Elevated CO2 modulates airway contractility.

Masahiko Shigemura,Jacob I Sznajder

doi:10.1098/rsfs.2020.0021

Abstract

Carbon dioxide (CO2), a primary product of oxidative metabolism, can be sensed by eukaryotic cells eliciting unique responses via specific signalling pathways. Severe lung diseases such as chronic obstructive pulmonary disease are associated with hypoventilation that can lead to the elevation of CO2 levels in lung tissues and the bloodstream (hypercapnia). However, the pathophysiological effects of hypercapnia on the lungs and specific lung cells are incompletely understood. We have recently reported using combined unbiased molecular approaches with studies in mice and cell culture systems on the mechanisms by which hypercapnia alters airway smooth muscle contractility. In this review, we provide a pathophysiological and mechanistic perspective on the effects of hypercapnia on the lung airways and discuss the recent understanding of high CO2 modulation of the airway contractility.

Highlights

Cells and tissues sense and respond to changes in the concentration of gaseous molecules through specific signalling pathways
We found that, in a small cohort of patients with chronic chronic obstructive pulmonary disease (COPD), patients with hypercapnia had higher airway resistance, which improved after correction of hypercapnia
Hypercapnia may worsen airway constriction and limit ventilation to poorly functioning lung units setting up a feedback loop that could culminate in respiratory failure

Summary

Introduction

Cells and tissues sense and respond to changes in the concentration of gaseous molecules through specific signalling pathways. Oxygen- and nitric oxide-activated cellular signalling pathways have been extensively studied [1,2,3], but much less is known about the mechanisms by which non-excitable cells sense and respond to changes in carbon dioxide (CO2) concentrations [3,4,5]. Recent studies suggest that high concentrations of CO2 activate specific gene expression [19,28,29] and signal transduction pathways with adverse consequences on alveolar epithelial function (alveolar fluid clearance) [17,30,31,32,33,34,35] and epithelial cell repair [36,37,38,39]. We review recent advances in our understanding of how elevated CO2 conditions modulate the airway tone, focusing on the effects of hypercapnia and respiratory acidosis

Hypercapnia-induced bronchoconstriction

Respiratory acidosis-related bronchodilation

Effect of hypocapnia on airway contractility

Findings

Conclusion