COVID-19-associated pulmonary fibrosis remains frequent. This study aimed to investigate pulmonary redox balance in COVID-19 ARDS patients and possible relationship with pulmonary fibrosis and long-term lung abnormalities. Baseline data, chest CT fibrosis scores, N-terminal peptide of alveolar collagen III (NT-PCP-III), transforming growth factor (TGF)-β1, superoxide dismutase (SOD), reduced glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde (MDA) in bronchoalveolar lavage fluid (BALF) were first collected and compared between SARS-CoV-2 RNA positive patients with moderate to severe ARDS (n = 65, COVID-19 ARDS) and SARS-CoV-2 RNA negative non-ARDS patients requiring mechanical ventilation (n = 63, non-ARDS). Then, correlations between fibroproliferative (NT-PCP-III and TGF-β1) and redox markers were analyzed within COVID-19 ARDS group, and comparisons between survivor and non-survivor subgroups were performed. Finally, follow-up of COVID-19 ARDS survivors was performed to analyze the relationship between pulmonary abnormalities, fibroproliferative and redox markers 3 months after discharge. Compared with non-ARDS group, COVID-19 ARDS group had significantly elevated chest CT fibrosis scores (p < 0.001) and NT-PCP-III (p < 0.001), TGF-β1 (p < 0.001), GSSG (p < 0.001), and MDA (p < 0.001) concentrations on admission, while decreased SOD (p < 0.001) and GSH (p < 0.001) levels were observed in BALF. Both NT-PCP-III and TGF-β1 in BALF from COVID-19 ARDS group were directly correlated with GSSG (p < 0.001) and MDA (p < 0.001) and were inversely correlated with SOD (p < 0.001) and GSH (p < 0.001). Within COVID-19 ARDS group, non-survivors (n = 28) showed significant pulmonary fibroproliferation (p < 0.001) with more severe redox imbalance (p < 0.001) than survivors (n = 37). Furthermore, according to data from COVID-19 ARDS survivor follow-up (n = 37), radiographic residual pulmonary fibrosis and lung function impairment improved 3 months after discharge compared with discharge (p < 0.001) and were associated with early pulmonary fibroproliferation and redox imbalance (p < 0.01). Pulmonary redox imbalance occurring early in COVID-19 ARDS patients drives fibroproliferative response and increases the risk of death. Long-term lung abnormalities post-COVID-19 are associated with early pulmonary fibroproliferation and redox imbalance.

Chronic obstructive pulmonary disease (COPD) is a characteristic chronic airway inflammatory disease that worsens over time, however, there are currently limited clinical therapeutics to suspend its progression. Circular RNAs (circRNAs), which have emerged as functional regulators in various diseases, including COPD, may server as new pharmacological targets in COPD. Here, it is identified a nuclear circRNA, circCANX, that is preferentially decreased in COPD. The linear splicing of CANX pre‐mRNA, enhanced by the ADAR1‐HNRNPL interaction, is responsible for the circCANX decline. Clinically, the higher circCANX expression is associated with a worse lung function index of FEV₁/FVC among patients with COPD. CircCANX suppresses autophagy and stress granule (SG) formation to strengthen inflammation of COPD in vivo and in vitro. Mechanistically, circCANX recruits the tumor suppressor protein P53 (P53) mRNA and RNA helicase upstream frameshift 1 (UPF1) to form a ternary complex, which mediates P53 mRNA degradation through nonsense‐mediated mRNA decay (NMD) process. Together, this study reveals an important circCANX‐mediated regulatory mechanism in COPD, and provides new insights into the potential of circRNA‐based drug and biomarker development for COPD.

Acidosis is the most common complication that seriously affects the prognosis of acute respiratory distress syndrome (ARDS). Acid-sensitive ion channel 1a (ASIC1a) is activated in acidic environments to regulate inflammatory process. However, the role of ASIC1a in ARDS is unclear. In this study, we examined the expression of ASIC1a in airway epithelial cells in an acidic environment. We then investigated whether blocking ASIC1a could inhibit pyroptosis of airway epithelial cells and the molecular mechanism. In the mouse acute lung injury (ALI) model, we observed the changes of lung histopathology, arterial blood gas and pyroptosis related indexes after ASIC1a inhibition. Bronchoalveolar lavage fluid (BALF) from patients with ARDS were collected to explore the expression level of ASIC1a in ARDS patients. Inhibiting ASIC1a can reduce the airway epithelial cell pyroptosis induced by an extracellular acidic environment. ASIC1a can bind to PRKACA, and silencing ASIC1a and PRKACA can inhibit the occurrence of pyroptosis in airway epithelial cells. Compared with control group, arterial blood pH and PaO₂ in ALI group were significantly reduced. The inflammation in the lungs is more intense, and the mRNA and protein of NLRP3, Caspase1 and GSDMD were increased, while ASIC1a specific blocker psalmotoxin-1 alleviated this phenomenon. The expression of ASIC1a in BALF of ARDS patients was significantly increased, especially in non-survival group. Acidic micro-environment can induce the increased expression of ASIC1a, and inhibition of ASIC1a can alleviate the inflammation and airway epithelial cell pyroptosis in ARDS. ASIC1a may be a new target for the treatment of ARDS.