Berisha H I, Bratut M, Bangale Yogesh, Colasurdo G, Paul S, Said Sami I
State University of New York at Stony Brook, N.Y. 11794-8172, Medical Center, Northport, NY 11768, USA.
Pulm Pharmacol Ther. 2002;15(2):121-7. doi: 10.1006/pupt.2001.0337.
The identity of the transmitter(s) of nonadrenergic, noncholinergic airway smooth muscle relaxation has long been investigated. Recently, nitric oxide (NO) has been proposed as the main, if not the only transmitter. We earlier suggested vasoactive intestinal peptide (VIP) as a candidate transmitter and target for pathogenic catalytic autoantibodies (VIPases) found in certain humans. To re-examine the role of VIP, we studied the airway transport and effects of a model monoclonal antibody (Ab) capable of binding and cleaving VIP. In vitro receptor binding assays indicated the catalytic light chain subunit of the VIPase Ab to inhibit the saturable binding of (Tyr(10-125)I) VIP by guinea pig lung membranes, whereas a catalytically deficient mutant of the Ab light chain was without significant inhibitory activity. Systemically administered IgG preparations of the VIPase Ab accumulated in the airway lavage fluid of guinea pigs at levels close to those in blood, suggesting that the Ab reaches the airways freely. Electrical field stimulation (EFS)-induced relaxations of tracheal strips were weaker and shorter in VIPase-treated animals than in control nonimmune IgG-treated animals. The inhibitory effect of the VIPase was dose-dependent. VIPase-mediated inhibition of EFS-induced relaxation was evident both in the absence and presence of blockade of beta-adrenergic and cholinergic receptors. Thus, circulating VIP binding and cleaving antibodies can reach the airways and attenuate the neurogenic relaxation of guinea pig tracheal smooth muscle, probably by neutralizing endogenously released VIP. The findings support a role for VIP as a major mediator of neurogenic relaxation of guinea pig tracheal smooth muscle. Lack of complete abrogation of relaxation is consistent with a co-transmitter role for NO.
非肾上腺素能、非胆碱能性气道平滑肌舒张的递质身份长期以来一直是研究的对象。最近，一氧化氮（NO）被认为是主要的递质，即便不是唯一的递质。我们之前曾提出血管活性肠肽（VIP）是一种候选递质，也是在某些人身上发现的致病性催化自身抗体（VIP酶）的作用靶点。为了重新审视VIP的作用，我们研究了一种能够结合并裂解VIP的模型单克隆抗体（Ab）在气道中的转运及作用。体外受体结合试验表明，VIP酶抗体的催化轻链亚基可抑制豚鼠肺膜对（Tyr(10 - 125)I）VIP的饱和结合，而该抗体轻链的催化缺陷突变体则无明显抑制活性。全身给药后，VIP酶抗体的IgG制剂在豚鼠气道灌洗液中的蓄积水平与血液中的水平相近，这表明该抗体可自由到达气道。电场刺激（EFS）诱导的气管条舒张在VIP酶处理的动物中比在对照非免疫IgG处理的动物中更弱且持续时间更短。VIP酶的抑制作用呈剂量依赖性。在β - 肾上腺素能和胆碱能受体被阻断或未被阻断的情况下，VIP酶介导的对EFS诱导舒张的抑制作用均很明显。因此，循环中的VIP结合并裂解抗体可到达气道，并可能通过中和内源性释放的VIP来减弱豚鼠气管平滑肌的神经源性舒张。这些发现支持了VIP作为豚鼠气管平滑肌神经源性舒张主要介质的作用。舒张未被完全消除与NO作为共同递质的作用是一致的。
