Today’s Quranic verse

1. Today’s Quranic verse For Muslim men and women,- for believing men and women, for devout men and women, for true men and women, for men and women who are patient and constant, for men and women who humble themselves, for men and women who give in Charity, for men and women who fast (and deny themselves), for men and women who guard their chastity, and for men and women who engage much in God's praise,- for them has God prepared forgiveness and great reward. [033:035]

2. Overview of Inflammation • Inflammation as one of the Tissue Response to Injury • The most important topic in Pathology • “If you understand Inflammation you understand Pathology” • “Otherwise you do so at your own risk” • A complex set of tissue response to injury at the site of injury involving 4 sets of tissue response and 4 stages • I = D+N+CD+GD+IIC • SOI=TC+VC+EnP+RnR

3. STIMULUS 1.DEGENERATION 2.NECROSIS NORMAL CELL MOLECULAR LESIONS Tissue Response to Injury(Histopathological Concept) RESPONSE TO THE NECROTIC TISSUES 9.PIGMENTATION NECROSIS 3.INFLAMMATION=COMPLEX SETS OF TISSUE RESPONSE TO INJURY AT SITE OF INJURY =D+N+CD+GD+IIC 4.CD=D OF CVS 5.GD=CHANGE IN NUMBER, SIZE, TYPE AND ARRANGEMENT IIC=INCREASED INFLAMMATORY CELLS GD→DYSPLASIA→6..NEOPLASIA GD→FOETAL STAGE →7.CONGENITAL ANOMALIES CHEMICAL+PHYSICAL STIMULI →8.TRAUMA PIGMENTS→9.PIGMENTATION OTHERWISE 10.MISCELLANEOUS

4. Overview of Inflammation(Robbins, 2:33) • The same stimuli that cause cell injury also elicit inflammation • Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult. • Inflammation accomplishes its protective mission by diluting, destroying, or otherwise neutralizing harmful agents. • Iinflammation then sets into motion the events that eventually heal and reconstitute the sites of injury • Inflammation is intimately interwoven with repair process whereby damaged tissue is replaced by the regeneration of parenchymal cells, and/or by filling of any residual defect with fibrous scar tissue • The inflammatory response involves circulating cells and plasma proteins, vascular wall cells, and cells and extracellular matrix of the surrounding connective tissue • The broad outline of inflammation are as follows: • An initial inflammatory stimulus triggers the release of chemical mediators from plasma or connective tissue cells. • The mediators amplify the initial inflammatory response and influence its development by regulating the subsequent vascular and cellular responses. • The inflammatory response is terminated when the injurious stimuli is removed and the inflammatory mediators catabolized or inhibited. • Inflammation is divided into 2 basic patterns: acute or chronic • Acute inflammation is of relatively short duration, lasting from a few minutes up to a few days, and is characterized by fluid and plasma protein exudation and a predominantly neutrophilic leukocyte accumulation. • Chronic inflammation is of longer duration, days to years, and is typified by influx of lymphocytes and macrophages with associated vascular profileration and scarring.

