Nitric oxide synthesis inhibition induces leukocyte adhesion via superoxide and mast cells

Abstract

Recent work has demonstrated that inhibition of nitric oxide production with various nitric oxide synthesis inhibitors (L-NAME, L-NMMA) initiate leukocyte adhesion to postcapillary venules. The objective of this study was to elucidate the mechanism (or mechanisms) that promote the L-NAME-induced leukocyte response. Intravital microscopy was used to examine 25-40 microns venules in the rat mesentery. Nitric oxide synthesis was inhibited with L-NAME and leukocyte adhesion was observed over the first 60 min. The fourfold increase in leukocyte adhesion was independent of alterations in venular red blood cell velocity. The adhesion was superoxide-mediated inasmuch as superoxide dismutase (SOD) abolished the rise in leukocyte adhesion associated with nitric oxide synthesis inhibition. Ketotifen, a mast cell stabilizer, also abolished the rise in leukocyte adhesion induced by L-NAME. Histology revealed that mast cell degranulation occurred only in animals treated with L-NAME but not in animals pretreated with SOD or ketotifen. This observation suggests that mast cells become activated in the absence of nitric oxide production and superoxide contributes to the mast cell activation. The L-NAME-induced leukocyte adhesion could be reproduced by infusing hypoxanthine/xanthine oxidase (a superoxide generating system) or compound 48/80 (an activator of mast cells) and both responses were attenuated by ketotifen. These data suggest that inhibition of nitric oxide synthesis results in a superoxide and mast cell-dependent leukocyte adhesion.

The role of the complement cascade in endotoxin-induced septic encephalopathy

“…The isoform responsible for NO production during inflammation is the calcium-independent iNOS. 29 iNOS has been shown to be strongly upregulated in a wide variety of tissues, including the brain, after the administration of LPS. 30 Further, increased iNOS activity was found in circulating neutrophils of septic shock patients compared with healthy volunteers.…”

An overview of the effects of annexin 1 on cells involved in the inflammatory process

“…A single study has reported mast cell derived ANXA1 as mediating the stabilising effect of interleukin-2, determined as inhibition of histamine release (Tasaka et al 1994). Due to the pivotal location of the mast cell and its role not only in initiation but possibly also in resolution of inflammation (Kubes et al 1993, Gotis-Graham et al 1998, Woolley 2003, it is likely that a role for ANXA1 in this cell type will soon emerge.…”

Óxido nítrico: revisão

“…A inibição do NO leva aumento no nível de antioxidantes e ativação de mastócitos que se degranulam e aumentam a permeabilidade vascular. A degranulação de mastócitos pode ser inibida pela adição de doadores de NO 44,45 . Porém, segundo SALVEMINI e col. (1996) 46 , o NO é um potente vasodilatador e seu envolvimento na resposta inflamatória pode ter relação com sua habilidade em aumentar a permeabilidade vascular e o edema através de mudanças no fluxo sangüíneo local e do aumento na produção de prostaglandinas pró-inflamatórias.…”