For Muslim men and women,- for believing men and women, for devout men and women, for true men and...

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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

Transcript of For Muslim men and women,- for believing men and women, for devout men and women, for true men and...

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