5. اﷲ Pathogenesis and Sequelae of Inflammation(a complex set of tissue response to injury at the site of injury involving 4 tissue responses with 4 stages and increased inflammatory cells ) Capillary,Venules,Arterioles Chemical Mediators (13) Vasodilation-Arteriolar Dilatn Endothelial Integrity Vascular Permeability Bld Flow- Axial,,LaminarFlow Bld Pr PMN-Nuet,Eos,Baso MNC- L,Mono,Histo,Plasma cell Macrophages,Giant Cells,Mast c Chemical Mediators,Cytokines Exudation,Infiltration Proliferation Phagocytosis Non specific Immune Response Blood/Vessel (Haemodynamics) Inflammatory cells (10 Types) Stimulus (Infectious,physical,chemical) Labile Stable cells Permanent cells ECM Interstitial Tissue Interstitial Tissue space Tissue (Cell Types) Hypoxia/Hypoglycaemia Free radical:O2÷,H2O2,OH• Trauma, Temperature extremes Virus, Bacteria, Fungi, Parasites, Toxins, Poisons, Drugs,Allergens, Stages of Inflammation (4) 1.Tissue Changes=Tissue Injury=Degeneration → Necrosis 2.Vas. Changes=CD=Vasodilation → V. Perm. → Oedema 3.Exudation + Infiltration=Increased Inflammatory Cells 4.Regeneration + Repair=GD=Hyperplasia + Fibroplasia Acute Inflammation AI(≈3 days) Mediated by 13 mediators (Histamine, Serotonin, Bradykinin, C3a, C5a, Prostaglandins, Leukotrienes C4, D4, E4, Oxygen metabolites, and PAF). Types of AI based on exudates and lesion 7 main Mechanisms of AI (Stages): 1.Tissue Injury: (refer to SAF on Cell Injury) 5 main mechanisms:ATP Depletn, Reactive O sp.,Loss of Ca homeostasis, Defects in Plasma memb.Perm., Mitochondrial Damage 2.Vasodilation: 3 main mechanisms: Preformed mediators eg Histamine,Serotonin NewlySynthMediators eg Prostaglandin,Cytoki SystemicMediators eg Bradykinin,C3a,C5a 3.Oedema: (refer to SAF on Oedema (IP)) 5 Mechanisms of Inc. Permeability (IP) at endothelia: EC, JR, DI, LDL, RE 4.Exudation: 4 main mechanisms(stages): Endo.Activatn, LeukocyteRolling,FirmAdhesn, Transmigratn. 5.Phagocytosis: 4 main mechanisms(steps): Recognitn, Engulfmt, Killing, Degradatn. 6.Regeneration: (refer to SAF on Regeneration) (Mechanisms of Hyperplasia) 7.Repair: (refer to SAF on Wound Healing) (Mechanisms of Fibroplasia) Chronic Inflammation CI(>2 weeks) Similar mechanisms to AI but Stimuli Persistent. Continuation after AI Types of CI based on cell types (Mainly MNC) Granulomatous Inflammation (GI)- Lymphocytes, Plasma Cells, Epithelioid Cells, Giant Cells, Fibrpblasts 5 Main Mechanisms of CI: 1.Mechanisms ofPersistence: i. Agent Evasion ii.Autoimmune reactions (Delayed Hypersensitivity) iii.Prolonged Exposure 2.Mechanisms of Granulomatous Inflammation: i.Caseous necrosis – Hypersensitivity Reactn ii.Fibrosis iii.Angiogenesis 3.Mechanisms of Macrophage Proliferation: i. Continued recruitment from blood ii.Local Proliferation iii.Immobilization 4.Mechanisms of Tissue Injury in CI: Toxic O2 metabolites, Proteases,Neutrophil Chemot. Factor, Coagulation factor, Arachidonic Acid(AA) metabolites, NO 5.Mechanisms of Macrophage-Lymphocyte interaction: Activated Lymphocytes and macrophages influence each other and also release mediators that affect other cells. Haemodynamic Changes Blood vessels Stimuli Mediators Vasodilation ↓ Velocity ↑ BP ↑ V. Perm. margination ↑ outflow exudation cells fluid ↑ IC (PMN+MNC) oedema proliferation fibrin infiltration - ±Persistence + AI CI ↑ PMN ↑ MNC IT=Interstitial Tissue V. Perm.=Vascular Permeability IC=Inflammatory Cells ITS=IT Space BP=Bld Pr SAF=Sys.App.Flowchart LESIONS: based on the type of exudates 1.Suppurative- ↑ neutrophils with liquefactive necrosis →abscess 2.Fibrinous – predominantly fibrin + PMN 3.Haemorrhagic – predominantly RBC + PMN LESIONS: based on the type of exudates 1.Predominantly MNC with caseous necrosis→granuloma 2.Fibrosis 3.Autoimmune reactions SIGNS: 5 cardinal signs of inflammation →Redness,Heat,Swelling, Pain, Loss of Fn. Systemic Effects: Pyrexia, Malaise, Anorexia, Nausea, Wt. loss, LN hyperplasia, splenomegaly Haematological: Inc. ESR, leukocytosis, Anaemia, SIGNS: based on the organs affected Systemic Effects: Pyrexia, Malaise, Anorexia, Nausea, Wt. loss, LN hyperplasia, splenomegaly Haematological SEQUELAE: based on type of inflammation and organ affected Resolution, Suppuration, Organisation, Fibrosis →CI SEQUELAE: based on the organ affected Fibrosis and Adhesions of organs Chulan2005

