Professor of Pathology Faculty of Medicine Ain Shams University Dr. Riham Abu-Zeid Professor of Pathology Faculty of Medicine Ain Shams University

Inflammation 1

Inflammation Definition: It is a protective response of living tissues to eliminate cause of cell injury by diluting destroying or neutralizing harmful agents e.g. micro- organisms and toxins. necrotic cells and tissues resulting from that injury.

Intended Learning Outcomes (ILOs): Define inflammation and recognize its clinical manifestations & systemic effects. Explain vascular & cellular events in acute inflammation and describe its morphology. Describe the cellular events in chronic inflammation. Compare acute inflammation with chronic inflammation. Define granulomatous inflammation and list its causes. Apply the rules of acute and chronic infl. to predict the features of infl. in the different organs of the body. Define toxemia, bacteremia, septicemia and pyemia. Recognize types, possible clinical manifestations and pathological features.

Types of inflammation: Acute inflammation Chronic inflammation onset duration Rapid Short (few minutes up to few days) IF severe →fulminant acute inflammation Gradual Longer duration (days to years) N.B Chronic active inflammation Chronic active :chronic with acute exacerbation Subacute a stae bet acute amd chronic N.B Subacute inflammation

Causes of acute inflammation

What is the aim of acute inflammation ? Leucocytes & plasma proteins injury

How does acute inflammation deliver leucocytes and Plasma prts ?

1-Acute inflammation Acute inflammatory response can be divided into two components: I.Vascular changes. II.Cellular events. 

I-Vascular changes Changes in vascular caliber & blood flow 1- Immediate Transient V.C of arterioles 2-Persistent progressive V.D >>>?? B-Increased vascular permeability VC for seconds in severe >>5 mins VD leads to readness permeability= remove the barriers on side of street so that cars can reach site of destruction and let the soldiers reach VD and permeabilty … edema

2-Persistent progressive vasodilatation mainly in arterioles within half an hour of injury ↑ blood flow & ↑local intravascular hydrostatic pr. with movement of fluid ( plasma containing little protein) . Erythema & Warmth transudate

How does Increased vascular permeability occur?

B-Increased vascular permeability Mechanisms of increased vascular permeability 1-Endothelial cell contraction Mediated by histamine, bradykinin, leukotrienes 2-Endothelial cell retraction Mediated by cytokines as TNF & interleukin-1 (IL-1). 3-Endothelial injury

B-Increased vascular permeability Mechanisms of increased vascular permeability 1.Endothelial cell contraction 2.Endothelial cell retraction 3.Endothelial injury Mediated by histamine, bradykinin, leukotrienes cytokines as TNF & interleukin-1 (IL-1). Direct (burns) Activated Leucocytes Most common cause of increased permeability Leads to intercellular gaps Change in cytoskeleton of endoth cells Cell necrosis> leakage 1& 2Reversible

B-Increased vascular permeability >movement of protein-rich fluid & cells into the interstitium (EXUDATE) Edema d.t outflow of water & ions into extravascular tissues. Stasis d.t ↑blood viscosity Margination of leucocytes (principally neutrophils) along the vascular endothelial surface The loss of protein-rich fluid into the perivascular space results in: 1. Reduction in the intravascular osmotic pressure and increase in the osmotic pressure of the interstitial fluid. The net result is outflow of water and ions into the extravascular tissues. Fluid accumulation in extravascular spaces (edema) is responsible for swelling at the local site of acute inflammation. 2. The red blood cells become more concentrated, thereby increasing blood viscosity and leads to slowing of circulation (stasis). As stasis develops, leucocytes (principally neutrophils) accumulate along the vascular endothelial surface, a process called margination.

transudate What is cause of edema in inflammation ? exudate Early dt inc vasodilatation >inc .hydrostatic pressure Late dt inc. Vasc. permeability transudate exudate

Remember Early steps in inflammation ?

II- Cellular events (A.Leucocyte recruitment B.Leuc. activation) 1) Margination and rolling 2) Firm adhesion 3)Transmigration 4)Chemotaxis

II- Cellular events A.Leucocyte recruitment B.Leuc. activation

1)Margination and Rolling (Selectin) Stasis leucocytes accumulate at the periphery of vessels SELECTIN (receptors expressed on leucocytes & endothelium) Margination SELECTIN Rolling & transient adhesion  As a result of stasis, leucocytes are pushed out of the central axial column and become accumulated at the periphery of vessels. This is called margination, (Fig.3.4).  Subsequently, leucocytes tumble on the endothelial surface, transiently sticking along the way, a process called rolling. The weak and transient adhesions involved in rolling are mediated by the selectin family (receptors expressed on leucocytes and endothelium).

