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

急性肺损伤（ALI）导致氧供应减弱和炎症相关组织缺氧。转录因子缺氧诱导因子(HIF)-1α是氧稳态的核心。HIF-1α调节细胞对有限氧可用性的适应并恢复组织氧水平。最近的研究表明，HIF调节和HIF依赖基因表达在肺部炎症和先天免疫的炎症终点。初步数据表明，在周期性机械拉伸期间，HIF-1α蛋白在肺上皮细胞和暴露于呼吸机诱导肺损伤（VILI）的小鼠肺中积累。toll样受体（TLR）的调节部分依赖于HIF-1α的激活。tlr是先天免疫调节的核心。他们检测病原体相关模式和内源性配体释放由于组织损伤，缺氧和应激。然而，HIF激活和TLR应答对VILI的影响尚未确定。因此，本研究将揭示HIF-1α的稳定和连续靶基因的表达是否会减轻ALI期间的肺部炎症和组织损伤。此外，还应分析tlr是否是ALI相关hifacactivation的终点，是否有助于VILI的预后。

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.