Role of HIF and induction of HIF-target genes during ventilator-induced lung injury

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Acute lung injury (ALI) results in attenuated oxygen supply and inflammationassociated tissue hypoxia. The transcription factor hypoxia-inducible factor (HIF)-1α is central to oxygen homeostasis. HIF-1α regulates cell adaption to limited oxygen availability and restores tissue oxygen levels. Recent studies demonstrated HIF regulation and a HIF-dependent gene expression in inflammatory endpoints of lung inflammation and innate immunity. Preliminary data indicate that HIF-1α protein accumulates, both, in pulmonary epithelial cells during cyclic mechanical stretch, and in lungs of mice exposed to ventilator-induced lung injury (VILI). Toll-like receptor (TLR) regulation partly depends on HIF-1α activation. TLRs are central to innate immune regulation. They detect pathogen associated patterns and endogenous ligands released due to tissue injury, hypoxia, and stress. However, the impact of HIF activation and TLR response to VILI have not been established. Therefore, the proposed study shall reveal whether HIF-1α stabilization and consecutive target gene expression attenuate pulmonary inflammation and tissue injury during ALI. Furthermore, it shall be analyzed whether TLRs are endpoints of ALI associated HIFactivation and contribute to the outcome of VILI.