Bradykinin-Induced Lung Inflammation and Bronchoconstriction: Role in Parainfluenze-3 Virus-Induced Inflammation and Airway Hyperreactivity
Bradykinin-Induced Lung Inflammation and Bronchoconstriction: Role in Parainfluenze-3 Virus-Induced Inflammation and Airway Hyperreactivity
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DOI：
10.1124/jpet.110.171876
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发表时间：
2010-12-01
影响因子：
3.5
通讯作者：
Ford, William R.
中科院分区：
文献类型：
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作者：
Broadley, Kenneth J.;Blair, Alan E.;Ford, William R.
吸入缓激肽会导致哮喘患者的支气管收缩，但不会导致非哮喘患者。到目前为止，吸入缓激肽的动物研究只在麻醉的豚鼠和大鼠身上进行，在那里它通过感觉神经通路引起支气管收缩。在本研究中，用全身体积描记技术记录清醒豚鼠的气道功能。吸入缓激肽(1 mM，20 S)可引起支气管收缩和炎症细胞进入肺内，但仅当卡托普利(1 mg/kg，i.p)抑制血管紧张素转换酶和中性内肽酶对缓激肽的分解。和磷酰胺(10 mM，20分钟吸入)。B-2激动素受体拮抗剂4-(S)-amino-5-(4-{4-[2，4-dichloro-3-(2，4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5-oxopentyl](trimethyl)ammonium盐酸盐(MEN16132)雾化吸入(1和10 mU M，20min)可拮抗支气管收缩和细胞内流，因此是通过B-2激动素受体介导的。然而，吸入MEN16132和B-2肽拮抗剂均不能拮抗这些缓激肽反应。卵清蛋白对豚鼠的致敏作用不足以引起吸入缓激肽引起的气道高反应性(AHR)。然而，致敏豚鼠卵清蛋白攻击可引起缓激肽和组胺的AHR。豚鼠经鼻腔滴注副流感3型病毒后，对吸入组胺和肺内炎症细胞产生AHR。这些反应被缓激肽B-2受体拮抗剂MEN16132和组织激肽释放酶抑制剂H-(4-chloro)DPhe-2‘(1-naphthylalanine)-(3-aminopropyl)guanidine(VA999024)减弱，组织激肽释放酶负责肺合成缓激肽。这些结果表明，缓激肽参与了病毒诱导的炎性细胞内流和AHR。
Inhaled bradykinin causes bronchoconstriction in asthmatic subjects but not nonasthmatics. To date, animal studies with inhaled bradykinin have been performed only in anesthetized guinea pigs and rats, where it causes bronchoconstriction through sensory nerve pathways. In the present study, airway function was recorded in conscious guinea pigs by whole-body plethysmography. Inhaled bradykinin (1 mM, 20 s) caused bronchoconstriction and influx of inflammatory cells to the lungs, but only when the enzymatic breakdown of bradykinin by angiotensin-converting enzyme and neutral endopeptidase was inhibited by captopril (1 mg/kg i.p.) and phosphoramidon (10 mM, 20-min inhalation), respectively. The bronchoconstriction and cell influx were antagonized by the B-2 kinin receptor antagonist 4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132) when given by inhalation (1 and 10 mu M, 20 min) and are therefore mediated via B-2 kinin receptors. However, neither intraperitioneal MEN16132 nor the peptide B-2 antagonist icatibant, by inhalation, antagonized these bradykinin responses. Sensitization of guinea pigs with ovalbumin was not sufficient to induce airway hyperreactivity (AHR) to the bronchoconstriction by inhaled bradykinin. However, ovalbumin challenge of sensitized guinea pigs caused AHR to bradykinin and histamine. Infection of guinea pigs by nasal instillation of parainfluenza-3 virus produced AHR to inhaled histamine and lung influx of inflammatory cells. These responses were attenuated by the bradykinin B-2 receptor antagonist MEN16132 and H-(4-chloro)DPhe-2'(1-naphthylalanine)-(3-aminopropyl)guanidine (VA999024), an inhibitor of tissue kallikrein, the enzyme responsible for lung synthesis of bradykinin. These results suggest that bradykinin is involved in virus-induced inflammatory cell influx and AHR.