today’s quranic verse
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Today’s Quranic verse. - PowerPoint PPT PresentationTRANSCRIPT
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]
Today’s Quranic verse
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
Tissue Response to Injury(Histopathological Concept)
STIMULUS
NORMALCELL
MOLECULARLESIONS
1.DEGENERATION 2.NECROSIS
NECROSIS
RESPONSETO THENECROTICTISSUES 3.INFLAMMATION=COMPLEX
SETS OF TISSUE RESPONSETO INJURY AT SITE OF INJURY=D+N+CD+GD+IIC
4.CD=D OF CVS
5.GD=CHANGE IN NUMBER, SIZE, TYPE AND ARRANGEMENTIIC=INCREASED INFLAMMATORY CELLS
GD→DYSPLASIA→6..NEOPLASIAGD→FOETAL STAGE →7.CONGENITAL
ANOMALIES
CHEMICAL+PHYSICAL STIMULI →8.TRAUMAPIGMENTS→9.PIGMENTATION
OTHERWISE 10.MISCELLANEOUS
9.PIGMENTATION
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.
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 )
Inflammatory cells(10 Types)
Blood/Vessel(Haemodynamics)
Stimulus(Infectious,physical,chemical)
Chulan2005
PMN-Nuet,Eos,BasoMNC- L,Mono,Histo,Plasma cell Macrophages,Giant Cells,Mast cChemical Mediators,CytokinesExudation,InfiltrationProliferationPhagocytosisNon specific Immune Response
LabileStable cellsPermanent cellsECM
Interstitial Tissue
Interstitial Tissue space
Hypoxia/HypoglycaemiaFree radical:O2
÷,H2O2,OH•
Trauma, Temperature extremesVirus, Bacteria, Fungi, Parasites, Toxins,Poisons, Drugs,Allergens,
Chronic Inflammation CI(>2 weeks)Similar mechanisms to AI but Stimuli Persistent.Continuation after AITypes 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 of Persistence:
i. Agent Evasionii.Autoimmune reactions (Delayed Hypersensitivity)iii.Prolonged Exposure
2.Mechanisms of Granulomatous Inflammation:i.Caseous necrosis – Hypersensitivity Reactnii.Fibrosisiii.Angiogenesis
3.Mechanisms of Macrophage Proliferation:i. Continued recruitment from bloodii.Local Proliferationiii.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.
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 lesion7 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 Damage2.Vasodilation: 3 main mechanisms:Preformed mediators eg Histamine,SerotoninNewlySynthMediators eg Prostaglandin,CytokiSystemicMediators eg Bradykinin,C3a,C5a3.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)
SEQUELAE: based on the organ affected Fibrosis and Adhesions of organs
اهللا
SIGNS: 5 cardinal signs of inflammation →Redness,Heat,Swelling, Pain, Loss of Fn.Systemic Effects: Pyrexia, Malaise, Anorexia, Nausea, Wt. loss, LN hyperplasia, splenomegalyHaematological: Inc. ESR, leukocytosis, Anaemia,
Tissue(Cell Types)
SEQUELAE: based on type of inflammation and organ affectedResolution, Suppuration, Organisation, Fibrosis →CI
LESIONS: based on the type of exudates1.Predominantly MNC with caseous necrosis→granuloma2.Fibrosis3.Autoimmune reactions
SIGNS: based on the organs affected Systemic Effects: Pyrexia, Malaise, Anorexia, Nausea, Wt. loss, LN hyperplasia, splenomegalyHaematological
LESIONS: based on the type of exudates1.Suppurative- ↑ neutrophils with liquefactive necrosis →abscess2.Fibrinous – predominantly fibrin + PMN3.Haemorrhagic – predominantly RBC + PMN
Stages of Inflammation (4)1.Tissue Changes=Tissue Injury=Degeneration → Necrosis2.Vas. Changes=CD=Vasodilation → V. Perm. → Oedema3.Exudation + Infiltration=Increased Inflammatory Cells4.Regeneration + Repair=GD=Hyperplasia + Fibroplasia
Vasodilation
fluid
Haemodynamic Changes
exudation
↑ V. Perm.
