Matsumoto Takafumi, Inoue Hiromasa, Sato Yosuke, Kita Yoshihiro, Nakano Takako, Noda Naotaka, Eguchi-Tsuda Miyuki, Moriwaki Atsushi, Kan-O Keiko, Matsumoto Koichiro, Shimizu Takao, Nagasawa Hiromichi, Sakuda Shohei, Nakanishi Yoichi
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Biochem Biophys Res Commun. 2009 Dec 4;390(1):103-8. doi: 10.1016/j.bbrc.2009.09.075. Epub 2009 Sep 24.
Acidic mammalian chitinase is upregulated in response to allergen exposure in the lung. We investigated the effects of chitinase inhibitors, allosamidin (Allo) and demethylallosamidin (Dma), on asthmatic responses. Mice were subjected to IL-13 instillation into the airways or to ovalbumin sensitization plus exposure with or without treatment of Allo or Dma. Airway hyperresponsiveness (AHR) and inflammation were evaluated. Allo and Dma attenuated airway eosinophilia and the upregulation of eotaxin after IL-13 instillation, while Dma, but not Allo, suppressed AHR in IL-13-induced asthma. Allo or Dma suppressed the elevated chitinase activity in BAL fluids after IL-13 to similar levels. The bronchoprotective PGE(2) levels in BAL fluids were elevated after IL-13 instillation. Allo, but not Dma, suppressed the overproduction of PGE(2) and the expression of COX-2 and PGE synthase-1 induced by IL-13. In ovalbumin-induced asthma, Dma suppressed AHR more strongly than Allo. These findings suggest that Dma attenuates asthmatic responses induced by IL-13 without affecting PGE(2) synthesis. Dma may have potential as therapeutic agents for asthma.
酸性哺乳动物几丁质酶在肺部暴露于变应原后会上调。我们研究了几丁质酶抑制剂别洛沙米定（Allo）和去甲基别洛沙米定（Dma）对哮喘反应的影响。将小鼠气道内滴注白细胞介素-13（IL-13），或进行卵清蛋白致敏并暴露，同时给予或不给予Allo或Dma治疗。评估气道高反应性（AHR）和炎症。Allo和Dma减轻了IL-13滴注后气道嗜酸性粒细胞增多和嗜酸性粒细胞趋化因子的上调，而Dma（而非Allo）在IL-13诱导的哮喘中抑制了AHR。Allo或Dma将IL-13后支气管肺泡灌洗（BAL）液中升高的几丁质酶活性抑制到相似水平。IL-13滴注后，BAL液中具有支气管保护作用的前列腺素E2（PGE2）水平升高。Allo（而非Dma）抑制了IL-13诱导的PGE2过量产生以及环氧化酶-2（COX-2）和PGE合酶-1的表达。在卵清蛋白诱导的哮喘中，Dma比Allo更强烈地抑制AHR。这些发现表明，Dma可减轻IL-13诱导的哮喘反应，而不影响PGE2合成。Dma可能具有作为哮喘治疗药物的潜力。