2) Firm adhesion (Integrins ) Normally Integrins are expressed on leucocyte and don’t bind to their ligands Cells at site of inflammation cytokines(chemokines) Activate endothelial cells to increase expression of ligands (ICAM-1 & VCAM-1) to integrins Activate loosely adherent leucocytes integrins  This adhesion is mediated by integrins expressed on leucocyte cell surfaces interacting with their ligands on endothelial cells.  Integrins are normally expressed on leucocyte membranes and do not adhere to their appropriate ligands until the leucocytes are activated by chemokines secreted by many cells at the sites of inflammation. (displayed on endothelial cell surface)  At the same time, other cytokines, notably TNF and IL-1 (also secreted at sites of infection and injury), activate endothelial cells to increase their expression of ligands for integrins. These ligands include:  ICAM-1 (intercellular adhesion molecule 1) and  VCAM-1 (vascular cell adhesion molecule 1). E L Leuc Int Firm adhesion

Chemokines 3)Transmigration (DIAPEDESIS) Leucocytic  migration by squeezing between cells at intercellular junctions diapedesis mainly in the venules. PECAM-1 (platelet endothelial cell adhesion molecule 1) mediated by Chemokines produced in extravascular tissues, PECAM-1 expressed on leucocytes & endothelial cells Chemokines

COLLAGENASES degrade vascular basement membranes Migration in interstitial tissues toward a chemotactic stimulus After passing through the endothelium, leucocytes cross vascular basement membranes by focally degrading them by secreted collagenases COLLAGENASES degrade vascular basement membranes .

What are the steps of leucocytic recruitment? a.Margination & rolling b.Firm adhesion c.Diapedesis chemokines a.L- selectin b.Integrins Stimulus activates inflamm cells either secrete preformed mediators or form new mediators at same time stimulationof the liver produce medaitors e both are differently activated according to enzymes produce other factors and mediators some have local effects eg chemoataxis or opsonization other have systemic effects as fever etc BM & VCAM-1 d.Chemotaxis

Neutrophils predominate in first 6-24 hrs Type of recruited cell depends on Nature of stimulus Age of inflammation Neutrophils predominate in first 6-24 hrs Replaced by Monocytes in 24-28 hrs

4)Chemotaxis directed movement of leukocytes toward sites of infection /injury Chemotactic agents Exogenous Endogenous IL-8 Cytokines C5a C3a Complement Leukoreine B4 Arachidonic acid metabolites Cytokines, (IL-8). Components of the complement system, (particularly C5a and C3a). Products of arachidonic acid metabolism, (leukotriene B4). Soluble bacterial products

Chemotactic molecules bind to specific cell surface receptors. How does the leucocyte recognize the chemotactic agents Chemotactic molecules bind to specific cell surface receptors.

B-Leucocyte Activation By Microbes Products of necrotic tissue Mediators

What are the functions of Leukocytes after their Activation?????????????? Phagocytosis Destroy phagocytosed microbes and remove dead tissues. Amplify the inflammatory reaction Phagocytosis of particles, an early step in the elimination of harmful substances. Production of substances that destroy phagocytosed microbes and remove dead tissues (lysosomal enzymes and reactive oxygen and nitrogen species). Production of mediators that amplify the inflammatory reaction, including arachidonic acid metabolites and cytokines.

Phagocytosis a.Recognition & attachment b.Engulfment Neutrophils & macrophages ingest bacteria & foreign particles. a.Recognition & attachment Opsonins IgG ,C3b b.Engulfment c.Killing and Degradation These opsonins are either present in the blood ready to coat microbes or are produced in response to the microbes. Engulfment: In engulfment, pseudopods are extended around the object, eventually forming a phagocytic vacuole. The membrane of the vacuole then fuses with the membrane of a lysosomal granule, resulting in discharge of the granule's contents into the phagolysosome.

b-Engulfment a-Recognition &attachment c-Killing and Degradation The complement system is a part of the immunesystem that helps or complements the ability of antibodies and phagocytic cells to clear pathogens from an organism. c-Killing and Degradation

Lysosomal enzymes of neutrophils c.Degradation ROS NOS Degradation Ros and lyosomes r most imp Lysosomal enzymes of neutrophils

Inflammatory exudate Pathogenesis Composition Increased vascular permeability Arteriolar V.D Increased osmotic pressure in interstitial fluid Composition Plasma or serum rich in fibrinogen Neutrophils Macrophages (tissue &blood) Increased osmotic pressure in interstitial fluid d.t splitting of large protein molecules into smaller ones

Functions? Dilutes bacterial toxins Brings antibodies to area of inflammation Agglutinins →fix bacteria Opsonins →coat bacteria to help phagocytosis Bacteriolysins→ destroy bacteria Bacteriolysins Contains fibrinogens changes to insoluble fibrin network on which leucocyes moves in direction of organisms localizes infection localizes infection by surrounding the inflamed area Contains leucocytes kill the organisms

Role of Mediators in Different Reactions of Inflammation Vasodilatation ↑ vascular permeability Histamine, prostaglandins, nitric oxide Histamine and serotonin, Leukotrienes C4, D4, E4 Bradykinin Leucocyte recruitment Activation (CHEMOTAXIS) Fever IL-1, TNF, prostaglandins C3a, C5a, Bacterial products, Leukotriene B4, IL-1 Most mediators induce their effects by binding to specific receptors on target cells. The actions of most mediators are tightly regulated; once activated and released from the cell, mediators quickly decay, inactivated by enzymes, eliminated or inhibited. Tissue damage Pain Lysosomal enzymes ROS NOS Prostaglandins bradykinin