Aldehyde metabolism governs resilience of mucociliary clearance to air pollution exposure
Noriko Shinjyo, … , Shigetada Kawabata, Yasutaka Okabe
Noriko Shinjyo, … , Shigetada Kawabata, Yasutaka Okabe
Published May 23, 2025
Citation Information: J Clin Invest. 2025;135(14):e191276. https://doi.org/10.1172/JCI191276.
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Research Article Cell biology Infectious disease Public Health

Aldehyde metabolism governs resilience of mucociliary clearance to air pollution exposure

Abstract

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.

Authors

Noriko Shinjyo, Haruna Kimura, Tomomi Yoshihara, Jun Suzuki, Masaya Yamaguchi, Shigetada Kawabata, Yasutaka Okabe

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Figure 2

Essential role of ALDH1A1 in detoxifying reactive aldehyde species in the airway.

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Essential role of ALDH1A1 in detoxifying reactive aldehyde species in th...
(A) Expression of mRNA of mouse ALDH family members in indicated tissues (n = 3) was determined by quantitative PCR, and copy numbers per Rpl13a mRNA are visualized using a heat map. (B) Lung of WT mice was analyzed by immunofluorescence staining for ALDH1A1 and nuclei (DAPI). Higher magnification of bronchiolar epithelium (gated in left panel) is shown in right panel. B, bronchus; A, alveolar duct. Scale bars: 100 μm (left), 10 μm (right). (C and D) Bulk RNA-seq and scRNA-seq data of human lungs obtained from ENCODE and LungMAP Consortium were analyzed. (C) Transcripts per kilobase million (TPM) of ALDH family members are visualized using a heat map. (D) Uniform manifold approximation and projection (UMAP) visualization of color-coded human lung cell populations (left) and ALDH1A1 mRNA projection with highest normalized expression level (right) are shown. (E and F) Aldh1a1+/+ and Aldh1a1–/– mice were intraperitoneally injected with 200 mg/kg naphthalene at 2-week intervals for a total of 2 times, and lungs were harvested 2 weeks after the second administration. Alternatively, mice were intranasally injected with 100 μg DEPs every other day for a total of 6 times, and lungs were harvested 3 days after the last administration. Immunofluorescence staining of longitudinal sections of the large airway was performed for acrolein adduct, cilia (TUBA), and nuclei (DAPI) (E) or 4-HNE adduct, airway epithelial cells (CYP2F2), and nuclei (DAPI) (F), and representative images are shown. Scale bars: 10 μm (E and F). Data represent at least 2 independent experiments with similar results (B, E, and F).