2. Academic Validation
  3. Diesel exhaust particles inhibit lung branching morphogenesis via the YAP/TAZ pathway

Diesel exhaust particles inhibit lung branching morphogenesis via the YAP/TAZ pathway

  • Sci Total Environ. 2022 Dec 5;861:160682. doi: 10.1016/j.scitotenv.2022.160682.
Yu-Ling Chung 1,  Vincent Laiman 2,  Po-Nien Tsao 3,  Chung-Ming Chen 4,  Didik Setyo Heriyanto 5,  Kian Fan Chung 6,  Kai-Jen Chuang 7,  Hsiao-Chi Chuang 8
Affiliations

Affiliations

  • 1 School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 2 International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Anatomical Pathology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada - Dr. Sardjito Hospital, Yogyakarta, Indonesia.
  • 3 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; The Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.
  • 4 Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan; Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 5 Department of Anatomical Pathology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada - Dr. Sardjito Hospital, Yogyakarta, Indonesia.
  • 6 National Heart and Lung Institute, Imperial College London, London, UK.
  • 7 School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan; Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 8 School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: [email protected].
PMID: 36481141 DOI: 10.1016/j.scitotenv.2022.160682
Abstract

Prenatal exposure to air pollution may associated with inhibition of lung development in the child, however the possible mechanism is unclear. We investigated the effects of traffic-related diesel exhaust particle (DEP) exposure on fetal lung branching morphogenesis and elucidate the possible mechanism. Ex vivo fetal lungs collected from ICR mice at an age of 11.5 embryonic (E) days were exposed to DEPs at 0 (control), 10, and 50 μg/mL and branching morphogenesis was measured for 3 days. Normal IMR-90 human fetal lung fibroblast cells were exposed to DEPs at 0 (control), 10, and 50 μg/mL for 24 h. We observed that DEP exposure significantly inhibited lung branching morphogenesis with reduced lung branching ratios and surface areas on day 3. RNA sequencing (RNA-Seq) showed that DEP increased the inflammatory response and impaired lung development-related gene expressions. DEPs significantly decreased Yes-associated protein (YAP), phosphorylated (p)-YAP, transcriptional coactivator with a PDZ-binding motif (TAZ), and p-TAZ in IMR-90 cells at 10 and 50 μg/mL. Treatment of fetal lungs with the YAP Inhibitor, PFI-2, also demonstrated restricted lung branching development similar to that of DEP exposure, with a significantly decreased lung branching ratio on day 3. DEP exposure significantly decreased the lung branching modulators Fibroblast Growth Factor receptor 2 (FGFR2), sex-determining region Y-box 2 (SOX2), and SOX9 in IMR-90 cells at 10 and 50 μg/mL. Fetal lung immunofluorescence staining showed that DEP decreased SOX2 expression in fibronectin+ fibroblasts. DEP exposure decreased the cellular senescence regulator, p-sirtuin 1 (SIRT1)/SIRT1 in IMR-90 cells, with RNA-Seq showing impaired telomere maintenance. DEP exposure impaired fetal lung growth during the pseudoglandular stage through dysregulating the Hippo signaling pathway, causing fibroblast lung branching restriction and early senescence. Prenatal exposure to traffic-related air pollution has adverse effects on fetal lung development.

Keywords

Air pollution; Branching morphogenesis; Fetal lung; Hippo signaling pathway; PM(2.5); Senescence.

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