Aldehyde metabolism governs resilience of mucociliary clearance to air pollution exposure
Noriko Shinjyo, Haruna Kimura, Tomomi Yoshihara, Jun Suzuki, Masaya Yamaguchi, Shigetada Kawabata, Yasutaka Okabe
Noriko Shinjyo, Haruna Kimura, Tomomi Yoshihara, Jun Suzuki, Masaya Yamaguchi, Shigetada Kawabata, Yasutaka Okabe
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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 3

ALDH1A1 deficiency leads to impaired cilia regeneration.

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ALDH1A1 deficiency leads to impaired cilia regeneration. (A–E) Mice with...
(A–E) Mice with indicated genotypes (control, Aldh1a1+/+ or Aldh1a1+/–; KO, Aldh1a1–/–) were intraperitoneally injected with 200 mg/kg naphthalene at 2-week intervals for a total of 2 times. Lungs were harvested 2 weeks after the second injection. Scale bars: 10 μm (A, C, and G). (A) immunofluorescence staining of longitudinal sections of the large airway was performed for cilia (TUBA), airway epithelial cells (CC10), and nuclei (DAPI), and representative images are shown. (B) The percentage of ciliated surface of large and small airway epithelium in (A) and Supplemental Figure 3A are shown (n = 3). (C) Representative scanning electron microscopy images of the naphthalene-exposed large airway epithelium are shown. (D) Flow cytometry analysis of lung cells in naphthalene-exposed mice was conducted. (E) TUBA and total α-tubulin levels of ciliated cells in (D) is shown. (F and G) Mice with indicated genotypes were intraperitoneally injected with 200 mg/kg naphthalene. (F) Mean fluorescence intensity (MFI) of TUBA levels (left) and number of lung ciliated cells (right) were determined at specified days after administration, and the mean values with SEM are shown (n = 3–9). The days of naphthalene injection are indicated by light blue arrows. (G) At specified days after administration, immunofluorescence staining of longitudinal sections of the large airway was performed for cilia (TUBA) and nuclei (DAPI). Each point represents one mouse, and the mean values are shown by red horizontal lines (B). *****P < 0.0001, ***P < 0.01, and NS, not significant by unpaired t test. Data represent at least 3 independent experiments with similar results (A, C–E, and G).