Inflammation and Immunology Research Unit, Pfizer, Cambridge, Massachusetts 02140, USA.
Am J Respir Cell Mol Biol. 2012 Jan;46(1):71-9. doi: 10.1165/rcmb.2011-0095OC.
The expression of acidic mammalian chitinase (AMCase) is associated with Th2-driven respiratory disorders. To investigate the potentially pathological role of AMCase in allergic airway disease (AAD), we sensitized and challenged mice with ovalbumin or a combination of house dust mite (HDM) plus cockroach allergen. These mice were treated or not treated with small molecule inhibitors of AMCase, which significantly reduced allergen-induced chitinolytic activity in the airways, but exerted no apparent effect on pulmonary inflammation per se. Transgenic and AMCase-deficient mice were also submitted to protocols of allergen sensitization and challenge, yet we found little or no difference in the pattern of AAD between mutant mice and wild-type (WT) control mice. In a separate model, where mice were challenged only with intratracheal instillations of HDM without adjuvant, total bronchoalveolar lavage (BAL) cellularity, inflammatory infiltrates in lung tissues, and lung mechanics remained comparable between AMCase-deficient mice and WT control mice. However BAL neutrophil and lymphocyte counts were significantly increased in AMCase-deficient mice, whereas concentrations in BAL of IL-13 were significantly decreased compared with WT control mice. These results indicate that, although exposure to allergen stimulates the expression of AMCase and increased chitinolytic activity in murine airways, the overexpression or inhibition of AMCase exerts only a subtle impact on AAD. Conversely, the increased numbers of neutrophils and lymphocytes in BAL and the decreased concentrations of IL-13 in AMCase-deficient mice challenged intratracheally with HDM indicate that AMCase contributes to the Th1/Th2 balance in the lungs. This finding may be of particular relevance to patients with asthma and increased airway neutrophilia.
酸性哺乳动物几丁质酶 (AMCase) 的表达与 Th2 驱动的呼吸紊乱有关。为了研究 AMCase 在过敏性气道疾病 (AAD) 中的潜在病理作用，我们用卵清蛋白或屋尘螨 (HDM) 加蟑螂过敏原对小鼠进行致敏和激发。这些小鼠用 AMCase 的小分子抑制剂进行治疗或不治疗，这些抑制剂显著降低了气道中的几丁质酶活性，但对肺炎症本身没有明显影响。转基因和 AMCase 缺陷小鼠也接受了过敏原致敏和激发的方案，但我们发现突变小鼠和野生型 (WT) 对照小鼠之间的 AAD 模式几乎没有差异。在另一个模型中，仅用 HDM 经气管内滴注而无佐剂对小鼠进行激发，AMCase 缺陷小鼠和 WT 对照小鼠之间的总支气管肺泡灌洗液 (BAL) 细胞计数、肺组织中的炎症浸润和肺力学仍然相似。然而，AMCase 缺陷小鼠的 BAL 中性粒细胞和淋巴细胞计数显著增加，而与 WT 对照小鼠相比，BAL 中 IL-13 的浓度显著降低。这些结果表明，尽管暴露于过敏原会刺激 AMCase 的表达并增加小鼠气道中的几丁质酶活性，但 AMCase 的过表达或抑制仅对 AAD 产生细微影响。相反，在 AMCase 缺陷小鼠经气管内滴注 HDM 后 BAL 中中性粒细胞和淋巴细胞数量增加，IL-13 浓度降低表明 AMCase 有助于肺部 Th1/Th2 平衡。这一发现可能与哮喘和气道中性粒细胞增多症患者特别相关。