↓ Velocity
Blood vessels
IT=Interstitial Tissue V. Perm.=Vascular PermeabilityIC=Inflammatory CellsITS=IT Space BP=Bld Pr SAF=Sys.App.Flowchart
cells
Capillary,Venules,ArteriolesChemical Mediators (13)Vasodilation-Arteriolar DilatnEndothelial IntegrityVascular PermeabilityBld Flow- Axial,,LaminarFlow Bld Pr
Stimuli
↑ IC (PMN+MNC)
margination
↑ BP
↑ outflow
±Persistence
oedema
-
proliferation
infiltration
+
fibrin
Mediators
↑ MNC↑ PMN
AI CI
Pathogenesis of Cellular Injury(cellular injury as reversible or irreversible conditions which occur after the limits of adaptive response to a stimulus are exceeded)
Environment(Non-infectious)
LESIONS(structural abnormalities)
Agents(Infectious)
Host(Inherent)
NECROSIS(IRREVERSIBLE)
SIGNS(functional abnormalities)
+ Inappropriate Immune Response
Chulan2003
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
Virus
Rickettsiae
Bacteria
Fungi
Parasites
Genetic defects
Hormonal imbalance
Electrolyte imbalance
Hepatic & renal failure
Allergy/autoimmunity
+ DEATH
DEGENERATION(REVERSIBLE)
Hypoxia/Hypoglycaemia
Free radical:O2÷,H2O2,OH•
Trauma
Temperature extremes
Atmospheric pressure
Radiation
Electric shock
Chemicals/Poisons
Drugs
Nutritional Imbalance
AlcoholCell membrane integrity ↓
Aerobic respiration ↓
Enzymatic protein synthesis ↓
Structural protein synthesis ↓
DNA integrity ↓
Metabolic derangements ↑
INFLAMMATION
ATP ↓→Ca++ ↑
Phospholipid synthesis ↓
Phospholipase+Protease+ATPase ↑
Endonuclease ↑
Phospholipid degradation ↑
Phospholipid loss ↑
Lipid peroxidation ↑
Membrane damage ↑
Oxidative phosphorylation ↓
ATP ↓
Na pump ↓→ Ca++ ↑ ,H20 ↑,K+ ↓
Glycolysis ↑ → pH↓ Glycogen↓
Protein synthesis ↓
Lipid deposition ↑
ADVERSE
INTERACTIONS
Ultrastructural changes
Cytoskeletal changes
Nuclear changes → pyknosis,
karyorrhexis, karyolysis
Lysosomes lysis
Membrane lysis
Myelin figures
ER lysis
Mitochondrial swelling
Large densities in mitochondria
Histopathology
Cytoplasmic changes
Nuclear changes
Membrane changes
اهللا
Histopathology
Water, fat & glycogen vacuoles
Cellular swelling
Cytoplasmic deposition of substances
NECROSIS
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)
Vessel(Permeability)
Blood/Fluid(Pressure/Vol)
Stimulus(Infectious,physical,chemical)
Chulan2005
CapillaryVenulesChemical Mediators Histamine, Serotonin Complement, Kinin VasodilationArteriolar DilationEndothelial IntegrityVascular Permeability
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
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
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
SEQUELAE Depends on organs affected
Prolonged oedema lead to fibrosis
اهللا
SIGNS
Depends on the organs affected eg. Vital organs could result in organ failure and death.
Tissue(Type)
SEQUELAE
Depends on organs affected -> death
Prolonged oedema lead to fibrosis
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.
LESIONS
Grossly organs appeared swollen and wet.
Microscopically tissues and cavities filled with fluid
Pressure Imbalance in Non-inflammatory oedemaOr
Increased Permeability in Inflammatory oedema(PINO or IPIO)
AP BOP
ITS
heart
HAEMODYNAMICS
lymphatics
BP VP
capillary
AP=Arterial Pr BP=Bld Pr
VP=Venous Pr ITS=IT Space
BOP=Bld Osmotic Pr IT=Inter. Tiss.
IT
Hydrostatic prArterial PrVenous PrCentral Venous PrBlood Osmotic PrStarling ForcesLymphatic PrIT Osmotic PrIT PrBlood VolumeCardiac OutputFluid Homeostasis
Pathogenesis of Cellular Regeneration(Regeneration as hyperplasia (of same cell type) which occur after the cells in the G 0 stage is recruited into the cell growth cycle)
Extracellular Matrix(Micro-environment)
Mediators(Growth Factors)
Stimuli(Infectious,chemical,physical)
Chulan2005
Mitosis → Proliferation → Hyperplasia → Regeneration
EpidermalGF
PlateletDerivedGF
FibroblastGF
TransformingGF
Insulin-likeGF
VasoPermeabilityF
HepaticGF
ColonyStimulatingF
Erythropoietin
Cytokines
NerveGF
Growth Inhibitors
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.
Infectious Agents
Chemical agents
Physical agents
Can activate the immediate early response genes including the proto-oncogenes
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+ + DAG release → 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.
اهللا
Cell(Types,Enzymes,genes)
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
Mechanisms of Wound Healing(Wound healing as a complex process involving inflammation, regeneration, remodelling and collagenization)
Extracellular Matrix(Micro-environment)
Mediators(Growth Factors)
Stimuli(Infectious,chemical,physical)
Chulan2005
Fibrosis → Fibroplasia → Repair
EpidermalGF
PlateletDerivedGF
FibroblastGF
TransformingGF
Insulin-likeGF
VasoPermeabilityF
HepaticGF
ColonyStimulatingF
Erythropoietin
Cytokines
NerveGF
Growth Inhibitors
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.
Infectious Agents
Chemical agents
Physical agents
Can activate the immediate early response genes including the proto-oncogenes
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.
اهللا
Cell(Types,Enzymes,genes)
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