Contribution of Connexin Hemichannels to the Pathogenesis of Acute Lung Injury
Connexin (Cx) family members form hemichannels (HCs) and gap junctions (GJs). Biological functions of Cx HCs have not been adequately characterized due to the inability to selectively target HCs or GJs. Recently, we developed a 6-mer peptide mimetic (P5) of the first extracellular loop of Cx43 and s...
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| Format: | Article |
| Language: | English |
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Wiley
2020-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2020/8094347 |
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| author | Shuaiwei Wang Yafang Sun Yu Bai Nannan Zhou Na Chen Edmund J. Miller Yijie Zhang Wei Li |
| author_facet | Shuaiwei Wang Yafang Sun Yu Bai Nannan Zhou Na Chen Edmund J. Miller Yijie Zhang Wei Li |
| author_sort | Shuaiwei Wang |
| collection | DOAJ |
| description | Connexin (Cx) family members form hemichannels (HCs) and gap junctions (GJs). Biological functions of Cx HCs have not been adequately characterized due to the inability to selectively target HCs or GJs. Recently, we developed a 6-mer peptide mimetic (P5) of the first extracellular loop of Cx43 and showed that it can block the permeability of HCs but not GJs formed by Cx43. In this study, we further characterized the HC blocking property of P5 and investigated the role of Cx HCs in acute lung injury (ALI). We found that P5 administration decreased HC permeability, in pulmonary microvascular endothelial cells, HepG2 cells, and even Cx43-deficient astrocytes, which express different sets of Cxs, suggesting that P5 is a broad spectrum Cx HC blocker. In addition, P5 reduced HC permeability of alveolar cells in vivo. Moreover, P5 decreased endotoxin-induced release, by vascular endothelial cells in vitro, of high mobility group box protein 1 (HMGB1), a critical mediator of acute lung injury (ALI), and reduced HMGB1 accumulation in bronchoalveolar lavage fluid (BALF) of mice subjected to intratracheal endotoxin instillation. Furthermore, P5 administration resulted in a significant decrease in the concentrations of ALT, AST, and LDH in the BALF, the accumulation of leukocytes in alveoli, and the mortality rate of mice subjected to ALI. Wright-Giemsa staining showed that P5 caused similar reductions of both neutrophils and monocytes in BALF of ALI mice. Together, these results suggest that Cx HCs mediate HMGB1 release, augment leukocyte recruitment, and contribute to ALI pathology. |
| format | Article |
| id | doaj-art-4bda57578eab461394de515362479322 |
| institution | DOAJ |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-4bda57578eab461394de5153624793222025-08-20T03:20:13ZengWileyMediators of Inflammation0962-93511466-18612020-01-01202010.1155/2020/80943478094347Contribution of Connexin Hemichannels to the Pathogenesis of Acute Lung InjuryShuaiwei Wang0Yafang Sun1Yu Bai2Nannan Zhou3Na Chen4Edmund J. Miller5Yijie Zhang6Wei Li7Sepsis Laboratory, Center for Translational Medicine, Huaihe Hospital, Henan University, Kaifeng, Henan, ChinaSepsis Laboratory, Center for Translational Medicine, Huaihe Hospital, Henan University, Kaifeng, Henan, ChinaSepsis Laboratory, Center for Translational Medicine, Huaihe Hospital, Henan University, Kaifeng, Henan, ChinaInternational Laboratory for Sepsis Research, Kaifeng, Henan, ChinaInternational Laboratory for Sepsis Research, Kaifeng, Henan, ChinaRDS2 Solutions, 25 Health Sciences Drive, Suite 208-B, Stony Brook, NY 11794, USASepsis Laboratory, Center for Translational Medicine, Huaihe Hospital, Henan University, Kaifeng, Henan, ChinaSepsis Laboratory, Center for Translational Medicine, Huaihe Hospital, Henan University, Kaifeng, Henan, ChinaConnexin (Cx) family members form hemichannels (HCs) and gap junctions (GJs). Biological functions of Cx HCs have not been adequately characterized due to the inability to selectively target HCs or GJs. Recently, we developed a 6-mer peptide mimetic (P5) of the first extracellular loop of Cx43 and showed that it can block the permeability of HCs but not GJs formed by Cx43. In this study, we further characterized the HC blocking property of P5 and investigated the role of Cx HCs in acute lung injury (ALI). We found that P5 administration decreased HC permeability, in pulmonary microvascular endothelial cells, HepG2 cells, and even Cx43-deficient astrocytes, which express different sets of Cxs, suggesting that P5 is a broad spectrum Cx HC blocker. In addition, P5 reduced HC permeability of alveolar cells in vivo. Moreover, P5 decreased endotoxin-induced release, by vascular endothelial cells in vitro, of high mobility group box protein 1 (HMGB1), a critical mediator of acute lung injury (ALI), and reduced HMGB1 accumulation in bronchoalveolar lavage fluid (BALF) of mice subjected to intratracheal endotoxin instillation. Furthermore, P5 administration resulted in a significant decrease in the concentrations of ALT, AST, and LDH in the BALF, the accumulation of leukocytes in alveoli, and the mortality rate of mice subjected to ALI. Wright-Giemsa staining showed that P5 caused similar reductions of both neutrophils and monocytes in BALF of ALI mice. Together, these results suggest that Cx HCs mediate HMGB1 release, augment leukocyte recruitment, and contribute to ALI pathology.http://dx.doi.org/10.1155/2020/8094347 |
| spellingShingle | Shuaiwei Wang Yafang Sun Yu Bai Nannan Zhou Na Chen Edmund J. Miller Yijie Zhang Wei Li Contribution of Connexin Hemichannels to the Pathogenesis of Acute Lung Injury Mediators of Inflammation |
| title | Contribution of Connexin Hemichannels to the Pathogenesis of Acute Lung Injury |
| title_full | Contribution of Connexin Hemichannels to the Pathogenesis of Acute Lung Injury |
| title_fullStr | Contribution of Connexin Hemichannels to the Pathogenesis of Acute Lung Injury |
| title_full_unstemmed | Contribution of Connexin Hemichannels to the Pathogenesis of Acute Lung Injury |
| title_short | Contribution of Connexin Hemichannels to the Pathogenesis of Acute Lung Injury |
| title_sort | contribution of connexin hemichannels to the pathogenesis of acute lung injury |
| url | http://dx.doi.org/10.1155/2020/8094347 |
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