Nagase Takahide, Ishii Satishi, Shindou Hideo, Ouchi Yasuyoshi, Shimizu Takao
Departments of Geriatric Medicine and Biochemistry and Molecular Biology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Am J Respir Crit Care Med. 2002 Jan 15;165(2):200-5. doi: 10.1164/ajrccm.165.2.2106131.
Platelet activating factor (PAF) is a potent mediator potentially involved in the pathogenesis of inflammatory disorders, including bronchial asthma. Recently, transgenic mice overexpressing the PAF receptor (PAFR) gene have been established, and exhibit bronchial hyperresponsiveness, one of the cardinal features of asthma. To elucidate the molecular and pathophysiologic mechanisms underlying PAF-associated bronchial hyperreactivity, we studied airway responsiveness to methacholine (MCh) and serotonin (5-hydroxytryptamine; 5-HT) in PAFR-transgenic mice. In addition, we examined the role of the muscarinic receptor in PAF-induced responses and the binding activities of the muscarinic receptor. The PAFR-transgenic mice exhibited hyperresponsiveness to MCh and PAF; however, no significant differences in 5-HT responsiveness were observed between the control and PAFR-transgenic mice. The administration of atropine significantly blocked PAF-induced responses in PAFR-transgenic mice. There were no differences between the two phenotypes in the binding activities of muscarinic receptor. Morphometric analyses demonstrated that PAFR overexpression did not affect airway structure. These findings suggest that the muscarinic pathway may have a key role in airway hyperresponsiveness associated with PAFR gene overexpression. More generally, PAFR-transgenic mice may provide appropriate models for study of the molecular mechanisms underlying PAF-associated diseases.
血小板活化因子（PAF）是一种强效介质，可能参与包括支气管哮喘在内的炎症性疾病的发病机制。最近，已建立了过表达PAF受体（PAFR）基因的转基因小鼠，这些小鼠表现出支气管高反应性，这是哮喘的主要特征之一。为了阐明PAF相关支气管高反应性的分子和病理生理机制，我们研究了PAFR转基因小鼠对乙酰甲胆碱（MCh）和血清素（5-羟色胺；5-HT）的气道反应性。此外，我们研究了毒蕈碱受体在PAF诱导反应中的作用以及毒蕈碱受体的结合活性。PAFR转基因小鼠对MCh和PAF表现出高反应性；然而，在对照小鼠和PAFR转基因小鼠之间未观察到5-HT反应性的显著差异。阿托品的给药显著阻断了PAFR转基因小鼠中PAF诱导的反应。两种表型在毒蕈碱受体的结合活性方面没有差异。形态计量学分析表明，PAFR的过表达不影响气道结构。这些发现表明，毒蕈碱途径可能在与PAFR基因过表达相关的气道高反应性中起关键作用。更一般地说，PAFR转基因小鼠可能为研究PAF相关疾病的分子机制提供合适的模型。
