Shinjyo Noriko, Kimura Haruna, Yoshihara Tomomi, Suzuki Jun, Yamaguchi Masaya, Kawabata Shigetada, Okabe Yasutaka
Laboratory of Immune Homeostasis, World Premier International Research Center Initiative, Immunology Frontier Research Center (IFReC), The University of Osaka, Osaka, Japan.
School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan.
J Clin Invest. 2025 May 15;135(14). doi: 10.1172/JCI191276. eCollection 2025 Jul 15.
Air pollution is a serious environmental threat to public health; however, the molecular basis underlying its detrimental effects on respiratory fitness remains poorly understood. Here, we showed that exposure to particulate matter ≤ 2.5 μm (PM2.5), a substantial fraction of air pollutants, induced the generation of reactive aldehyde species in the airway. We identified aldehyde dehydrogenase 1A1 (ALDH1A1), which was selectively expressed in airway epithelium, as an enzyme responsible for detoxifying these reactive aldehyde species. Loss of ALDH1A1 function resulted in the accumulation of aldehyde adducts in the airway, which selectively impaired mucociliary clearance (MCC), a critical defense mechanism against respiratory pathogens. Thus, ALDH1A1-deficient mice pre-exposed to PM2.5 exhibited increased susceptibility to pneumonia. Conversely, pharmacological enhancement of ALDH1A1 activity promoted the restoration of MCC function. These findings elucidate the critical role of aldehyde metabolism in protecting against PM2.5 exposure, offering a potential target to mitigate the negative health consequences of air pollution.
空气污染是对公众健康的严重环境威胁；然而，其对呼吸适应性产生有害影响的分子基础仍知之甚少。在此，我们表明，暴露于细颗粒物≤2.5微米（PM2.5），即空气污染物的很大一部分，会诱导气道中活性醛类物质的产生。我们鉴定出醛脱氢酶1A1（ALDH1A1），它在气道上皮中选择性表达，是负责解毒这些活性醛类物质的一种酶。ALDH1A1功能丧失导致醛加合物在气道中积累，这选择性地损害了黏液纤毛清除（MCC），这是一种抵御呼吸道病原体的关键防御机制。因此，预先暴露于PM2.5的ALDH1A1缺陷小鼠对肺炎的易感性增加。相反，药理学增强ALDH1A1活性促进了MCC功能的恢复。这些发现阐明了醛代谢在抵御PM2.5暴露中的关键作用，为减轻空气污染对健康的负面影响提供了一个潜在靶点。