6. ﺍﷲ Pathogenesis of Cellular Injury(cellular injury as reversible or irreversible conditions which occur after the limits of adaptiveresponse to a stimulus are exceeded) Agents (Infectious) Environment (Non-infectious) Virus Rickettsiae Bacteria Fungi Parasites ADVERSE INTERACTIONS Hypoxia/Hypoglycaemia Free radical:O2÷,H2O2,OH• Trauma Temperature extremes Atmospheric pressure Radiation Electric shock Chemicals/Poisons Drugs Nutritional Imbalance Alcohol Host (Inherent) Genetic defects Hormonal imbalance Electrolyte imbalance Hepatic & renal failure Allergy/autoimmunity + Inappropriate Immune Response Cell membrane integrity ↓ Aerobic respiration ↓ Enzymatic protein synthesis ↓ Structural protein synthesis ↓ DNA integrity ↓ Metabolic derangements ↑ Oxidative phosphorylation ↓ ATP ↓ Na pump ↓→ Ca++ ↑ ,H20 ↑,K+ ↓ Glycolysis ↑ → pH↓ Glycogen↓ Protein synthesis ↓ Lipid deposition ↑ ATP ↓→Ca++ ↑ Phospholipid synthesis ↓ Phospholipase+Protease+ATPase↑ Endonuclease ↑ Phospholipid degradation ↑ Phospholipid loss ↑ Lipid peroxidation↑ Membrane damage↑ LESIONS (structural abnormalities) DEGENERATION (REVERSIBLE) NECROSIS (IRREVERSIBLE) SIGNS (functional abnormalities) Histopathology Water, fat & glycogen vacuoles Cellular swelling Cytoplasmic deposition of substances Histopathology Cytoplasmic changes Nuclear changes Membrane changes + DEATH Ultrastructural changes Cellular swelling Mitochondrial swelling Loss of microvilli Blebs ER swelling Myelin figures Nuclear chromatin clumping Ribosomal detachment Intramembranous particle aggregatn Autophagy by lysosomes Ultrastructural changes Cytoskeletal changes Nuclear changes → pyknosis, karyorrhexis, karyolysis Lysosomes lysis Membrane lysis Myelin figures ER lysis Mitochondrial swelling Large densities in mitochondria NECROSIS INFLAMMATION Chulan2003

