Effects of Connexin 32-Mediated Lung Inflammation Resolution During Liver Ischemia Reperfusion
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ORIGINAL ARTICLE
Effects of Connexin 32‑Mediated Lung Inflammation Resolution During Liver Ischemia Reperfusion Zheng Zhang1 · Weifeng Yao1 · Dongdong Yuan1 · Fei Huang1 · Yue Liu1 · Gangjian Luo1 · Ziqing Hei1 Received: 30 June 2019 / Accepted: 17 December 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Background Hepatic ischemia reperfusion (HIR) leads to a lung inflammatory response and subsequent pulmonary barrier dysfunction. The gap junction communication protein connexin 32 (Cx32), which is widely expressed in the lungs, participates in intercellular signaling. This study determined whether the communication protein Cx32 could affect pulmonary inflammation caused by HIR. Methods Mice were randomly allocated into four groups (n = 8/group): (i) Cx32+/+ sham group; (ii) Cx32+/+ HIR model group; (iii) Cx32−/− sham group; and (iv) Cx32−/− HIR model group. Twenty-four hours after surgery, lung tissues were collected for bright field microscopy, western blot (Cx32, JAK2, p-JAK2, STAT3, p-STAT3), and immunofluorescence (ZO-1, 8-OHDG) analyses. The collected bronchoalveolar fluid was tested for levels of interleukin-6 (IL-6), matrix metalloproteinase 12 (MMP-12), and antitrypsin (α1-AT). Lung mmu-miR-26a/b expression was detected using a PCR assay. Results Increased expression of Cx32 mRNA and protein was noted in the lungs after HIR. Cx32 deletion significantly aggravated pulmonary function from acute lung injury induced by HIR. In addition, Cx32 deletion decreased the protein level of ZO-1 (pulmonary function) and increased the level of the oxidative stress marker 8-OHDG in the lungs. Moreover, in the Cx32−/− HIR model group, the levels of IL-6 and MMP-12 in bronchoalveolar lavage fluid were significantly increased leading to activation of the JAK2/STAT3 pathway, and decreased α1-AT levels. Furthermore, we found mmu-miR-26a/b was significantly downregulated in the Cx32−/− HIR model group. Conclusion HIR leads to acute lung inflammatory injury. Cx32 deletion aggravates hepatic-derived lung inflammation, partly through blocking the transferring of mmu-miR-26a/b and leading to IL-6-related JAK2/STAT3 pathway activation. Keywords Acute lung injury · Connexin · Hepatic ischemia reperfusion · Signal transducer and activator of transcription 3
Introduction Hepatic ischemia reperfusion (HIR) is a common pathophysiological process that occurs in many situations, such as trauma [1], partial hepatectomy [2], and liver transplantation [3]. HIR not only causes liver injury, but also affects many remote organs, eventually leading to a high complication rate Zheng Zhang and Weifeng Yao have contributed equally to this work. * Ziqing Hei [email protected] Gangjian Luo [email protected] 1
Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
and mortality [4]. HIR causes severe lung injury and thereby increases susceptibility of the patient to pulmonary complications leading to prolonged hospital stays, expenses, or eve
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