Vascular and Cellular Events in Inflammation PDF

College of Medicine – ‫كلية الطب‬ Vascular and Cellular Events in Inflammatio n Dr....

College of Medicine – ‫كلية الطب‬ Vascular and Cellular Events in Inflammatio n Dr. Noha Noufal  Learning Objectives Upon completion of this lecture, students should be able College of Medicine – ‫كلية الطب‬ to:  Describe the steps involved in extravasation of leukocytes from the blood to the tissues  Know the steps at which selectins and integrins act  Describe the meaning and utility of chemotaxis  Understand the role that chemokines play in inflammation  Describe the steps involved in phagocytosis and the role of IgG and C3b as opsonins and receptors  List the mechanisms of microbial killing  Know various defects in leukocyte function College of Medicine – ‫كلية الطب‬ Eliminate Ingest & the kill the necrotic microbes tissue or foreign body  Sequence of Events In Acute Inflammation VASCULAR RESPONSE: College of Medicine – ‫كلية الطب‬ - Vasoconstriction - Vasodilatation - Stasis CELLULAR RESPONSE (Recruitment of Leukocytes): EMIGRATION CHEMOTAXIS PHAGOCYTOSIS  1- The Vascular response has the following steps: College of Medicine – ‫كلية الطب‬ A. Transient Vasoconstriction B. Vasodilatation of arterioles and venules resulting in increased blood flow. C. Increased vascular permeability that lead to leakage of exudate (Inflammatory fluid). D. Stasis: After the phase of increased blood flow there is a slowing of blood flow & stasis due to increased vascular permeability and leakage of exudate. College of Medicine – ‫كلية الطب‬  Cellular Response: Leukocyte Recruitment to Sites of Inflammation (Emigration) - Leukocytes are normally flow rapidly and centrally in the College of Medicine – ‫كلية الطب‬ blood vessels. - In inflammation, WBCs have to be stopped and brought to the affected site outside the blood vessels. - The passage of leukocytes from the vessel lumen to the tissue is a multistep process:  1- In the lumen  Margination (peripheral positioning of leukocytes), rolling, and adhesion  2- Transmigartion across the endothelium (Diapedesis).  3- Migration in interstitial tissue toward targeted site Chemoattractants and certain cytokines also affect these processes  Leukocytes Recruitment:  This process has 4 steps: College of Medicine – ‫كلية الطب‬ Margination & Rolling along the vessel wall Adhesion to the Leukocyt endotheliu e m Recruitm Transmigration ent between endothelial cells Migration in the interstitial tissue to the targeted site and  Leukocyte Recruitment to Sites of Inflammation 1- Margination College of Medicine – ‫كلية الطب‬ Definition: Leukocyte accumulation at the periphery of vessels. As the blood flow slows early in inflammation (stasis), Since the RBCs are faster and smaller than WBCs, the RBCs will occupy the center and start to push the WBCs to the periphery along the endothelial surface. College of Medicine – ‫كلية الطب‬ Margination: white cells take on a peripheral position along the endothelial surface  Leukocyte Recruitment to Sites of Inflammation 2- Rolling: Definition: These cells bind and detach and thus begin to College of Medicine – ‫كلية الطب‬ tumble on the endothelial surface. If the endothelial cells are injured or activated by chemical mediators, they will express adhesion molecules on their cell membrane that have receptors on WBCs. These contacts are mediated by surface adhesion molecules called selectins. These molecules will bind loosely and detached from WBC leading to rolling of WBCs over the endothelial cells. College of Medicine – ‫كلية الطب‬ SELECTINS NS INTEGRI  Leukocyte Recruitment to Sites of Inflammation 3- Adhesion: Definition: the process in which the leukocytes adhere College of Medicine – ‫كلية الطب‬ firmly (strongly) and attached to the endothelial cells. Progressive activation of leukocytes cells leads to expression of polypeptide adhesion molecules integrins. Adhesion is mediated by Integrin (on WBCs) and Integrin- ligand (on endothelium) Integrins firmly bind these leukocytes and endothelial cells to each other  Leukocyte Recruitment to Sites of Inflammation 4- Transmigration College of Medicine – ‫كلية الطب‬ leukocytes start to