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A7565 - G Protein-Coupled Receptor 1 Deficiency Exacerbates Ozone-Induced Lung Injury and Lung Inflammation
Author Block: R. A. Johnston1, C. J. Sinal2, J. L. Rourke2, C. L. Atkins3, S. R. Siddiqui3, W. T. Jackson3, N. M. Husainat3, I. U. Haque3; 1Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, United States, 2Pharmacology, Dalhousie University, Halifax, NS, Canada, 3Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, United States.
Rationale: We previously reported that chemerin, a non-chemokine chemoattractant, reduced the severity of lung injury, lung inflammation, and increases in airway responsiveness induced by acute exposure to ozone (O3), a gaseous air pollutant that exacerbates asthma symptoms (Jackson et al., Am J Respir Crit Care Med, 191:A3230, 2015). Chemerin can bind three different seven-transmembrane domain receptors: chemokine (C-C motif) receptor-like 2 (Ccrl2), chemokine-like receptor 1 (Cmklr1), and G protein-coupled receptor 1 (Gpr1). We also previously demonstrated that neither Ccrl2 nor Cmklr1 mediated the protective effects of chemerin following acute exposure to O3 (Malik et al., Am J Respir Crit Care Med, 191:A3218, 2015 and Johnston et al., Am J Respir Crit Care Med, 195:A2548, 2017). Consequently, the purpose of this study was to determine if chemerin acts through Gpr1 to decrease the severity of O3-induced lung pathology. Methods: Four and twenty-four hours following cessation of exposure to either filtered room air (air) or O3 (2 parts per million for 3 hours) indices of lung injury [bronchoalveolar lavage fluid (BALF) protein and epithelial cells] and lung inflammation [BALF chemerin, eotaxin, hyaluronan, interleukin (IL)-6, osteopontin, keratinocyte chemoattractant (KC), macrophage inflammatory protein-3α, and neutrophils] were measured in wild-type (C57BL/6J) and mice genetically deficient in Gpr1 (Gpr1-deficient mice) using biochemical and histological analyses. In a separate cohort of similarly exposed mice, responses to methacholine for respiratory system resistance (RRS) were measured using the forced oscillation technique twenty-four hours following cessation of exposure to either air or O3. Results: When compared to genotype-matched air-exposed controls, O3 increased BALF indices of lung injury and lung inflammation. However, BALF epithelial cells, IL-6, KC, and neutrophils were significantly greater in Gpr-1-deficient as compared to wild-type mice. O3 also increased responses to methacholine for RRS in mice of both genotypes. However, there were no genotype-related differences in responsiveness to methacholine following O3 exposure. Conclusions: These data suggest that chemerin-Gpr1 signaling limits the severity of O3-induced lung injury and lung inflammation but has no effect on increases in airway responsiveness induced by O3. Because deficiency of Ccrl2, Cmklr1, and Gpr1 alone has no effect on O3-induced airway hyperresponsiveness (AHR), this suggests that perhaps Ccrl2, Cmklr1, and Gpr1 must all be present for chemerin to limit the severity of O3-induced AHR. Nevertheless, Gpr1 agonists may be of benefit to ameliorate O3-induced lung injury and lung inflammation.