Extreme temperatures modulate gene expression in the airway epithelium of the lungs in mice and asthma patients

Firdian Makrufardi ^1,2 Syue-Wei Peng ³ Kian Fan Chung ⁴ Marc Chadeau-Hyam ^5,6 Kang-Yun Lee ^7,8 Ta-Chih Hsiao ⁹ Kin-Fai Ho ¹⁰ Desy Rusmawatiningtyas ² Indah K Murni ² Eggi Arguni ² Yuan-Hung Wang ^11,12 Shu-Chuan Ho ^3,8 Feng-Ming Yang ³ Kai-Jen Chuang ^13,14 Sheng-Chieh Lin ^15,16* Hsiao-Chi Chuang ^17,18,4,8*

• ¹ International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
• ² Department of Child Health, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada – Dr. Sardjito Hospital, Yogyakarta, Indonesia, Yogyakarta, West Java, Indonesia
• ³ School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan, Taipei, Taiwan
• ⁴ National Heart and Lung Institute, Imperial College London, London, United Kingdom, London, United Kingdom
• ⁵ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
• ⁶ MRC Centre for Environment and Health Imperial College London, London, United Kingdom, London, United Kingdom
• ⁷ Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
• ⁸ Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, Taipei, Taiwan
• ⁹ Graduate Institute of Environmental Engineering, National Taiwan University, Taipei, Taiwan
• ¹⁰ JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR China
• ¹¹ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
• ¹² Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, New Taipei City, Taiwan
• ¹³ School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan, Taipei, Taiwan
• ¹⁴ Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, Taipei, Taiwan
• ¹⁵ Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, Taipei, Taiwan
• ¹⁶ Division of Allergy, Asthma, and Immunology, Department of Pediatrics, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, New Taipei City, Taiwan
• ¹⁷ School of Respiratory Therapy, Taipei Medical University, Taipei, Taiwan
• ¹⁸ Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, Taipei, Taiwan

Background: The objective of this study was to examine the effects of extreme temperatures on the gene signature and pathways of airway epithelial cells in mice and asthma patients. Methods: We investigated the effects of temperature exposure at normal (22°C), and extreme low (10°C), high (40°C) and temperature fluctuation (40°C for 2 hours followed by 10°C for next 2 hours) in B6.Sftpc-CreERT2;Ai14(RCL-tdT)-D mice and pediatric and adult patient’s airway epithelial exposed to extreme temperatures. Results: We observed that Mmp8, Sftpb, Cxcl15 and Cd14 were significantly upregulated in airway epithelial cells in mice model. Cma1, Kit, Fdx1, Elf1a, Cdkn2aipnl, Htatsf1, Mfsd13a, Gtf2h5, Tiam2, and Trmt10c were significantly upregulated in 40°C exposure in airway epithelial cells. Sftpc, Gpr171, Sic34a2, Cox14, Lamp3, Luc7l, Nxnl, Tmub2, Tob1, and Cd3e genes were significantly upregulated in 10°C exposure group. Pediatric asthma subjects in the extreme high temperature group consistently showed decreased Wfdc21, Cib3, and Sftpc, at the same time increased Tiam2 and Cma1 expression, while in the extreme low temperature group exhibited consistently higher expression of Sftpc and Nxnl, at the same time decreased Wfdc21, Cib3, Cma1, and Dld expression. Notably, the mice in the extreme temperature fluctuation group showed decreased Wfdc21, Cib3, Gpr171, and Cttnbp2 expression, while increased Hbb-bs expression. Adult asthma subjects in the extreme temperature fluctuation group showed consistently decreased Wfdc21, Cib3, Gpr171, and Cttnbp2 expression, while increased Tiam2 and Cma1 expression. We observed that the mild, moderate, and severe asthma subject in the extreme low temperature group showed increased Tob1, Mub2, Sic34a2, Sftpc, Nxnl, Luc71, Lamp3, Gpr171, Cox14, and Cd3e expression, while in the severe asthma subjects showed increased expression in all temperature exposure group. Conclusion: Our study highlights the effects of extreme temperatures on the gene signature of the airway epithelium in both mice and asthma patients. These findings suggest that extreme temperatures modulate gene expression in the airway epithelium, potentially serving as clinical indicators or biomarkers in response to climate change.