Glucocorticoid Alleviates Mechanical Stress-Induced Airway Inflammation and Remodeling in COPD via Transient Receptor Potential Canonical 1 Channel

Abstract

Background

Increased airway resistance and hyperinflation in chronic obstructive pulmonary disease (COPD) are associated with increased mechanical stress that modulate many essential pathophysiological functions including airway remodeling and inflammation. Our present study aimed to investigate the role of transient receptor potential canonical 1 (TRPC1), a mechanosensitive cation channel in airway remodeling and inflammation in COPD and the effect of glucocorticoid on this process.

Methods

In patients, we investigated the effect of pathological high mechanical stress on the expression of airway remodeling-related cytokines transforming growth factor β1 (TGF-β1), matrix metalloproteinase-9 (MMP9) and the count of inflammatory cells in endotracheal aspirates (ETAs) by means of different levels of peak inspiratory pressure (PIP) under mechanical ventilation, and analyzed their correlation with TRPC1. Based on whether patients regularly used inhaled corticosteroid (ICS), COPD patients were further divided into ICS group (n = 12) and non-ICS group (n=15). The ICS effect on the expression of TRPC1 was detected by Western blot. In vitro, we imitated the mechanical stress using cyclic stretch and examined the levels of TGF-β1 and MMP-9. The role of TRPC1 was further explored by siRNA transfection and dexamethasone administration.

Results

Our results revealed that the TRPC1 level and the inflammatory cells counts were significantly higher in COPD group. After mechanical ventilation, the expression of TGF-β1 and MMP-9 in all COPD subgroups was significantly increased, while in the control group, only high PIP subgroup increased. Meanwhile, TRPC1 expression was positively correlated with the counts of inflammatory cells and the levels of TGF-β₁ and MMP-9. In vitro, mechanical stretch significantly increased TGF-β1 and MMP-9 levels and such increase was greatly attenuated by TRPC1 siRNA transfection and dexamethasone administration.

Conclusion

Our results suggest that the increased TRPC1 may play a role in the airway inflammation and airway remodeling in COPD under high airway pressure. Glucocorticoid could in some degree alleviate airway remodeling via inhibition of TRPC1.

Keywords:

• chronic obstructive pulmonary disease
• COPD
• transient receptor potential canonical 1
• TRPC1
• airway inflammation
• airway remodeling
• mechanical stress

Ethics Approval and Consent to Participate

The study was conducted following the Declaration of Helsinki and has been approved by the Ethics Committee of Suining Central Hospital (No. LSLH20180001) and the Second Affiliated Hospital of Chongqing Medical University (No. 2014(65)), and all participants signed informed consent. All methods were carried out in accordance with relevant guidelines and regulations.

Acknowledgments

We would like to acknowledge the members in the Division of Hepatobiliary and Pancreas Surgery of Suining Central Hospital, the Second Affiliated Hospital of Chongqing Medical University and the support from the hospitals in supporting this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas. All authors took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.

Additional information

Funding

The present study was funded by the National Natural Science Foundation of China (grant no. 81270102) and Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau, grant no.2022MSXM013).