Both endothelin-1 (ET-1) and high mobility group box 1 (HMGB1) reportedly are closely involved in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). In this study, we explored the regulatory effects of ET-1 on the expression of HMGB1 in human bronchial epithelial cells (HBEpCs). Primary HBEpCs were treated with ET-1 with or without transcription inhibitor actinomycin D, ETA receptor blocker BQ123, ETB receptor blocker BQ788, focal adhesion kinase (FAK) inhibitor or shRNA, or different kinase inhibitors. ET-1 increased the HMGB1 mRNA level in a statistically significant dose- and time-dependent manner within 8 hours of treatment, which was reflected in the dose-dependent induction of the HMGB1 protein level and the FAK activity. BQ123 and FAK inhibitor or shRNA, but not BQ788, completely abolished the promoting effect of ET-1 on the expression of HMGB1. Luciferase reporter assays revealed that neither ET-1 nor ETA nor FAK inhibition had any significant effect on the HMGB1 gene promoter activity. In the presence of the transcription inhibitor actinomycin D, the HMGB1 mRNA level markedly decreased over time, and ET-1 dose-dependently rescued the HMGB1 mRNA level. This effect of ET-1 was completely abolished by BQ123 and FAK inhibitor or shRNA, but not by BQ788. In conclusion, this study provides the first evidence that ET-1 upregulates the expression of HMGB1 in HBEpCs by increasing the stability of HMGB1 mRNA via the ETA receptor by a FAK-dependent mechanism. It adds new insights into the molecular mechanisms underlying ALI/ARDS.

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