Hypercapnia increases airway smooth muscle contractility via caspase-7–mediated miR-133a–RhoA signaling

Abstract

The elevation of carbon dioxide (CO) in tissues and the bloodstream (hypercapnia) occurs in patients with severe lung diseases, including chronic obstructive pulmonary disease (COPD). Whereas hypercapnia has been recognized as a marker of COPD severity, a role for hypercapnia in disease pathogenesis remains unclear. We provide evidence that CO acts as a signaling molecule in mouse and human airway smooth muscle cells. High CO activated calcium-calpain signaling and consequent smooth muscle cell contraction in mouse airway smooth muscle cells. The signaling was mediated by caspase-7-induced down-regulation of the microRNA-133a (miR-133a) and consequent up-regulation of Ras homolog family member A and myosin light-chain phosphorylation. Exposure of wild-type, but not caspase-7-null, mice to hypercapnia increased airway contraction and resistance. Deletion of the gene prevented hypercapnia-induced airway contractility, which was restored by lentiviral transfection of a miR-133a antagonist. In a cohort of patients with severe COPD, hypercapnic patients had higher airway resistance, which improved after correction of hypercapnia. Our data suggest a specific molecular mechanism by which the development of hypercapnia may drive COPD pathogenesis and progression.

Risk and impact of using mask on COPD patients with acute exacerbation during the COVID-19 outbreak: a retrospective study

“…The clinical parameters values of the patients without wearing masks (group A and group B), including ion concentration of serum, vital signs, in ammation markers and artery blood gas, were showed in Table 2.There were no signi cantly changes inPaCO 2, HCO 3 − act, BE and other parameters between these two hospitalizations. [16]. Hypercapnia could change autonomic nerve function which increase heart rate and blood pressure, especially at higher workloads [17,18].…”

Hypercapnia: An Aggravating Factor in Asthma

“…The effects of hypercapnia on the airways and airway smooth muscle is complicated. There are reports attesting to it causing increased airway contractility [ 26 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ] or airway relaxation [ 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. We review recent advances in our understanding of how elevated CO 2 conditions modulate the airway tone, focusing on the effects of hypercapnia and respiratory acidosis.…”

“…Furthermore, several reports of bronchoconstriction in the hypercapnia-exposed animal models [ 78 , 80 , 82 ] revealed that the blockage of the vagus nerve did not entirely abolish the bronchoconstrictor response to the high CO 2 exposure, suggesting that other mechanisms contribute to the hypercapnia-mediated airway constriction. More recently, we have reported that high CO 2 acts as a signaling molecule to increase smooth muscle contraction in mouse and human airway smooth muscle cells [ 26 ]. We found that high concentrations of CO 2 , independently of hypoxia and extracellular pH, increased acetylcholine-induced cell contraction dependent on CO 2 dose and exposure time in cell culture systems.…”

“…Intracellular acidification has been reported to decrease intracellular Ca 2+ levels through voltage-dependent Ca 2+ channels in the K + -induced contractile model, thereby inhibiting airway smooth muscle cell contraction [ 96 ]. We have reported that airway smooth muscle relaxation occurred during acute hypercapnia, but it was early, modest and transient [ 26 ]. As such, we reason that elevated CO 2 levels may have a transient relaxing effect on contracted airways due to the decrease in pH, i.e., respiratory acidosis.…”

“…The lower tidal volumes during protective ventilation can lead to hypercapnia and an associated drop in pH resulting in hypercapnic respiratory acidosis that has been reported as a protective effect via the inhibition of the nuclear factor-κB (NF-κB) pathway, a pivotal transcription activator in inflammation and injury [ 7 , 22 ]. However, in recent years, it has become increasingly evident that elevated CO 2 acts as a gaso-signaling molecule, resulting in deleterious effects in various organs such as the lung [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ] and skeletal muscles [ 30 , 31 , 32 ] as well as innate immunity system [ 25 , 29 , 33 , 34 , 35 , 36 , 37 ]. In the lung, recent studies reported that high levels of CO 2 activate specific gene expression [ 26 , 38 , 39 , 40 ] and signal transduction pathways with adverse consequences on alveolar fluid clearance through Na, K-ATPase endocytosis via intracellular calcium- or extracellular signal-regulated kinase (ERK)-mediated AMP-activated protein kinase (AMPK)/protein kinase C-ζ/c-Jun-N-Terminal Kinase (JNK) signaling or soluble adenylyl cyclase-mediated protein kinase A-Iα signaling [ 24 , 41 , 42 , 43 , 44 , 45 , 46 ] and epithelial cell repair via AMPK-mediated Rac1-GTPase signaling, NF-κB pathways or miR-183-regulated mitochondrial dysfunction [ 28 , 47 , 48 , 49 ].…”