بسم الله الرحمن الرحيم Inflammation Dr. Samar Saleh Pathology Department Faculty of Medicine University of Mosul

Definition of INFLAMMATION Inflammation is the response of living tissues to cell injury. Its purpose is to localize & eliminate the causative agent, to limit tissue injury & then to restore the tissue to normality or as close to normality as possible. It is often beneficial, but sometime harmful. The nomenclature used to describe inflammation in different tissues employs the tissue name and the suffix “-itis” e.g., Appendicitis ,Dermatitis ,Cholecystitis , hepatitis ,lung , brain …..ect.

Cardinal signs of (acute) inflammation Rubor = redness due to V.D. Tumor = swelling due to exudate. Calor = heat due to V.D. Dolor = pain due to secretion of PG,BK & nerve compression & irritation. (described by Celsus 1st. Century AD) Functio laesa = loss of function due to pain & swelling i.e. reflux immobilization due to pain. (added by R. Virchow) Cellulits = acute skin infection commonly caused by Streptococcus pyogenes or Staphylococcus aureus

Causes of Inflammation: 1.Infections:e.g., bacterial, viral, parasitic fungal ….. 2.Physical agents: e.g., heat, cold, radiation……. 3.Chemical agents: e.g., acid, alkaline, drugs…….. 4.Hypersensitivity: e.g., rheumatic fever……….. 5.Tissue necrosis: e.g., Ischemic necrosis.

Components involved in inflammation Blood vessels. Plasma & plasma proteins. Cells Circulating cells include :Neutrophiles, Monocytes, L, E, B, & plasma cells. Connective tissue cell include : mast cells, fibroblasts, Macrophage & Lymphocytes. Extra-celluar matrix Collagen, elastic tissue, adhesive glycoproteins, protoglycans & basement membrane.

Types of inflammation 1.Acute inflammation. 2.Chronic inflammation. 3. Acute on chronic inflammation.

Acute inflammation Chronic inflammation Short duration: hours -days –weeks. Exudative fluid (protein rich fluid + inflammatory cells + debris). Main inflammatory cells Neutrophile & Macrophage. Chronic inflammation Long duration: months – years. Fibrosis ( productive ). Main inflammatory cells L, M, plasma cells + fibroblasts & endothelial cells.

Definitions: Edema: excess fluid in interstitial tissue or body cavities. May be either an exudate or transudate Exudate: an inflammatory extravascular fluid that has a high protein concentration( 35-50 gm/l), cellular debris, and a specific gravity above 1.020. Transudate: an extravascular fluid with low protein content and a specific gravity of less than 1.015.essentially an ultrafiltrate of blood plasma resulting from eleveted hydrostatic pressure or diminished osmotic forces in the plasma. Pus (purulent exudate): an inflammatory exudate rich in leukocytes (mostly neutrophils), cellular debris, and in many cases microbes.

Vascular changes and fluid leakage during acute inflammation lead to Edema in a process called Exudation Transudate result of hydrostatic or osmotic imbalance ultrafiltrate of plasma Low protein content specific gravity < 1.015 Exudate result of inflammation vascular permeability high protein content specific gravity >1.020

Exudate Due to increase vascular permeability induced by chemical mediators and due to the direct damage of the vessels, excessive fluid passes to the extra-cellular spaces result in edema. It is consist of: 1.Fluid rich in plasma proteins. 2.Fibrin. 3.Cells: Neutrophils, Macrophages, eosinophils, few lymphocytes & red blood cells. 4.Debris.

What are the function of EXUDATE? 1.It dilutes toxins. 2.It contains fibrin which localize infection. 3.It carries oxygen, nutrients to the inflammatory cells. 4.It carries Drugs, antibodies against bacteria. It may have harmful effects e.g. causing life- threatening hypersensitivity reactions, or relentless and progressive organ damage from chronic inflammation and subsequent fibrosis ( e.g. rheumatoid arthritis, atherosclerosis).

Acute inflammation It is the response of living vascularised tissue to injury . This response is: 1.Uniform, 2.Last for short time. 3.Characterised by exudation of fluid (Edema) and cells (Neutrophile). Neutrophiles are predominant inflammatory cells in early stages (6 - 24 hours). Monocytes ( macrophages) predominate inflammatory cells in later stages (24 - 48 hours).

Processes of acute inflammatory response I- Vascular changes Alteration in vascular caliber resulting in local increase in blood flow. Structural changes resulting in increase vascular permeability. II- Leukocyte cellular events Margination or pavementation & rolling Adhesion & transmigration. Chemotaxis & activation. Phagocytosis & degranulation. Release of leukocyte products.

