound HEALING © Wound healing Is a complex and dynamic process . @ Wound Is defined as any type of cut or tnury which bredks the continuity of tissue © Wound rel ts defined a8 repair and regeneration of damage tissues due to any type of injury. Phases of Wound Healin There are basicaly 4 phases of wound healing © Hemostasis @ Tnflammotion ® Praliferation / Granulation @ Remodeling / Maturation Hemostasis © Hemastasis 1s the first step of healing © Tt begins (ust after the ae fo step the bleeding © Tn this step body body activates blood clotting fen thet blocks the blood loss. © Blood clotting occurs by vasoconstriction € Accumulation of plotdets on the site of injury . lucet Co© Tis the second phase of wound healing . © Tt is the defensive phase focuses on destoyng badenia -€ ober foreign poices © This inflammatory phase is further dlividecl into two subphoses : Early inflammatory phase and late inflammatory phase . ' © During early Infiammatory phase WBCs C specially neutrophils deste baci £ oie fe last for ae aie ® During late inflammatory phase WwB(s ( specially macrophages ) Gntinve destroying bacteria 4 cing debris . ; © The ceils also secreting growth facors that helps in Hssue repat. The late inflammatory " phase often last for 4-6 days © Th is the 34 phase of wound healing © This stage is mainly focuses on : ~ Filing the wound = Contraction of wound masgins = Covering the wound © Th ts first granulated tissue fills the wound , then wound ins contacts and afte that Rally epithelial tissue starteel to Covering the wound. © The protifaction phase oRen last for 20-25 days .© During the maturation phase , newly formed tissues gains strength and Pecbility . © Tis the last phase of wound healing . © Th this phase, Collagen fibres reoryanize , Hissue temadels -€ Matures € overall strength increased. © The maturation phase last ftom 94 days - 2 years depending on type of wound . Factors affecting wound _heali The following ters can affed the ime duration of wound healing @ Infection © Blood Supply © Hypoxia oA © Diabetes © Alcohol , Tobaco etc.THANK FE ORICHOOSING|IMPEREECT/PHARMACY/AS)Y OURISTUDYIPARTNER, a by lvperrecl @IMPERFECTPHARMACY, (4 am IMPERFEC TPHARMACY, | > JRIMPERFEC T7PHARMACY,