Affiliation:
1. Department of Respiratory Diseases Longhua Hospital Shanghai University of Traditional Chinese Medicine Shanghai China
2. Henan Key Laboratory of Chinese Medicine for Respiratory Disease Henan University of Chinese Medicine Zhengzhou China
3. Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co‐constructed by Henan Province & Education Ministry of P.R. China, Henan University of Chinese Medicine Zhengzhou China
4. Academy of Chinese Medical Sciences Henan University of Chinese Medicine Zhengzhou China
5. Department of Respiratory Diseases The First Affiliated Hospital of Henan University of Chinese Medicine Zhengzhou China
Abstract
AbstractBackgroundThe airway epithelium acts as a physical barrier to protect pulmonary airways against pathogenic microorganisms and toxic substances, such as cigarette smoke (CS), bacteria, and viruses. The disruption of the structural integrity and dysfunction of the airway epithelium is related to the occurrence and progression of chronic obstructive pulmonary disease.PurposeThe aim of this study is to compare the effects of CS, Klebsiella pneumoniae (KP), and their combination on airway epithelial barrier function.MethodsThe mice were exposed to CS, KP, and their combination from 1 to 8 weeks. After the cessation of CS and KP at Week 8, we observed the recovery of epithelial barrier function in mice for an additional 16 weeks. To compare the epithelial barrier function among different groups over time, the mice were sacrificed at Weeks 4, 8, 16, and 24 and then the lungs were harvested to detect the pulmonary pathology, inflammatory cytokines, and tight junction proteins. To determine the underlying mechanisms, the BEAS‐2B cells were treated with an epidermal growth factor receptor (EGFR) inhibitor (AG1478).ResultsThe results of this study suggested that the decreased lung function, increased bronchial wall thickness (BWT), elevated inflammatory factors, and reduced tight junction protein levels were observed at Week 8 in CS‐induced mice and these changes persisted until Week 16. In the KP group, increased BWT and elevated inflammatory factors were observed only at Week 8, whereas in the CS + KP group, decreased lung function, lung tissue injury, inflammatory cell infiltration, and epithelial barrier impairment were observed at Week 4 and persisted until Week 24. To further determine the mechanisms of CS, bacteria, and their combination on epithelial barrier injury, we investigated the changes of EGFR and its downstream protein in the lung tissues of mice and BEAS‐2B cells. Our research indicated that CS, KP, or their combination could activate EGFR, which can phosphorylate and activate ERK1/2, and this effect was more pronounced in the CS + KP group. Furthermore, the EGFR inhibitor AG1478 suppressed the phosphorylation of ERK1/2 and subsequently upregulated the expression of ZO‐1 and occludin. In general, these results indicated that the combination of CS and KP caused more severe and enduring damage to epithelial barrier function than CS or KP alone, which might be associated with EGFR/ERK1/2 signaling.ConclusionEpithelial barrier injury occurred earlier, was more severe, and had a longer duration when induced by the combination of CS and KP compared with the exposure to CS or KP alone, which might be associated with EGFR/ERK signaling.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Henan Province
Subject
Health, Toxicology and Mutagenesis,Management, Monitoring, Policy and Law,Toxicology,General Medicine
Cited by
1 articles.
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