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Exogenous: bacterial products Endogenous: Chemotaxis & activation Chemotaxis:controled movement of WBCs toward a chemical gradient known as chemotaxins. Chemotaxins:The substance which induce (stimulate) chemotaxis e.g. bacteria, chemical mediators………. Types of chemotaxins: Exogenous: bacterial products Endogenous: C5a (complement factor) LTB4 (lipo-oxygenase pathway) IL-8 (Cytokines) PAF (platelate activating factor)

Phagocytosis & degranulation By neutrophiles & macrophages. Three steps 1-Recognition & attachment facilitated by coating of microorganisms by serum proteins called OPSONINS. Mainly IgG & C3b that bind to Fc & C receptors on the WBC. 2-Engulfment through formation of pseudopodia, phagosome, phagolysosome. 3-Killing or degradation through formation of free radicals (Superoxides, hydrogen peroxide (H2O2) & hydrochloride (HOCL) ).

Release of leukocyte products These include: Lysosomal enzymes (protease). Oxygen-derived active metabolites (free radicals). Products of Arachidonic acid metabolism (lipo- oxygenase & cyclo-oxygenase products) .

Functions of leukocytes Leukocytes extra-vasation have critical function in inflammation it: 1.Ingest offending agents. 2. Kill bacteria. 3.Digest necrotic materials. 4.Release lysosomal enzymes. 5.Release free radicles. 6. Release chemical mediators.

Diapedesis Passage of RBCs through the defect created by the WBCs. It is a passive process.

Summary Changes of Acute Inflammation Transient vasoconstrictionProlonged vasodilatationIncreased blood flow (Active hyperemia  increased vascular permeability-Stasis of blood Swelling of endothelial cells  margination or pavementation of WBC Exudation of WBC (emigration) and passage of RBC(Diapedesis) & exudation of fluid.

Chemical Mediators 2.Increased permeability of the blood vessels. A substances which play a role in genesis and modulation of inflammatory reaction. They are responsible for: 1.Vasodilatation. 2.Increased permeability of the blood vessels. 3.Emigration of WBC (Chemotactic agent).

Types of chemical mediators 1.Those formed in plasma 2.Those formed in tissue cells.

Mediators of acute inflammation Plasma factors synthesized mainly in liver Kinin system Factor XII = coagulation system (Hageman factor) activation Coagulation system Plasma proteins C3a C5a C3b C5b-C9 anaphylatoxins Complement activation opsonin MAC

1) Histamine: secreted from mast cells, basophiles & platelets. Chemical Mediators of Inflammation A/ Vasoactive Amines 1) Histamine: secreted from mast cells, basophiles & platelets. 2) Serotonin: secreted from platelets, enterochromaffin cells. Effects: arteriolar vasodilatation & increase vascular permeability.

AA present in the cell membrane phospholipids. B/ Arachidonic Acid (AA) Metabolites AA present in the cell membrane phospholipids. Release from phospholipids through the action of phospholipase enzyme by mechanical, chemical & physical stimuli. AA metabolism proceeds along one of two pathways Cyclo-oxygenase pathway--- Postoglandins (PG) Lipo-oxygenase pathway------Leukotriens (LT)

Arachidonic Acid Metabolites Cyclo-oxygenase pathway Thromboxane A2 Vasoconstriction Platelet aggregation Protacyclin (PGI2) Vasodilatation Inhibits Platelet aggregation PGD2, PGE2 & PGF2 VD & edema PGE2: Fever Pain Lipo-oxygenase pathway 5-HETE: Chemotaxis LTB4: Aggregation of neutrophils LTC4, LTD4, LTE4 Vasoconstriction Bronchospasm Increase vascular permeability

C/ Platelet-Activating Factor (PAF) Synthesized from membrane phospholipids through the action of phospholipase A2 in basophiles, endothelial cells & neutrophiles. Effect: Platelet aggregation. V.D. & increase vascular permeability. Chemotaxis. Smooth muscle contraction.

Polypeptides produced by activated lymphocytes & macrophages. D) Cytokines Polypeptides produced by activated lymphocytes & macrophages. It involved in cellular immunity & inflammatory responses. IL-1 & TNF Acute phase reaction including fever & Neutrophilia. Promote endothelial secretion of PG & NO. Induce fibroblastic proliferation & collagen synthesis. IT-6 Acute phase reactions. IT-8 Chemotactant & neutrophiles activating agent.

