LYMPHATIC-BORNE IL-1β AND THE INDUCIBLE ISOFORM OF NITRIC OXIDE SYNTHASE TRIGGER THE BRONCHIAL HYPORESPONSIVENESS AFTER INTESTINAL ISCHEMA/REPERFUSION IN RATS

Abstract

Intestinal I/R (i-I/R) is an insult associated to further adult respiratory distress syndrome and multiple organ failure. This study was designed to evaluate the repercussions of i-I/R on bronchial reactivity to the cholinergic agent methacholine. Anesthetized rats were subjected to superior mesenteric artery occlusion (45 min) and killed after clamp release and defined intestinal reperfusion periods (30 min, 2, 4, or 24 h). Intestinal I/R caused a progressive bronchial hyporesponsiveness (BHR) that was maximal upon 2 h but reverted within 24 h of intestinal reperfusion. The BHR observed at 2-h i-I/R was prevented by NOS inhibitors (N-L-nitroarginine methyl ester and aminoguanidine) or the KATP channel blocker glibenclamide. Moreover, 2-h i-I/R increased the pulmonary iNOS mRNA expression, a fact prevented by lymphatic thoracic duct ligation. The methacholine reactivity of 2-h i-I/R bronchial segments incubated with NOS inhibitors or glibenclamide was similar to that of naive tissues. In vivo blockade of IL-1beta receptors or lymphatic duct ligation before 2-h i-I/R both abolished BHR. Incubation of naive bronchial segments with lymph collected from 2-h i-I/R rats determined BHR, an effect fully preventable by ex vivo blockade of IL-1beta receptors. Incubation of naive bronchial segments with IL-1beta, but not with IL-10 or TNF-alpha, significantly induced BHR that was prevented by N-L-nitroarginine methyl ester. Our data suggest that a gut ischemic insult generates IL-1beta that, upon reperfusion, travels through the lymph into the lungs. In this tissue, IL-1beta would stimulate the generation of NO that orchestrates the ensuing BHR for which the opening of KATP channels seems to play a pivotal role.

Intestinal Lymph-Borne Factors Induce Lung Release of Inflammatory Mediators and Expression of Adhesion Molecules After an Intestinal Ischemic Insult

“…*P < 0.05, **P < 0.01, ***P < 0.001. understanding of the role of thoracic lymphatic duct ligation in ALI due to intestinal I/R. We previously found that cytokines such as TNF-a, IL-1b, IL-10, and IL-6 were elevated in lymph obtained during the intestinal reperfusion period [17][18][19] and that IL-1b mediates bronchial hyporesponsiveness by inducing iNOS expression in the lung [24]. In the present study, we therefore investigated whether the lymph drained after intestinal I/R could stimulate lung production of inflammatory mediators.…”

Lymphatics and lymph in acute lung injury

“…Coelho et al [12 ] showed in an elegant study that intestinal ischemia and reperfusion caused an increased bronchial hyper-reactivity and that this distant effect was mediated via the lymphatic system. They occluded the mesenteric artery for 45 min and studied the effects of reperfusion periods ranging from 2 to 24 h. Bronchial hyper-reactivity was maximal after 2 h and returned to baseline after 24 h. Lymphatic duct ligation abolished the hyper-reactivity.…”

Perfil temporal da inflamação pulmonar induzida pela isquemia/reperfusão intestinal em ratos. Estudo do papel do sistema linfático.

“…Por causa disso, dois aspectos acerca da SDRA tornam seu estudo relevante: a falta de terapia medicamentosa eficaz e a alta taxa de mortalidade (LUH et al, 2007;LEWANDOWSKI e LEWANDOWSKI, 2006). Além disso, baseados em estudos do nosso laboratório (CAVRIANI et al, 2005;CAVRIANI et al, 2007;COELHO et al, 2007;BREITHAUPT-FALOPPA et al, 2009) e naqueles descritos para eventos traumáticos associados ao choque hemorrágico (DEITCH et al, 2001;DAVIDSON et al, 2004), lançamos a hipótese de que o intestino, sob sofrimento isquêmico, pode ser considerado um potente gerador de mediadores inflamatórios, os quais, uma vez drenados pelo sistema linfático, atingem a circulação pulmonar, comprometem a sua homeostasia, causam recrutamento de neutrófilos, edema, contribuindo para a lesão tecidual e para a disfunção pulmonar frequentemente observada na SDRA. Nesse sentido, a questão sobre os efeitos prolongados da reperfusão intestinal associados a distúrbios inflamatórios permanece aberta.…”

“…Uma possível explicação seria o papel da IL-1β na indução da IL-10, que por sua vez exerceria ação antiinflamatória modulando o dano pós I/R (SOUZA et al, 2003). Por outro lado, dados do nosso grupo mostraram que os níveis séricos de IL-1β estão elevados em ratos submetidos a I/R intestinal , e que sua neutralização previne a hiporreatividade brônquica induzida pela I/R intestinal (COELHO et al, 2007). Vale lembrar que o sistema linfático é importante via de ligação entre a IL-1β gerada pela I/R intestinal e a inflamação pulmonar observada.…”

“…Posteriormente mostramos perfil similar nos níveis de IL-1β e IL-10 no soro dos animais após obstrução do ducto linfático torácico . Também mostramos que a I/R intestinal gera IL-1β no pulmão e esta induz a geração de NO que se associa a redução da contratilidade à metacolina (COELHO et al, 2007). Neste mesmo modelo mostramos ainda que o bloqueio da geração de NO, eleva os níveis linfáticos de IL-6 e que esta citocina reduz a expressão de PECAM-1 no pulmão .…”