Abstract
High mobility group box 1 (HMGB1) protein is a danger-signaling molecule, known to activate an inflammatory response via TLR4 and RAGE. HMGB1 can be either actively secreted or passively released from damaged alveolar epithelial cells. Previous studies have shown that IL-1β, a critical mediator acute lung injury in humans that is activated by HMGB1, enhances alveolar epithelial repair, although the mechanisms are not fully understood. Herein, we tested the hypothesis that HMGB1 released by wounded alveolar epithelial cells would increase primary rat and human alveolar type II cell monolayer wound repair via an IL-1β-dependent activation of TGF-β1. HMGB1 induced in primary cultures of rat alveolar epithelial cells results in the release of IL-1β that caused the activation of TGF-β1 via a p38 MAPK-, RhoA- and αvβ6 integrin-dependent mechanism. Furthermore, active TGF-β1 accelerated the wound closure of primary rat epithelial cell monolayers via a PI3 kinase α-dependent mechanism. In conclusion, this study demonstrates that HMGB1 released by wounded epithelial cell monolayers, accelerates wound closure in the distal lung epithelium via the IL-1β-mediated αvβ6-dependent activation of TGF-β1, and thus could play an important role in the resolution of acute lung injury by promoting repair of the injured alveolar epithelium.
Highlights
Re-epithelialization of the distal lung during the recovery from acute respiratory distress syndrome (ARDS) is necessary to clear the edema fluid from the distal airspace of the lung and to restore a physiologic alveolar epithelial function [1]
We found that High mobility group box 1 (HMGB1), released by primary rat alveolar epithelial type II (ATII) cell monolayers after scratch wound, enhanced the wound closure across primary cultures of rat and human alveolar epithelial cell monolayers via an IL-1b-dependent mechanism
We found that HMGB1 was elevated in MS Cell Sup (9.160.9 ng/ml) compared to condition media of monolayers that did not undergo scratch wounds (0.960.1 ng/ ml) measured by enzyme-linked immunosorbent assay (ELISA) (Figure 1A)
Summary
Re-epithelialization of the distal lung during the recovery from acute respiratory distress syndrome (ARDS) is necessary to clear the edema fluid from the distal airspace of the lung and to restore a physiologic alveolar epithelial function [1]. The initial loss of the epithelial barrier integrity is associated with the activation of a severe inflammatory response, resulting in increased numbers of neutrophils and increased concentrations of proinflammatory mediators including TNF-a, IL-1b, and TGFb1, in the bronchoalveolar-lavage fluid (BALF) from patients with ALI [5,6,7]. Among these mediators, IL-1b was shown to increase lung vascular permeability, and to enhance alveolar epithelial wound closure [2,3]. The role of TGF-b1 in IL-1b-induced alveolar epithelial wound closure remains unknown
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