Up-regulation of bradykinin receptors in rat bronchi via I kappa B kinase-mediated inflammatory signaling pathway.
IkappaB kinase (IKK)-mediated intracellular signaling mechanisms may be involved in airway hyperresponsiveness through up-regulation of bradykinin receptors. This study was designed to examine if organ culture of rat bronchial segments induces airway hyperresponsiveness to bradykinin and if inhibition of IKK can abrogate the airway hyperresponsiveness to bradykinin via suppressing the expression of bradykinin B1 and B2 receptors. Rat bronchi were isolated and cut into ring segments. The segments were then organ cultured in the presence or absence of IKK inhibitors, BMS-345541 or TPCA-1. des-Arg9-bradykinin (B1 receptor agonist)--and bradykinin (B(2) receptor agonist)--induced contractions of the segments were monitored by a sensitive organ bath system. The expression of bradykinin B1 and B2 receptors, inflammatory mediators and phosphorylated IKK were studied by a real-time PCR and/or by immunohistochemistry using confocal microscopy. Organ culture of the bronchial segments induced a time-dependent up-regulation of bradykinin B1 and B2 receptors. The IKK inhibitors abolished the organ culture-induced up-regulation of bradykinin B1 and B2 receptor-mediated contractions in a concentration-dependent manner. This was paralleled with inhibition of IKK activity (phosphorylation), reduced mRNA and protein expressions of bradykinin B1 and B2 receptors and decreased mRNA expression of inflammatory mediators (interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2 and matrix metalloproteinase 9). Our results show that organ culture induces IKK-mediated inflammatory changes in airways which subsequently results in airway hyperresponsiveness to bradykinin via the up-regulated bradykinin receptors. Thus, IKK inhibition might be a promising approach for treatment of airway inflammation and airway hyperresponsiveness that are often seen in asthmatic patients.
Lei
Ying
Y
Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, SE-22184 Lund, Sweden.
Zhang
Yaping
Y
Cao
Yongxiao
Y
Edvinsson
Lars
L
Xu
Cang-Bao
CB
D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D016535:Bronchial Hyperreactivity / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051550:I-kappa B Kinase / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009924:Organ Culture Techniques; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018002:Receptors, Bradykinin / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D007093:Imidazoles; D018836:Inflammation Mediators; D011810:Quinoxalines; D018002:Receptors, Bradykinin; D051550:I-kappa B Kinase