migrate outside the blood vessel by Squeezing between endothelial cells at intercellular junctions This extravasation of leukocytes is called “diapedesis” This process is mediated by chemokines which stimulate the WBCs to move toward the chemical gradient  Leukocyte Recruitment to Sites of Inflammation 5- Migration: in the interstitial tissue to the targeted site and phagocyte it. College of Medicine – ‫كلية الطب‬ Definition of Chemotaxis: Chemotaxis is the process by which leukocytes are attracted to and move toward the affected site under the influence of chemical gradients (chemoattractants). Both exogenous and endogenous substances can act as chemoattractants, including the following:  Exogenous: Bacterial products  Endogenous: Chemical mediators (Cytokines, complements, cell membrane products) College of Medicine – ‫كلية الطب‬ Chemotaxis  Chemotaxis The nature of the leukocyte infiltrate differs with the age of the inflammatory response and the type of College of Medicine – ‫كلية الطب‬ stimulus Neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours, this is the commonest type of WBCs in acute inflammation (why?) as is the commonest type of WBCs in the blood, response quickly, adhere firmly, live shortly for 24- 48 h. Neutrophils replaced by macrophages over 24 to 48 hours There are exceptions to this pattern of cellular infiltration:  Phagocytosis Definition: Phagocytosis is the ingestion of particulate material (tissue College of Medicine – ‫كلية الطب‬ debris, living or dead bacteria, and other foreign cells) by phagocytic cells. - Neutrophils and monocytes–macrophages are the most important phagocytic cells. - They serve to eliminate pathogens and noxious substances.  Steps of Phagocytosis College of Medicine – ‫كلية الطب‬ Recognition & attachment of the particles to the ingesting WBCs Engulfment of the particle with subsequent 3 Steps of phagocytosis phagocytotic vacuole formation Killing & degradation of the phagocytoed particle  Steps of Phagocytosis: 1-Recognnition and attachment: College of Medicine – ‫كلية الطب‬ Indirectly Directly Directly recognize recognize recognize the the dead some microbes tissue components through of the Opsonin microbes What is Opsonin?  Steps of Phagocytosis Opsonization: The process by which opsonin bind to the surface of antigen to be identified College of Medicine – ‫كلية الطب‬ and engulfed by phagocytes for destruction. Opsonins are proteins normally found in the plasma and interstitial fluids The main opsonins are: Immunoglobulin G (IgG) C3b fragment of the complement  College of Medicine – ‫كلية الطب‬ Steps of Phagocytosis  Steps of Phagocytosis 2- Engulfment of the particle with subsequent College of Medicine – ‫كلية الطب‬ formation of phagocytic vacuoles involves:  Focal invagination of the cell surface membrane  Accompanied by the elongation of the cytoplasmic process laterally to that invagination (pseudopods)  Pseudopodial extensions enclose the foreign particle, forming phagosome  Phagosomes fuse with cytoplasmic lysosomes and form phagolysosomes  Steps of Phagocytosis 3. Killing and degradation: College of Medicine – ‫كلية الطب‬ Microbial killing is mediated within phagocytic cells Phagocytic cells killing the offending agent by: 1- Release of bactericidal substances , such as lysozyme, major basic protein, cationic proteins 2- Toxic substances (Oxygen free radicals).  Defects in leukocytes College of Medicine – ‫كلية الطب‬ Congenital defects of leukocyte function present as increased susceptibility to infections especially opportunistic infections The examples of abnormal leukocyte function:  Defects in leukocyte adhesion (deficiency of integrins and selectins)  Defects of phagocytosis (deficiency of complement C3 impairs opsonization).  Defective bactericidal activity.  Summary VASCULAR RESPONSE: College of Medicine – ‫كلية الطب‬ Transient vasoconstriction  Vasodilatation  Increased Vascular Permeability  Leakage of Exudate  Stasis CELLULAR RESPONSE: EMIGRATION: Margination, Rolling, Adhesion  Transmigration (DIAPEDESIS)  CHEMOTAXIS (Migration)  PHAGOCYTOSIS: Recognition & Attachment, Engulfment, Killing (degradation or digestion) College of Medicine – ‫كلية الطب‬