Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response.

Abstract

Leukotrienes B4, C4, and D4, members of a recently discovered family of substances biosynthesized from arachidonic acid, were found to have potent microvascular actions in the hamster cheek pouch. When applied topically to the vascular network, leukotrienes C4 and D4 caused an intense constriction of arterioles, being similar to angiotensin in potency in this respect. The vasoconstriction induced by leukotrienes C4 and D4 was short-lived, and it was consistently followed by a marked and dosedependent extravasation of macromolecules from postcapillary venules. Histamine did not constrict arterioles, but it elicited leakage of plasma, although on a molar basis it was no more than 1/ 1000th as potent as the leukotrienes. When used in the same concentration range as leukotrienes C4 and D4, leukotriene B4 did not evoke vasoconstriction or promote plasma leakage. On the other hand, leukotriene B4 caused a conspicuous and reversible adhesion ofleukocytes to the endothelium in postcapillary venules. Our findings that leukotrienes induce microcirculatory alterations in vivo, closely resembling the early events in the acute inflammatory response, imply that leukotrienes, formed in several blod-borne and tissue-bound cells, may mediate important microcirculatory adjustments to noxious stimuli.

Overall and regional hemodynamic effects of leukotriene D4 in spontaneously hypertensive rats.

“…17 In the present study, the first significant increase in hematocrit ( + 7%) occurred with the reduction of CO, stroke volume, and dp/dt 5 minutes after LTD 4 administration. This hemoconcentration appears to be indicative of plasma extravasation into the extracellular space and decreased circulatory volume, which would impair venous return and contribute to the reduction of CO. By 10 minutes after LTD 4 administration hemoconcentration became even more pronounced ( + 28%), as were the cardiovascular derangements in SHR.…”

Leukotriene A4, and not leukotriene B4, is the main 5‐lipoxygenase metabolite released by bovine leukocytes

“…Endothelial cells, smooth muscle cells and platelets have been shown to possess LTC4-synthase (EC 2.5.1.37) and are able to synthesize LTC4 using exogenous LTAa as well as PMNLderived LTA4. This process may lead to a pronounced shift from the production of a chemotactic lipid mediator, such as LTBa, to cysteinyl leukotrienes, which cause oedema and vasoconstriction [23,24]. The overall potential for LTA4 transfer from PMNL (donor cell) to acceptor cells [25], has usually been quantitated using the amounts of non-enzymatic LTA4 metabolites in purified PMNL incubations [9].…”

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

“…In addition, it has been shown that LTB 4 stimulates adhesion of leukocytes to vascular endothelia for extravasation into adjacent tissue (12,17). LTB 4 also initiates neutrophil aggregation and degranulation (12).…”

“…LTC 4 and its metabolites, LTD 4 and LTE 4 , are secreted in vivo by eosinophils, mast cells, and macrophages (12,13). These mediators act directly on the microvasculature by inducing vasoconstriction and increasing postcapillary venule permeability, thereby allowing leakage of fluid and proteins and facilitating migration of leukocytes into the inflammatory site (12,13,17). The cysteinyl-LT mediate their activities through at least two distinct receptors termed Cys-LT 1 (formerly the "LTD 4 receptor") and Cys-LT 2 (formerly the "LTC 4 receptor") (19,20).…”