Effects of the Nitric Oxide: E) Nitric Oxide (NO) Soluble free radical gas synthesized by endothelial cells, macrophages & specific neurons in the brain. Effects of the Nitric Oxide: Vascular smooth muscle relaxation causing vasodilatation. Decreased platelet aggregation & adhesion. Microbicidal agent.

Effect: F) Lysosomal Constituents Potentially act as inflammatory mediators when released from neutrophiles & macrophages. Effect: Destruction of ECM. Direct cleavage of C3 & C5.

Effects: G) Oxygen Free Radicals Superoxide (O2-), OH-, H2O2 & NO Endothelial cell damage causing increase vascular permeability. Activation of proteinases. Injury to surrounding cells.

Present as inactive form in the plasma H/ Plasma Proteases 1)Complement System Present as inactive form in the plasma Vascular effect (anaphylotaxins): C3a, C5a & C4a causing V.D. & increase vascular permeability. Leukocyte adhesion, chemotaxis & activation: C5a Phagocytosis: C3b & C3b1 act as opsonin.

Activated by activation of Hageman factor (XII) 2) Kinin System Activated by activation of Hageman factor (XII) Bradykinin: increase vascular permeability , V.D., pain & smooth muscle contraction. Kallikrein: has chemotactic activity.

3) Clotting System A cascade activated by Hageman factor (XII) resulting in conversion of fibrinogen to fibrin. Fibrinopeptides: increase vascular permeability & chemotaxis.

4) Fibrinolytic System: Plasmin: lyses fibrin clots, degrades fibrin to fibrin degradation products. Fibrin degradation products: Increase vascular permeability.

Microscopic appearance of acute inflammation Congestion of blood vessels. Exudation of fluid. Exudation of inflammatory cells mainly neutrophiles.

3. Suppurative (Purulent) Macroscopic types of acute inflammation 1. Cattarhal Acute inflammation + mucus hypersecretion of mucus membrane (common cold). 2. Serous Low protein content, low cellular fluid (pleural effusion). 3. Suppurative (Purulent) Pus: creamy yellow or blood stained fluid consist of N, M.O., & tissue debris (acute appendicitis). Abscess: localized collection of pus material. Empyema: Collection of pus in the hallow organ. 4. Fibrinous Accumulation of thick exudate rich in fibrin, which may resolve by fibrinolysis or organize into thick fibrous tissue. Fibrinous inflammation –bread &butter appearance to the inflamed serous membrane.

Morphologic patterns of acute inflammation Serous inflammation: Tissue fluid accumulation indicating a modest increase in vascular permeability Pleura, pericardium, peritoneum: effusion ,Blister in burns

Fibrinous inflammation: More marked increase in vascular permeability, with exudates containing large amounts of fibrinogen Involvement of serosal surfaces ( pericardium or pleura) : fibrinous pericarditis or pleuritis

Suppurative or purulent inflammation: Production of purulent exudates consisting of leukocytes and necrotic cells.

What’s the fates (outcomes) of acute inflammation? Depending on the nature of lesion, site & response of the host. The followings are the outcome of acute inflammation: 1-Complete resolution: restoration of site of acute inflammation to normal. It involve: removal of the exudate, fibrin & debris. reversal of the microvascular changes. regeneration of lost cells.

Complete resolution

4-Progression to chronic inflammation: Fates (outcomes) of acute inflammation (cont.) 2-Healing & organization: replacement of dead tissue by granulation tissue which mature in to fibrous tissue. It is seen in chronic inflammation, In excessive tissue damage & excessive fibrin deposition. 3-Suppuration It may be diffuse in tissue, localized in tissue (abscess) , on the surface of a wound, or in serous cavity. 4-Progression to chronic inflammation: Acute inflammation progress in to chronic inflammation when there is persistent infection, when there is foreign body…………….

Ulcer: Local erosions ( Loss of continuity ) of epithelial surfaces produced by sloughing of inflamed necrotic tissue.

Role of lymphatic system in inflammation The local inflammatory reaction may fail in containing the injurious agent Secondary lines of defense Lymphatic system; causing lymphangitis (lymphatic vessels inflammation) lymphadenitis (lymph nodes inflammation) Monocytic-phagocytic system; involve phagocytic cells of spleen, liver & Bone marrow.

What’s the effects of Acute Inflammation BENIFITIAL effect Dilution of toxins Entry of antibodies Drug transport Fibrin formation Delivery of nutrient & O2 Stimulation of immune system HARMFUL effect Digestion of normal tissue Swelling & pain Inappropriate inflammatory response.