title: Lymphatic-borne IL-1beta 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.
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Fernando Rodrigues
authors.initials: FR
authors.lastname: Coelho
authors.forename: Gabriela
authors.initials: G
authors.lastname: Cavriani
authors.forename: Alexandre Learth
authors.initials: AL
authors.lastname: Soares
authors.forename: Simone Aparecida
authors.initials: SA
authors.lastname: Teixeira
authors.forename: Paula Campi Locatelli
authors.initials: PC
authors.lastname: Almeida
authors.forename: Lia Siguemi
authors.initials: LS
authors.lastname: Sudo-Hayashi
authors.forename: Marcelo Nicolas
authors.initials: MN
authors.lastname: Muscará
authors.forename: Ricardo Martins
authors.initials: RM
authors.lastname: Oliveira-Filho
authors.forename: Bernardo Boris
authors.initials: BB
authors.lastname: Vargaftig
authors.forename: Wothan
authors.initials: W
authors.lastname: Tavares-de-Lima
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology*; D007422:Intestines / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology; D008208:Lymphatic System / Q000378:metabolism; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D053583:Interleukin-1beta; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D016753:Interleukin-10; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester