Increase in vascular permeability induced by leukotriene b4 and the role of polymorphonuclear leukocytes

Abstract

Leukotriene B4 (LTB4), a metabolite of arachidonic acid, is known to be a potent chemotactic and chemokinetic substance. We have used the hamster cheek pouch microcirculation model to study the effect of LTB4 on vascular permeability and the involvement of neutrophil granulocytes in this response. Intravascular fluorescein-labeled dextran (mol wt 150,000) was used as a tracer of macromolecular permeability. Topical application of LTB4 (150 nM-5 microM) to the hamster cheek pouch resulted in an immediate increase in adhering leukocytes in postcapillary venules and later venules. Leukocyte accumulation was reversible, but continued longer the higher the dose of LTB4 used. Subsequently, a dose-dependent increase in vascular permeability was seen at post-capillary and larger venules, with a maximum 10-20 min after application; the maximum occurred later the higher the dose of LTB4. Depletion of neutrophil granulocytes by pretreatment of the animals with antineutrophil serum obtained from immunized rabbits significantly decreased the permeability response to LTB4, whereas the response to histamine was unaffected. These results suggest that neutrophil granulocytes play a role in LTB4-mediated permeability increase. LTB4 may be of importance both for the leukocyte accumulation and for the edema formation seen in inflammatory reactions.

Leukocyte adhesion in angiogenic blood vessels. Role of E-selectin, P-selectin, and beta2 integrin in lymphotoxin-mediated leukocyte recruitment in tumor microvessels.

“…Treatment of mice with anti-␤2 mAb 2E6 resulted in significant inhibition of both these steps, suggesting a ␤2-activation-dependent mechanism of leukocyte stable arrest and emigration in TMV. Our studies provide evidence that appropriate stimulation of TMV with specific cytokines and chemotactic mediators such as LT and LTB4 (30,38) can result in efficient recruitment of leukocytes into the tumor stroma. Since extravasation of leukocytes is crucial to their subsequent ability to induce tumor killing, further studies will determine if treatment of LT-stimulated mice with chemokines, especially those that lack the ELR motif (44) can result in an effective recruitment of leukocytes as well as inhibition of growth of microtumors and angiostatic response in vivo.…”

“…(c) The rolling induced by LT-stimulation is not sufficient to establish stable arrest and spontaneous emigration of leukocytes from TMV. This activation-dependent process (4,5) can however be simulated by local superfusion of the angiogenic blood vessels with LTB4, a metabolite of arachidonic acid and a potent inflammatory and chemotactic mediator (30).…”

“…The ability of circulating leukocytes to interact with neovasculature is important for their extravasation into the tumor stroma. Using intravital microscopy, we have therefore examined the efficacy of LT in combination with LTB4, an inflammatory mediator and a po-tent chemotactic substance that causes emigration from post capillary venules (30), to mediate early events of leukocyte adhesion and their transmigration from TMV into stroma of microtumors.…”

Leukotriene B4 increases the lymphocyte binding to endothelial cells

“…LTB4 has also been shown to increase granulocyte adherence to EC in vitro [6]. LTB4 also rapidly increases vascular permeability, measured with fluorescence-labelled dextran in a hamster cheek pouch model [4]. LTB4 possesses chemotactic and chemokinetic properties [ 141 and it increases leukocyte influx into the skin, when injected topically intradermally [2].…”

“…LTB4 increases granulocyte adherence to the microvascular endothelium in the hamster cheek pouch [3,4], and granulocyte extravasation after intradermal injection [2,5]. Increased adherence of granulocytes has been demonstrated after in vitro treatment of endothelial cell monolayers with LTB4 [6].…”