Contribution of Connexin Hemichannels to the Pathogenesis of Acute Lung Injury
| Autor: | Yi-Jie Zhang, Nannan Zhou, Sun Yafang, Shuaiwei Wang, Edmund J. Miller, Yu Bai, Wei Li, Na Chen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Article Subject Immunology Acute Lung Injury Connexin Lung injury HMGB1 Connexins Permeability Pathogenesis Alveolar cells 03 medical and health sciences Mice 0302 clinical medicine In vivo medicine Pathology Leukocytes RB1-214 Animals Humans HMGB1 Protein Cells Cultured biology medicine.diagnostic_test Chemistry Gap junction Endothelial Cells Gap Junctions Cell Biology Hep G2 Cells respiratory system Molecular biology respiratory tract diseases 030104 developmental biology medicine.anatomical_structure Bronchoalveolar lavage RAW 264.7 Cells Alveolar Epithelial Cells Astrocytes Connexin 43 biology.protein NIH 3T3 Cells sense organs Bronchoalveolar Lavage Fluid 030217 neurology & neurosurgery Research Article |
| Zdroj: | Mediators of Inflammation Mediators of Inflammation, Vol 2020 (2020) |
| ISSN: | 1466-1861 0962-9351 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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