7. اﷲ Pathogenesis and Sequelae of Oedema(a condition of excessive fluid accumulation in interstitial tissue space and body cavities due to pressure imbalance or increased permeability) Hydrostatic pr Arterial Pr Venous Pr Central Venous Pr Blood Osmotic Pr Starling Forces Lymphatic Pr IT Osmotic Pr IT Pr Blood Volume Cardiac Output Fluid Homeostasis Capillary Venules Chemical Mediators Histamine, Serotonin Complement, Kinin Vasodilation Arteriolar Dilation Endothelial Integrity Vascular Permeability Blood/Fluid (Pressure/Vol) Vessel (Permeability) Stimulus (Infectious,physical,chemical) Tissue (Type) Interstitial Tissue Interstitial Tissue Space Tissues of Lower Extremities Tissues with Thrombosis Tissues with Venous Obstruction Vital Organs Hypoxia/ Hypoglycaemia Free radical:O2÷,H2O2,OH• Trauma, Temperature extremes Virus, Bacteria, Fungi, Parasites, Toxins, Poisons, Drugs, Allergens Pressure Imbalance in Non-inflammatory oedema Or Increased Permeability in Inflammatory oedema (PINO or IPIO) Pressure Imbalance (PI) 4 mechanisms of PI based on inc. or dec. Pr: 1.Increased Hydrostatic Pr (IHP=IAP) due to: Excessive parenteral fluid infusion → ↑PVol Excessive salt intake in renal insufficiency → ↑PVol →IAP Heart failure →3 compensatory mechanisms (Sympathetic, RAA,ADH)→ ↑renal retension of Na+H2O → ↑PVol →IAP 2. Decreased Osmotic Pr (DOP) due to: PLGlo=Protein-losing Glomerulopathies, PLGas=Protein-losing Gastroentropathies Protein Malnutrition, Hepatic Diseases 3. Increased Venous Pr (IVP) due to: CHF=Congestive Heart Failure →Congestion Thrombus, Embolus, Immobilization of limbs 4. Lymphatic Obstruction= ↑LPr=ILP due to: Inflammation, Neoplasia, Parasites, Post- surgical, Postradiation HAEMODYNAMICS Increased Permeability (IP) Mediated by 11 mediators (Histamine, Serotonin, Bradykinin, C3a, C5a, Prostaglandins, Leukotrienes C4, D4, E4, Oxygen metabolites, and PAF). 5 Mechanisms of IP at endothelia: 1.Endothelial Contraction (EC) →widened intercell. jn in venules only by Histamine, Bradykinin,, Leukotrienes + others 2.Junctional Retraction (JR) →Cytoskeletal & junctional reorganisation by IL-1,TNF,IFN 3.Direct Injury (DI) involving Necrosos & Apoptosis → endothelial detachment of venules, capillaries, arterioles dt bact. Toxins 4.Leukocyte Mediated (LM) → release of free radicals & proteolytic enzymes →endo. Detachment 5.Regenerating Endothelium (RE) in angiogenesis with capillary sprouts which are leaky capillary AP BP BOP VP ITS IT heart lymphatics AP=Arterial Pr BP=Bld Pr VP=Venous Pr ITS=IT Space BOP=Bld Osmotic Pr IT=Inter. Tiss. LESIONS Grossly organs appeared swollen and wet. Microscopically tissues and cavities filled with fluid LESIONS Grossly organs appeared swollen and wet. Microscopically tissues and cavities filled with fluid SIGNS Depends on the organs affected eg. Vital organs could result in organ failure and death. SIGNS Depends on the organs affected eg. Vital organs could result in organ failure and death. SEQUELAE Depends on organs affected -> death Prolonged oedema lead to fibrosis SEQUELAE Depends on organs affected Prolonged oedema lead to fibrosis Chulan2005

8. ﺍﷲ Pathogenesis of Cellular Regeneration(Regeneration as hyperplasia (of same cell type) which occur after the cells in the G0 stage is recruited into the cell growth cycle) EpidermalGF PlateletDerivedGF FibroblastGF TransformingGF Insulin-likeGF VasoPermeabilityF HepaticGF ColonyStimulatingF Erythropoietin Cytokines NerveGF Growth Inhibitors Mediators (Growth Factors) Extracellular Matrix (Micro-environment) Stimuli (Infectious,chemical,physical) Fibrous Structural Protein Collagens(15 Types) + Elastin Interstitial Matrix(IM) Basement membrane (BM) IM composed of adhesive glycoproteins (AG) embedded in a gel of proteoglycans and glycosaminoglycans AG= Fibronectin + Laminin Cell (Types,Enzymes,genes) 1.Ligand-Receptor Binding at cell surface or inside cells. Steroid receptors are intracellular in nuclei or cytoplasm. 2.Growth Factor Receptor Activation Most growth factor receptors have intrinsic protein tyrosine kinase activity. Otherwise intracellular protein kinases recruited to cell periphery. Tyrosine kinase activity activitated after ligand binding Dimerization of receptors Phosphorylation of kinase Activation of protein phosphorylation cascade Quiescent cells enter growth cycle (G0 → G1) 3.Signal Transduction and Second Messengers Activation of signalling proteins: Phospholipase C-γ convert PIP2→ IP3 → Ca2+ + DAGrelease → PKC activated GTP-binding proteins: G proteins + ras family of proteins for coupling the extracellular signals to cellular effectors (phospholipase). Conversion of GDP →GTP controlled by GAP. Activated ras phosphorylates MAPKs → activation of transcription factors Raf-1 aactivated by ras activates MAPK Cellular phosphotases act as growth inhibitors 4.Transcription Factors Cascade of MAP kinases Growth signals transmitted to nucleus Induction of cellular genes Early growth-regulated genes: c-fos, c-jun, c-myc Late growth-regulated genes: myc, fos, jun Regulation of mRNA and DNA sysnthesis 5.Cell Cycle and Cyclin: G1 and G2 cyclins controls DNA replication with bcl1, Rb and p53 genes. G2 cyclins degraded after mitosis. Daughter cells start new cell cycle again. Infectious Agents Chemical agents Physical agents Can activate the immediate early response genes including the proto-oncogenes 1.Labile cells (dividing) of skin, oral cavity, vagina, cervix, glandular ducts, GIT, uterus, urinary tract, bone marrow, haemopoeitic tissues of stem cells. Continue to proliferate throughout life. 2.Stable cells (quiescent) parenchymal cells of liver, kidney, pancreas, fibroblasts, smooth muscle, mesenchymal cells, connective tissues, endothelium. Can be stimulated to go from from G0 to G1 stage of cell growth cycle. BM needed for organised regeneration 3.Nondividing cells (permanent) cannot undergo mitosis or regeneration. Include nerve cells, skeletal and cardiac muscles. Skeletal muscles may regenerate from transformation of satellite cells in the endomysial sheaths. Neurons replaced by glial cells. Cardiac muscles replaced by fibrous tissues. Chulan2005 Mitosis → Proliferation →Hyperplasia →Regeneration

