The maintenance of microcirculatory vascular permeability is largely dependent on the integrity of the endothelium. During inflammation, the following mechanisms can cause an increase in vascular permeability. Leukocyte-mediated endothelial injury In the early stages of inflammation, leukocytes attach to the wall and adhere to endothelial cells, causing activation of leukocytes and release of reactive oxygen metabolites and protein hydrolases. The latter can cause damage to or shedding of endothelial cells, which increases vascular permeability. The high permeability of the nascent capillary wall in the new capillary buds formed during the repair process with immaturely developed endothelial cell junctions can account for fluid extravasation and edema in healing inflammation. Endothelial cell contraction can be rapidly induced upon binding of histamine, bradykinin, and other inflammatory mediators to endothelial cell receptors, resulting in the formation of gaps between endothelial cells approximately 0.5 to 1.0 μm wide. Because the half-life of these inflammatory mediators is only 15-30 minutes, this reaction is called the rapid-onset transient response. This reaction only involves fine veins of 20-60 μm caliber, while fine arteries and capillaries are not involved. Antihistamines can suppress this reaction. Severe irritation such as severe burns and septic infection can directly cause endothelial cell damage, resulting in necrosis and detachment. The increase in vascular permeability occurs rapidly and persists at high levels for hours to days until a thrombus forms in the damaged vessel, a process known as a rapid-onset sustained reaction. Microcirculatory vessels at the fine arterial, capillary and venous levels can be involved. Mild to moderate thermal injury, x-ray and UV damage, and direct endothelial cell damage caused by certain bacterial toxins occur later, often after 2 to 12 hours, but can last from a few hours to a few days, and are referred to as late onset sustained reactions. This reaction involves only capillaries and small veins.