Activation of Hypoxia-Inducible Factor-1α Via Succinate Dehydrogenase Pathway During Acute Lung Injury Induced by Trauma/Hemorrhagic Shock

Hypoxia-inducible factor (HIF)-1 alpha is a transcription factor that is critical for tissue adaptation to hypoxia and inflammation. Previous studies had indicated that normoxic activation of HIF-1 alpha in cancer involves inhibition or mutation of the metabolic enzyme succinate dehydrogenase (SDH). We have found that local inhibition of HIF-1 alpha ameliorates acute lung injury (ALI) induced by trauma/hemorrhagic shock (T/HS) in rats. In this study, we found pulmonary activation of HIF-1 alpha and inhibition of SDH during THS-induced ALI in rats and transcriptional activation of HIF-1 alpha during ALI induced by T/HS lymph via SDH pathwayin vitro. Furthermore, pharmacologic inhibition of HIF-1 alpha attenuates lung inflammation and pulmonary edema during ALI by T/HS. Activation of HIF-1 alpha is detrimental to ALI induced by T/HS. Thus, our data suggest that HIF-1 alpha activation by T/HS is necessary for T/HS-induced lung injury and a critical role for SDH in the initiation of acute inflammatory response after ALI. Nevertheless, this is a preclinical work and several limitations impede translation of the findings to patients, such as uncontrolled bleeding and simultaneous treatment, and prolonged course of clinical shock on the outcome of the work, which needs to be addressed in future.