Mizutani Nobuaki
Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Yakugaku Zasshi. 2003 Jan;123(1):1-8. doi: 10.1248/yakushi.123.1.
Cysteinyl leukotrienes (CysLTs: LTC4, LTD4, and LTE4) are a family of potent inflammatory mediators that appear to contribute to the pathophysiologic features of allergic rhinitis. Because treatment with a CysLT1 receptor antagonist and a 5-lipoxygenase inhibitor modified allergen-induced nasal blockage in patients with allergic rhinitis, and CysLTs were detected in nasal cavity lavage fluid, it has been suggested that CysLTs act as significant inflammatory mediators in allergic rhinitis. The role of CysLTs was evaluated in our experimental allergic rhinitis model in sensitized guinea pigs which shows biphasic nasal blockage, sneezing and nasal hyperresponsiveness to LTD4 induced by repetitive inhalation challenge with Japanese cedar pollen. In this model, the CysLT1 receptor antagonist pranlukast suppressed the late-phase nasal blockage but not early blockage and sneezing. Nasal hyperresponsiveness (nasal blockage) to LTD4 was largely blocked by pranlukast, naphazoline, and N omega-nitro-L-arginine-methyl ester. The results demonstrate that nasal blockage induced by CysLTs is mainly due to dilatation of nasal blood vessels, which can be induced by the nitric oxide produced through CysLT1 receptor activation. On the other hand, when pollen inhalation challenge was performed in the presence of nasal hyperresponsiveness, antigen-induced biphasic nasal blockage and sneezing were considerably enhanced and CysLTs contributed to both symptoms, suggesting that nasal hyperresponsiveness induces aggravation of antigen-induced nasal symptoms. The results presented in this study further suggest that our model is a good representative of human allergic rhinitis and offer evidence that CysLTs are chemical mediators mainly responsible for allergic nasal symptoms.
半胱氨酰白三烯（CysLTs：LTC4、LTD4和LTE4）是一类强效炎症介质，似乎在变应性鼻炎的病理生理特征中起作用。由于使用半胱氨酰白三烯1（CysLT1）受体拮抗剂和5-脂氧合酶抑制剂治疗可改善变应性鼻炎患者变应原诱导的鼻阻塞，且在鼻腔灌洗液中检测到了CysLTs，因此有人提出CysLTs在变应性鼻炎中作为重要的炎症介质发挥作用。在我们建立的致敏豚鼠实验性变应性鼻炎模型中评估了CysLTs的作用，该模型表现为双相鼻阻塞、打喷嚏以及对日本雪松花粉反复吸入激发诱导的LTD4出现鼻高反应性。在该模型中，CysLT1受体拮抗剂普仑司特可抑制晚期鼻阻塞，但不能抑制早期阻塞和打喷嚏。普仑司特、萘甲唑啉和N-ω-硝基-L-精氨酸甲酯可很大程度上阻断对LTD4的鼻高反应性（鼻阻塞）。结果表明，CysLTs诱导的鼻阻塞主要是由于鼻血管扩张，这可由通过CysLT1受体激活产生的一氧化氮诱导。另一方面，当在存在鼻高反应性的情况下进行花粉吸入激发时，抗原诱导的双相鼻阻塞和打喷嚏会显著增强，且CysLTs对这两种症状均有作用，这表明鼻高反应性会导致抗原诱导的鼻部症状加重。本研究结果进一步表明，我们的模型是人类变应性鼻炎的良好代表，并提供了证据证明CysLTs是主要导致变应性鼻部症状的化学介质。
