GPRC5A reduction contributes to pollutant benzo[a]pyrene injury via aggravating murine fibrosis, leading to poor prognosis of IIP patients.

Abstract

Air pollution exposure is recently reported to be one of the drivers of exacerbation in idiopathic pulmonary fibrosis (IPF). But there was a lack of direct evidence between pollution and lung fibrosis. Here, our data show effects of pollutant benzo[a]pyrene (BaP) and protein G-protein-coupled receptor family C group 5 type A (GPRC5A) on pulmonary fibrosis, which might help limit potential pollutant injury and disease progression. We cross-referenced epithelial differentially-expressed-genes (DEGs) from pollutant injury and published experimental fibrosis and IPF patients' data, top common-DEG (CO-DEG) GPRC5A was identified as a potential link between exposure-damage and fibrogenesis. The role of GPRC5A was evaluated under BaP exposure, in idiopathic interstitial pneumonia (IIP) tissue-array and via CRISPR/Cas9 knockout mice (Gprc5a-/-). BaP exposure enhanced bleomycin (BLM)-induced murine pulmonary fibrosis with increased Fibronectin and α-SMA expression in primary fibroblasts, thickened respiratory membrane and damaged alveolar type II cell, combined with Gprc5a decline in fibrotic mass. GPRC5A mRNA reduced after 10-14 days' BaP exposure in human epithelial cell A549. GPRC5A protein was further found to decrease in IIP epithelium, especially hyperplastic regions. A high epithelial GPRC5A expression score was positively associated with long survival time (R = 0.34) while negatively with high age (R = -0.4) and IIP type IPF (R = -0.5). Low GPRC5A expression predicts poor prognosis (HR = 4.5). Gprc5a depletion aggravated mortality rate (50%) with increased collagen deposition and myofibroblast activation under BLM treatment and exacerbated BaP injury in lung remodeling. Vitamin metabolic imbalance and Mitofusion2 (Mfn2) or Opa1-regulated mitochondrial dynamics were deduced to contribute to Gprc5a depletion and fibrogenesis. Pollutant BaP exposure worsens murine fibrosis and myofibroblast activation via GPRC5A reduction in the damaged epithelium. GPRC5A deficiency was first confirmed to contribute to both poor prognosis of IIP patients and fibrogenesis in murine model; thus, GPRC5A could serve as a novel therapeutic target in pollutant injury and pulmonary fibrosis.

• Authors: Ziling Huang, Siqi Wang, Yuting Liu, Lichao Fan, Yu Zeng, Hongxiu Han, Haoyang Zhang, Xiaoting Yu, Yudong Zhang, Dandan Huang, Yunjin Wu, Wenxia Jiang, Peipei Zhu, Xuyou Zhu, Xianghua Yi
• Journal: The Science of the total environment (Sci Total Environ) Vol. 739 Pg. 139923 (Oct 15 2020) ISSN: 1879-1026 [Electronic] Netherlands
• PMID: 32758941 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Environmental Pollutants
• GPRC5A protein, human
• GPRC5A protein, mouse
• Receptors, G-Protein-Coupled
• Benzo(a)pyrene

Topics

• Animals
• Benzo(a)pyrene (toxicity)
• Environmental Pollutants
• Fibrosis
• Humans
• Idiopathic Interstitial Pneumonias
• Idiopathic Pulmonary Fibrosis
• Lung
• Mice
• Mice, Inbred C57BL
• Receptors, G-Protein-Coupled