Lecture 7 (P) PDF

LECTURE-II PMED-DENT-PHARM Pathology Team By the end of this session students should be able to: Session’s Objectives ◦ Discuss in detail the cellular events of acute inflammation (continued). ◦ Describe the process of phagocytosis and degradation ◦ Discuss briefly the cell derived chemical mediator...

LECTURE-II PMED-DENT-PHARM Pathology Team By the end of this session students should be able to: Session’s Objectives ◦ Discuss in detail the cellular events of acute inflammation (continued). ◦ Describe the process of phagocytosis and degradation ◦ Discuss briefly the cell derived chemical mediators of inflammation. 1. Margination & Rolling: Already covered in the last lecture Cellular Events: Leukocyte Recruitment continued Recap: ◦ Margination: In stasis- leukocytes accumulate at the periphery of the vessels. ◦ Rolling: WBCs tumble down on the endothelial cells because of Selectins, which are receptors on the WBCs & endothelium. (L-selectin on leucocytes, E-selectin on endothelium) 2. Firm Adhesions & Pavementing Cellular Events: leukocyte Recruitment ◦ Firm adhesions of WBC to the endothelial cells is by Integrins on WBC cell surfaces interacting with ligands on endothelial cells. ◦ Integrins & ligands are expressed on the cell surface in response to the chemical mediators of inflammation. ◦ Pavementing: WBCs adhere to the surface of the endothelium & assume a flattened appearance as paving stones. ADHESION- Integrin attachment Integrins PAVEMENTING- shape change. 3. Transmigration: Cellular Events: Leukocyte Recruitment ◦ Diapedesis: Leukocytes migrate through vessel wall by squeezing out at intercellular junctions. PECAM on WBCs & endothelial cells take part. ◦ WBCs degrade & cross basement membrane by the action of collagenases. ◦ Leukocyte move out by pseudopodia. PSEUDOPODIA formation. PECAM DIAPEDESIS- extravasation. 4. Chemotaxis: Cellular Events: Leukocyte Recruitment After extravasation WBCs migrate towards the site of injury along a chemical gradient. ◦ Leukocytes express different kinds of receptors to sense. ◦ Chemotactic products can be: ◦ Bacterial products ◦ Cytokines ◦ Complement components TRANSMIGRATION & CHEMOTAXIS Summary Leukocyte Recruitment https://youtu.be/suCKm97yvyk ◦ In acute inflammation, neutrophils predominate in the inflammatory infiltrate in first 6-24 hrs & are replaced by monocytes in 24-48 hrs. Cellular Events: Leukocyte Recruitment ◦ Predominant cells: ◦ Bacterial infections: Neutrophils ◦ Viral infections: Lymphocytes ◦ Parasitic & hypersensitivity reactions: Eosinophils Leukocyte Recruitment leads to: ◦ Phagocytosis of the particles. ◦ Production of substances that destroy the phagocytosed microbes and remove the dead tissue. ◦ Production of mediators that amplify the inflammatory reaction. 1. Recognition and attachment by specific surface receptors on leucocytes. ◦ Opsonization: Opsonins are the host proteins that coat the target for phagocytosis and leucocytes possess numerous receptors for them. ◦ These include IgG, complement proteins and collectins. Phagocytosis and its steps 2. Engulfment & formation of phagocytic vacuole (Phagolysosome). 3. Killing and degradation of the ingested material. ◦ Microbicidal substances are reactive oxygen species(ROS), reactive nitrogen species and lysosomal enzymes. Neutrophils have azurophilic granules with enzyme myeloperoxidase (MPO). ◦ LEUKOCYTE-INDUCED TISSUE INJURY ◦ The mechanisms that function to eliminate the microbes and the dead cells are also capable of damaging the normal tissues. Phagocytosis ◦ The substances that are released at the site of injury or reach this site through blood. Chemical Mediators: ◦ They bring about the cellular and vascular changes in acute inflammation. ◦ Most mediators induce their effects by binding to the specific receptors on the target cells. 1. Cell derived: Locally produced by the cells at the site of inflammation a. Preformed intracellular granules and are rapidly released upon activation of the cell. Chemical Mediators: b. Newly synthesized in response to a stimulus. 2. Plasma derived: (synthesized by the liver) ◦ Circulate as inactive precursors & are activated at the site of inflammation by proteolytic cleavage. Chemical Mediators: ◦ Cell derived Mediators: ◦ Preformed: ◦ Histamine ◦ Serotonin ◦ Newly Synthesized: ◦ Prostaglandins ◦ Leukotrienes ◦ Platelet activating factor ◦ Reactive Oxygen species ◦ Nitric oxide ◦ Cytokines ◦ Neuropeptides ◦ Plasma Derived Mediators: ◦ Complement system: ◦ C3a ◦ C5a ◦ C3b ◦ C5b – 9 membrane attack complex(MAC) ◦ Factor XII Activation: ◦ Kinin system (bradykinin) ◦ Coagulation system /fibrinolysis 1. VASOACTIVE AMINES (Histamine & Serotonin) ◦ Histamine is found in platelets, basophils, mast cells. ◦ Serotonin is found in platelets only. Cell derived Mediators: ◦ Mediators in the immediate active phase of increased permeability. ◦ Bring about arteriolar dilatation & increase in vascular permeability ◦ Releasing stimuli include: ◦ Direct physical or chemical injury ◦ Binding of IgE- to mast cells ◦ Anaphylatoxins- C3a, C5a ◦ Cytokines 2. ARACHIDONIC ACID METABOLITES (Eicosanoids): Cell derived Mediators: ◦ Present in esterified form with membrane phospholipids and are released by the action of Phospholipases by mechanical, chemical and physical stimuli Two major pathways: ◦ Cyclo-oxygenase pathway ◦ Thromboxane A2 ◦ Prostacyclin ◦ Prostaglandins ◦ Lipoxygenase pathway ◦ Leukotrienes ARACHIDONIC ACID METABOLITES 3. CYTOKINES: Cell derived Mediators: ◦ Cytokines are produced from many cell types mainly activated macrophages and lymphocytes. ◦ Tumor Necrosis Factor(TNF), IL-1, IL-8, Chemokines. ◦ IL-1 and TNF are the “Master Cytokines” 4. Reactive Oxygen Species & NO: ◦ Reactive O2 species destroy phagocytosed microbes & necrotic cells. ◦ NO-Nitric Oxide Cell derived Mediators: ◦ Macrophages use it to kill microbes & tumor cells. ◦ Lysosomal Enzymes ◦ Elastase, collagenase & cathepsins to degrade elastin, collagen and basement membrane. 5. Platelet Activating Factor ◦ Aggregate & stimulate platelets Summary