HMGB1 accelerates alveolar epithelial repair via an IL‐1β‐dependent activation of TGF‐β1 by the αvβ6 integrin.

Abstract

High mobility group box 1 (HMGB1) protein, recently described as a proinflammatory mediator of acute lung injury, is a danger‐signaling molecule shown to be actively secreted or passively released from damaged cells. We hypothesized that HMGB1 would accelerate the re‐epithelialisation of the distal lung epithelium, a mechanism that is crucial for the recovery from acute lung injury. We found in the present study that HMGB1 is released in the extracellular space by alveolar epithelial cells that underwent a scratch wound. HMGB1 increased primary rat and human alveolar type II cell monolayer wound repair via an IL‐1β‐dependent activation of TGF‐β1. Specifically, HMGB1 induced 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 PI3Kα‐dependent mechanism. In conclusion, this study demonstrates that HMGB1 accelerates wound closure in the distal lung epithelium via the IL‐1β‐induced αvβ6‐dependent activation of TGF‐β1, and could thus play a critical role in the resolution of acute lung injury by promoting repair of the injured alveolar epithelium.