9. ﺍﷲ Mechanisms of Wound Healing(Wound healing as a complex process involving inflammation, regeneration, remodelling and collagenization) EpidermalGF PlateletDerivedGF FibroblastGF TransformingGF Insulin-likeGF VasoPermeabilityF HepaticGF ColonyStimulatingF Erythropoietin Cytokines NerveGF Growth Inhibitors Mediators (Growth Factors) Extracellular Matrix (Micro-environment) Stimuli (Infectious,chemical,physical) Fibrous Structural Protein Collagens(15 Types) + Elastin Interstitial Matrix(IM) Basement membrane (BM) IM composed of adhesive glycoproteins (AG) embedded in a gel of proteoglycans and glycosaminoglycans AG= Fibronectin + Laminin Cell (Types,Enzymes,genes) 1.Healing by first intention. In uninfected surgical incision. Minimal necrosis of epithelial and connective tissues. Blood clot with fibrin + RBC form scab. Within 24 h neutrophil appear + basal cell hyperplasia. Epithelial cells migrate and grow along cut margin, and fused in the midline beneath the surface sacb. By day 3, macrophages replaced neurophil, and granulation tissue invades incision space. Collagen fibres present. Epithelial cell profileration. By day 5, incision space filled with granulation tissue. Neo vascularization maximal. Collagen abundant. Mature epidermal structure with keratinization. 2nd week – collagen and fibroblast increase. Exudate, oedema, and increase vascularity disappeared. 1st month – scar formation covered by intact epidermis and no inflammatory cells. Dermal appendages permanently lost. 2. Healing by second intention. More extensive loss of cells and tissues as occurs in infarction, inflammatory ulcerations, abscess formation and skin wounds with large defects. Regeneration of parenchymal cells cannot completely reconstitute the original architecture. Abundant granulation tissue grows in from the margin to complete the repair. Wound contractions occurs in large surface wound by myofibroblasts. Collagen Synthesis and Degradation and W.Strength See Fig. 3-43 Cross linkages between alpha chains of adjacent molecules is basis for structural stability of collagen. Cross-linking contributes to tensile strength of collagen. Nett collagen accumulation depends on synthesis and degradation. Degradation of collagen by metalloproteinases dependent on Zn ions. Infectious Agents Chemical agents Physical agents Can activate the immediate early response genes including the proto-oncogenes 1.Labile cells (dividing) of skin, oral cavity, vagina, cervix, glandular ducts, GIT, uterus, urinary tract, bone marrow, haemopoeitic tissues of stem cells. Continue to proliferate throughout life. 2.Stable cells (quiescent) parenchymal cells of liver, kidney, pancreas, fibroblasts, smooth muscle, mesenchymal cells, connective tissues, endothelium. Can be stimulated to go from from G0 to G1 stage of cell growth cycle. BM needed for organised regeneration 3.Nondividing cells(permanent) cannot undergo mitosis or regeneration. Include nerve cells, skeletal and cardiac muscles. Skeletal muscles may regenerate from transformation of satellite cells in the endomysial sheaths. Neurons replaced by glial cells. Cardiac muscles replaced by fibrous tissues. Chulan2005 Fibrosis → Fibroplasia →Repair