Formation of transudates and exudates

1. Formation of transudates and exudates

2. Cellular events (leukocytes) • Leukocytes infiltration occurs due to the action of various combinations of mediators that are secreted in response to : • 1. infections • 2. tissue damage • 3. immunologic reactions

3. Leukocyte Recruitment • The sequence of events in the recruitment of leukocytes from the vascular lumen to the extravascular space consists of: (1) margination, loose adhesion to endothelium, and rolling along the vessel wall; (2) firm adhesion to the endothelium; (3) transmigration between endothelial cells; (4) migration in interstitial tissues toward a chemotactic stimulus . • Rolling, adhesion, and transmigration are mediated by the binding of complementary adhesion molecules on leukocytes and endothelial surfaces. • Chemical mediators-chemoattractants and certain cytokines-affect these processes by modulating the surface expression or avidity of the adhesion molecules and by stimulating directional movement of the leukocytes

4. Margination & rolling • Margination:The process of leukocyte accumulation at the periphery of vessels due to stasis. • Rolling: a process where leukocytes tumble on the endothelial surface, transiently sticking along the way, the weak and transient adhesions involved in rolling are mediated by the selectin family of adhesion molecules

5. Selectins • Selectins are receptors expressed on leukocytes and endothelium that contain an extracellular domain that binds sugars (hence the lectin part of the name). • The three members of this family are: • 1) E-selectin (also called CD62E), expressed on endothelial cells; • 2) P-selectin (CD62P), present on endothelium and platelets; • 3) L-selectin (CD62L), on the surface of most leukocytes. • Selectins bind sialylated oligosaccharides (e.g., sialyl-Lewis X on leukocytes) that are attached to mucin-like glycoproteins on various cells. • The endothelial selectins are typically expressed at low levels or are not present at all on normal cells. They are up-regulated after stimulation by specific mediators, such as TNF and IL-1.

6. Adhesion • Firm adhesion of leukocytes to endothelial cell surface • Mediated by integrins, expressed on leukocyte cell surfaces interacting with their ligands on endothelial cells. • Integrins are transmembraneheterodimericglycoproteins (composed of different α and β chains) that also function as cell receptors for extracellular matrix. Integrins are normally expressed on leukocyte plasma membranes in a low-affinity form and do not adhere to their appropriate ligands until the leukocytes are activated by chemokines. • The endothelial ligands include: • ICAM-1 (intercellular adhesion molecule 1), which binds to the integrins LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18), • VCAM-1 (vascular cell adhesion molecule 1), which binds to the integrin VLA-4

7. Chemokines • are chemoattractant cytokines that are secreted by many cells at sites of inflammation and are displayed bound to proteoglycans on the endothelial surface. • When the adherent leukocytes encounter chemokines, the cells are activated, and their integrins undergo conformational changes and cluster together, forming a high-affinity form. At the same time, other cytokines ( TNF and IL-1), activate endothelial cells to increase their expression of ligands for integrins.

8. Transmigration • After being arrested on the endothelial surface, leukocytes migrate through the vessel wall primarily by squeezing between cells at intercellular junctions • This movement of leukocytes, called diapedesis, occurs mainly in the venules of the systemic vasculature • PECAM-1 (platelet endothelial cell adhesion molecule 1, also called CD31), a cellular adhesion molecule expressed on leukocytes and endothelial cells, mediates the binding events needed for leukocytes to traverse the endothelium

9. The complex process of leukocyte migration through blood vessels

10. Endothelial and Leukocyte Adhesion Molecules

11. Chemotaxis • After extravasating from the blood, leukocytes migrate toward sites of infection or injury along a chemical gradient by a process called chemotaxis. • Both exogenous and endogenous substances can be chemotactic for leukocytes, including: (1) bacterial products, particularly peptides with N-formylmethionine termini (2) cytokines, especially those of the chemokine family (3) components of the complement system, particularly C5a (4) products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly leukotriene B4 (LTB4).

12. The type of emigrating leukocytes varies with: 1- The age of the inflammatory response 2- The type of stimulus. In acute inflammation, the predominant cells are neutrophilsduring the first 6-24 hours, replaced by monocytes in 24-48 hours. Exceptions: 1.Viral infection lymphocytes predominate 2. Hypersensitivity reaction eosinophils predominate

13. Leukocyte Activation Leukocytes at the site of infection or tissue necrosis must be activated to perform their function Stimuli for activation include: Microbes Products of necrotic cells Chemical Mediators

14. Leukocyte activation results in many enhanced functions: 1- Phagocytosis of particles, an early step in the elimination of harmful substances. 2- Production of substances that destroy phagocytosed microbes and remove dead tissues; these leukocyte products include lysosomal enzymes and reactive oxygen and nitrogen species. 3- Production of mediators that amplify the inflammatory reaction, including arachidonic acid metabolites and cytokines.

15. Phagocytosis • Opsonins: components of the microbes and dead cells, or host proteins that coat microbes and target them for phagocytosis; these have specific surface receptors on leukocytes helping leukocytes to bind and ingest most microorganisms and dead cells, a process called opsonization). • The most important opsonins are: • antibodies of the immunoglobulin G (IgG) class • breakdown products of the complement protein C3 • plasma carbohydrate-binding lectins called collectins, which bind to microbial cell-wall sugar groups.

16. Engulfment • Leukocytes express receptors for opsonins that facilitate rapid phagocytosis of the coated microbes. These receptors include the Fc receptor for IgG (called FcγRI), complement receptors 1 and 3 (CR1 and 3) for complement fragments, and C1q for the collectins. • Binding of opsonized particles triggers 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

17. Killing and Degradation of Microbes • The key steps in this reaction are the production of microbicidal substances within lysosomes and fusion of the lysosomes with phagosomes, thus selectively exposing the ingested particles to the destructive mechanisms of the leukocytes. • The most important microbicidal substances are reactive oxygen species (ROS) and lysosomalenzymes. Phagocytosis stimulates an oxidative burst characterized by a sudden increase in oxygen consumption, glycogen catabolism (glycogenolysis), increased glucose oxidation, and production of ROS. • Reactive nitrogen species, particularly NO, act in the same way as ROS

18. Leukocytes-Induced injury Underlying Human disease Enzymes and ROS may be released into the extracellular environment. The mechanisms that function to eliminate microbes and dead cells (the physiologic role of inflammation) are also capable of damaging normal tissues (the pathologic consequences of inflammation). Acute Disorders Acute respiratory distress syndrome (Neutrophil) Acute transplant rejection (Lymphocytes, Abs & complement.) Asthma (esonophil, IgE) Septic shock ( cytokines) Vasculitis (Ab, complement, Neutrophils)

19. Chronic disorders Arthritis (lymphocytes, macrophages, Ab) Asthma ( esinophils, other WBC, IgE) Atherosclerosis (Macrophage, lymphocytes) Chronic transplant rejection (Lymphocyte, cytokines) Pulmonary fibrosis (Macrophages, Fibroblasts)