Abstract
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.
Highlights
Acute respiratory distress syndrome (ARDS) is an intense inflammatory disorder, characterized by severe respiratory failure requiring mechanical ventilation, that occurs within a week after initial pulmonary or nonpulmonary insults [1]
In light of HC inhibitory effects of P5 on HPMVEC, we examined whether P5 can suppress high mobility group box protein 1 (HMGB1) release by these endothelial cells
We have previously shown that HMGB1 release by macrophages is an active process and is under the control of HCs [10, 11]
Summary
Acute respiratory distress syndrome (ARDS) is an intense inflammatory disorder, characterized by severe respiratory failure requiring mechanical ventilation, that occurs within a week after initial pulmonary or nonpulmonary insults [1]. The prognosis of ARDS is dependent on the severity of the lung injury [2, 3]. ARDS-associated acute lung injury (ALI) is characterized by widespread inflammation and subsequent alveolar epithelial-endothelial barrier damage, which are largely attributable to a variety of inflammatory mediators including TNF-α, IL-8, IFN-γ, and HMGB1 [2,3,4,5]. HMGB1 is predominantly located in cell nuclei but can be actively released by activated innate immune cells, such as macrophages and neutrophils, during inflammation [7, 8]. In contrast to TNF-α and IFN-γ, which are released by macrophages within
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