Hypoxia-inducible Factor 1a Mediated Lactylation to Enhance Inflammatory Response during Hypoxia induced lung dysfunction

Hypoxia can result in tissue dysfunction, metabolic alterations, and structural damage within the pulmonary tissue, thereby impacting lung ventilation and air exchange. The identification of Hypoxia-inducible factor (Hif) 1a as a pivotal mediator in the inflammatory cascade subsequent to hypoxia induction has been established. However, the mechanism remains elusive. To delve deeper into this phenomenon, we have developed a murine model of sustained hypoxia and utilized nanocarriers for the delivery of lentivirus Hif-1a for knockdown purposes. Our findings suggest that under conditions of sustained hypoxia, knockdown of Hif-1a effectively ameliorated SpO2 levels and attenuated lung injury in our murine model. We observed that Hif-1a-mediated Histone Lactylation was evident in the lungs exposed to sustained hypoxia. Through RNA-seq and ChIP-seq profiling, we determined that upregulation of Hif-1a expression in sustained hypoxic lung tissue is essential for inducing lactylation enrichment of inflammatory response genes. Furthermore, knockdown of Hif-1a returned to normal inflammatory cytokines (e.g. TNF-a, IL-6 and IL-1ß). Analysis of plasma metabolites from individuals experiencing restrictive/ obstructive lung disease revealed a significant enrichment of the Warburg effect within the sustained hypoxic group. Thus, our study provides compelling evidence supporting the notion that targeting Hif-1a-mediated histone lactylation may represent a promising therapeutic strategy for managing sustained hypoxia-induced lung injury. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for histone modification Kla in mice lung tissues.