Anaphylactic shock depends on Pi3K and eNOS-derived NO

Molecular Pathophysiology and Experimental Therapy Unit, Department for Molecular Biomedical Research, Ghent University, Belgium, and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 09/2006; 116(8):2244-51. DOI: 10.1172/JCI25426
Source: PubMed


Anaphylactic shock is a sudden, life-threatening allergic reaction associated with severe hypotension. Platelet-activating factor (PAF) is implicated in the cardiovascular dysfunctions occurring in various shock syndromes, including anaphylaxis. Excessive production of the vasodilator NO causes inflammatory hypotension and shock, and it is generally accepted that transcriptionally regulated inducible iNOS is responsible for this. Nevertheless, the contribution of NO to PAF-induced shock or anaphylactic shock is still ambiguous. We studied PAF and anaphylactic shock in conscious mice. Surprisingly, hyperacute PAF shock depended entirely on NO, produced not by inducible iNOS, but by constitutive eNOS, rapidly activated via the PI3K pathway. Soluble guanylate cyclase (sGC) is generally regarded as the principal vasorelaxing mediator of NO. Nevertheless, although methylene blue partially prevented PAF shock, neither 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) nor sGCalpha1 deficiency did. Also, in 2 different models of active systemic anaphylaxis, inhibition of NOS, PI3K, or Akt or eNOS deficiency provided complete protection. In contrast to the unsubstantiated paradigm that only excessive iNOS-derived NO underlies cardiovascular collapse in shock, our data strongly support the unexpected concept that eNOS-derived NO is the principal vasodilator in anaphylactic shock and define eNOS and/or PI3K or Akt as new potential targets for treating anaphylaxis.

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Available from: Anje Cauwels
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    • "The effects of PAF as a bronchoconstrictor and mediator of airway hyperreactivity in bronchial asthma have long been recognized, although the use of PAF inhibitors as a therapeutic option in asthma has been ineffective (Kasperska-Zajac et al., 2008). PAF also causes severe hypotension and cardiovascular dysfunction during acute anaphylaxis, an effect that, at least in mice, is dependent on a PAF-mediated activation of eNOS and consequent NO formation (Cauwels et al., 2006). In mouse models, PAF antagonists effectively attenuated IgG-induced anaphylaxis (Jiao et al., 2014; Jonsson et al., 2011; Strait et al., 2002; Tsujimura et al., 2008) and peanut-induced anaphylaxis severity (Arias et al., 2009), but did not effectively attenuate IgEmediated anaphylaxis, which is more dependent on histamine release (Strait et al., 2002). "
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    ABSTRACT: Sphingosine-1phosphate (S1P), platelet activating factor (PAF) and eicosanoids are bioactive lipid mediators abundantly produced by antigen-stimulated mast cells that exert their function mostly through specific cell surface receptors. Although it has long been recognized that some of these bioactive lipids are potent regulators of allergic diseases, their exact contributions to disease pathology have been obscured by the complexity of their mode of action and the regulation of their metabolism. Indeed, the effects of such lipids are usually mediated by multiple receptor subtypes that may differ in their signaling mechanisms and functions. In addition, their actions may be elicited by cell surface receptor-independent mechanisms. Furthermore, these lipids may be converted into metabolites that exhibit different functionalities, adding another layer of complexity to their overall biological responses. In some instances, a second wave of lipid mediator synthesis by both mast cell and non-mast cell sources may occur late during inflammation, bringing about additional roles in the altered environment. New evidence also suggests that bioactive lipids in the local environment can fine-tune mast cell maturation and phenotype, and thus their responsiveness. A better understanding of the subtleties of the spatiotemporal regulation of these lipid mediators, their receptors and functions may aid in the pursuit of pharmacological applications for allergy treatments. Copyright © 2015. Published by Elsevier B.V.
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    • "It has been shown that endothelial-myocardial interactions are important in maintaining physiological regulation of cardiomyocyte [26]. ENOS is constitutively expressed in endothelium [27], and eNOS-derived NO serves as a critical endothelium-derived modulator that maintains normal function of the vasculature [28]. Recently, Thorsten et al reported that addition of endothelial to cardiomyocyte significantly increased NO production and protected cardiomyocyte from I/R injury, and endothelial dysfunction by triton X-100 incubation attenuated the recovery of cardiac function during reperfusion in Langendorff-perfused hearts subjected to I/R injury [29]. "
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    • "[29], [38], [40] eNOS is constitutively expressed in ECs, [41] and eNOS-derived NO serves as a pivotal endothelium-derived modulator that maintains normal function of the vasculature. [42], [43] Short episodes of myocardial I/R (ischemic preconditioning) have previously been shown to increase the release of NO from the endothelium. [22], [23] To investigate whether EC-derived NO contributes to CM protection, co-culture experiments were performed in the presence of L-NMMA, a non-specific inhibitor of NOS. "
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