Anaphylactic shock depends on PI3K and eNOS-derived NO
Anje Cauwels, … , Patrick Sips, Peter Brouckaert
Anje Cauwels, … , Patrick Sips, Peter Brouckaert
Published August 1, 2006
Citation Information: J Clin Invest. 2006;116(8):2244-2251. https://doi.org/10.1172/JCI25426.
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Research Article Immunology

Anaphylactic shock depends on PI3K and eNOS-derived NO

Abstract

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 sGCα1 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.

Authors

Anje Cauwels, Ben Janssen, Emmanuel Buys, Patrick Sips, Peter Brouckaert

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Figure 4

BSA anaphylactic shock in WT and eNOS–/– mice.

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BSA anaphylactic shock in WT and eNOS–/– ...
(A) Survival plot of C57BL/6 mice sensitized with BSA, treated with vehicle (controls), l-NAME, or WM, and finally challenged with BSA in EB. The number of mice in each experimental group is shown in parentheses. **P = 0.0022. (B) Temperature plot (mean ± SD) of mice sensitized by BSA or PBS and challenged 15 days later with BSA in EB (BSA + EB) or EB alone. The total number of mice is shown in parentheses; numbers beneath time points indicate the number of mice still alive at the indicated times. (C) Survival plot of WT and eNOS–/– mice sensitized with BSA and challenged with BSA in EB. Total number of mice is shown in parentheses. ***P = 0.0007. (D) Temperature plot (mean ± SD) of mice sensitized by BSA or PBS and challenged with BSA in EB or EB alone. The total number of mice is shown in parentheses, numbers above the time points indicate the number of mice still alive at the indicated times. (E) Western blot for p-eNOS in kidney homogenates of individual, BSA-sensitized mice 12 minutes after BSA challenge. Where indicated, mice had been pretreated with WM. (F) Vascular leakage assayed by EB extravasation into ear tissues. Inner ear rims were removed 90 minutes after i.v. challenge with BSA in EB or EB only and subsequently extracted in formamide. Plots show mean OD620 ± SD. #P < 0.001; ##P < 0.01.