Connexin 43 Upregulation in Mouse Lungs during Ovalbumin-Induced Asthma

PLOS ONE, Dec 2019

Background Connexin (Cx)-based gap junction channels play important roles in the inflammatory response. Cx43 is involved in the pathogenesis of some lung diseases such as acute lung injury. However, the Cx43 expression in asthma is unclear. In the present study, we used a murine model of ovalbumin (OVA)-induced allergic airway disease to examine the levels of Cx43 and analyze the relationship between Cx43 and airway inflammation in allergic airway disease. Methods Asthma was induced in mice via sensitization and challenge with OVA. Cx43 mRNA and protein expression levels were investigated via QT-PCR, western blot, and immunohistochemistry 0 h, 8 h, 1 d, 2 d and 4 d after the first challenge. The relationship between Cx43 protein levels and inflammatory cell infiltration, cytokine levels was analyzed. Results The OVA-induced mice exhibited typical pathological features of asthma, including airway hyper-responsiveness; strong inflammatory cell infiltration surrounding the bronchia and vessels; many inflammatory cells in the bronchoalveolar lavage fluid (BALF); higher IL-4, IL-5 and IL-13 levels; and high OVA specific IgE levels. Low Cx43 expression was detected in the lungs of control (PBS) mice. A dramatic increase in the Cx43 mRNA and protein levels was found in the asthmatic mice. Cx43 mRNA and protein expression levels increased in a time-dependent manner in asthma mice, and Cx43 was mostly localized in the alveolar and bronchial epithelial layers. Moreover, lung Cx43 protein levels showed a significant positive correlation with inflammatory cell infiltration in the airway and IL-4 and IL-5 levels in the BALF at different time points after challenge. Interestingly, the increase in Cx43 mRNA and protein levels occurred prior to the appearance of the inflammatory cell infiltration. Conclusion Our data suggest that there is a strong upregulation of Cx43 mRNA and protein levels in the lungs in asthma. Cx43 levels also exhibited a positive correlation with allergic airway inflammation. Cx43 may represent a target to treat allergic airway diseases in the future.

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Connexin 43 Upregulation in Mouse Lungs during Ovalbumin-Induced Asthma

December Connexin 43 Upregulation in Mouse Lungs during Ovalbumin-Induced Asthma Yin Yao 0 1 Qing-Xiang Zeng 0 1 Xue-Quan Deng 0 1 Guan-Nan Tang 0 1 Jie-Bo Guo 0 1 Yue-Qi Sun 0 1 Kun Ru 0 1 Alicia N. Rizzo 0 1 Jian-Bo Shi 0 1 Qing-Ling Fu 0 1 0 1 Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou, Guangdong province, China , 2 Otorhinolaryngology Institute, Sun Yat-sen University , Guangzhou, Guangdong province, China , 3 Division of Pulmonary, Critical Care , Sleep, and Allergy , University of Illinois at Chicago , Chicago, Illinois , United States of America 1 Editor: Christopher Torrens, University of Southampton, UNITED KINGDOM Connexin (Cx)-based gap junction channels play important roles in the inflammatory response. Cx43 is involved in the pathogenesis of some lung diseases such as acute lung injury. However, the Cx43 expression in asthma is unclear. In the present study, we used a murine model of ovalbumin (OVA)-induced allergic airway disease to examine the levels of Cx43 and analyze the relationship between Cx43 and airway inflammation in allergic airway disease. Data Availability Statement; Our data are all contained within the paper - OPEN ACCESS Background Methods Results Asthma was induced in mice via sensitization and challenge with OVA. Cx43 mRNA and protein expression levels were investigated via QT-PCR, western blot, and immunohistochemistry 0 h, 8 h, 1 d, 2 d and 4 d after the first challenge. The relationship between Cx43 protein levels and inflammatory cell infiltration, cytokine levels was analyzed. The OVA-induced mice exhibited typical pathological features of asthma, including airway hyper-responsiveness; strong inflammatory cell infiltration surrounding the bronchia and vessels; many inflammatory cells in the bronchoalveolar lavage fluid (BALF); higher IL-4, IL 5 and IL-13 levels; and high OVA specific IgE levels. Low Cx43 expression was detected in the lungs of control (PBS) mice. A dramatic increase in the Cx43 mRNA and protein levels was found in the asthmatic mice. Cx43 mRNA and protein expression levels increased in a time-dependent manner in asthma mice, and Cx43 was mostly localized in the alveolar and bronchial epithelial layers. Moreover, lung Cx43 protein levels showed a significant positive correlation with inflammatory cell infiltration in the airway and IL-4 and IL-5 levels in the BALF at different time points after challenge. Interestingly, the increase in Cx43 mRNA and protein levels occurred prior to the appearance of the inflammatory cell infiltration. Competing Interests: The authors have declared that no competing interests exist. Conclusion Our data suggest that there is a strong upregulation of Cx43 mRNA and protein levels in the lungs in asthma. Cx43 levels also exhibited a positive correlation with allergic airway inflammation. Cx43 may represent a target to treat allergic airway diseases in the future. Introduction Asthma is a common heterogeneous respiratory disease that has increased over the past 50 years [ 1 ]. Asthma is caused by allergen inhalation, leading to airway hyper-responsiveness, inflammation infiltration, mucous production, structural changes in the airway walls and airway obstruction [ 2 ]. Recently, a substantial body of evidence suggested the importance of epithelial cells [ 3,4 ] and innate lymphoid cells [ 5,6 ] in initiating and sustaining the allergic cascade. Despite increasing evidence regarding the import role of epithelial cells in airway allergy inflammation, including contribution of activation and survival of mast cells, basophil and eosinophils [ 7 ], the underlying molecular mechanisms remain incompletely characterized, especially regarding the cell-cell interactions and the molecules involved. Direct cell-to-cell communication mediated by gap junction channels (GJCs) plays several central roles in cell growth and differentiation, cell cycle regulation and carcinogenesis [ 8–10 ]. GJCs are essential for coordinating tissue homeostasis and regulating inflammatory responses, which directly link the cytoplasm, which allows for conduction of intercellular signals between adjacent cells. This behavior enables the lung, which is composed of many types of cells, to behave as an integrated system [ 11–13 ]. Connexins from both cells dock to form a GJC and allow the passage of metabolites (i.e., ATP), second messengers and small soluble molecules between the cell interior and the interstitial space, thereby coupling the cells both electrically and metabolically [ 14,15 ]. More than twenty types of connexins have been characterized in humans, including Cx26, Cx32, Cx37, Cx40, Cx43 and Cx46. Cx43 is one of the most frequently expressed connexins [ 11,12 ]. As an inflammatory mediator and signal conductor, Cx43 plays an important role in the pathogenesis of many lung diseases, including acute lung injury (ALI), cystic fibrosis (CF), pulmonary arterial hyper (...truncated)


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Yin Yao, Qing-Xiang Zeng, Xue-Quan Deng, Guan-Nan Tang, Jie-Bo Guo, Yue-Qi Sun, Kun Ru, Alicia N. Rizzo, Jian-Bo Shi, Qing-Ling Fu. Connexin 43 Upregulation in Mouse Lungs during Ovalbumin-Induced Asthma, PLOS ONE, 2015, Volume 10, Issue 12, DOI: 10.1371/journal.pone.0144106