Normal fluid exchange and microvascular permeability are critically dependent on an intact endothelium. How then does the endothelium become leaky in acute inflammation? Following mechanisms have been proposed: 1. Gaps due to endothelial contraction Endothelial cell contraction leads to intercellular gaps in venules.
It is the most common form of increased vascular permeability and is elicited by histamine, bradykinin, leukotrienes and many other classes of chemical mediators. Its action is fast and short lived. 2. Direct InjuryDirect endothelial injury results in vascular leakage by causing endothelial cell necrosis and detachment.
This effect is usually seen after severe injuries like burns, toxins and chemicals. Venules, arterioles, and capillaries can all be affected depending on site of injury. Its action is fast and may be long lived (hours to days). 3. Leukocyte-dependent injury Leukocyte dependant endothelial injury usually happens in venules and pulmonary capillaries, the vascular sites where leukocytes can adhere to the endothelium.
This is a late response and is long lived. 4. Increased transcytosisIncreased transcytosis also augments venular permeability, especially after exposure to vascular endothelium derived growth factor. This occurs in venules. 5.
New blood vessel formation New blood vessel formation at sites of angiogenesis also increases vascular permeability. This persists till intercellular junctions form. [pic] Cellular Events The next requirement for the inflammatory response is to get the inflammatory cells (leukocytes) to the site of injury. Vascular dilatation increases the volume of blood to the tissue site but also changes the flow characteristics within the vessel.
The cells are normally contained in the central or axial part of the blood column. Dilatation increases cross sectional area of the vessel and decreases the net flow rate per unit area. This causes cells to fall out of the central region of the vessel; they begin to tumble along the epithelial surface. Sequence of cellular events in journey of leukocytes from vessel lumen to interstitial tissue is divided to 3 phases, in the lumen, diapedesis, and migration in interstitial tissue towards chemotactic stimulus.
A: In the lumen: [pic] B: Diapedesis The next step is migration of cells through the endothelium, called diapedesis . Therefore the process of transmigration across the endothelium, also known as diapedesis which happens after adhesion Diapedesis occurs predominantly in the venules. PECAM-1 (platelet endothelial cell adhesion molecule-1, CD31) in intercellular junctions of endothelium is involved in the migration of leukocyte towards site of infection.Leukocytes pierce the basement membrane by secreting collagenases, insert pseudopods into the junction between endothelial cells and then squeeze through interendothelial junction. In extravascular connective tissue, leukocytes adhere to extracellular matrix by ? 1 and CD44. Eventually they traverse the basement membrane and escape into extravascular space.
Leukocyte adhesion and transmigration is regulated by chemical mediators and binding of complementary adhesion molecules on leukocytes and endothelial surfaces. The adhesion receptors involved belongs to 4 families: ) selectins b) immunoglobulin super family c) integrins d) mucin like glycoprotein a) Selectins are proteins which function in the adhesion of leukocytes to endothelial cells. P-selectin (CD62P) - present in platelets and endothelium
