Therapeutic targeting of hypoxia inducible factor in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is characterized by bilateral chest infiltration and acute hypoxic respiratory failure. ARDS carries significant morbidity and mortality despite advancements in medical management, calling for the development of novel therapeutic targets. Hypoxia-inducible factor (HIF) is a heterodimeric protein involved in various essential pathways, including metabolic reprogramming, immune modulation, angiogenesis and cell cycle regulation. HIF is routinely degraded in homeostasis conditions via the prolyl hydroxylase domain/von Hippel-Lindau protein pathway. However, HIF is stabilized in ARDS via various mechanisms (oxygen-dependent and independent) as an endogenous protective pathway and plays multifaceted roles in different cell populations. This review focuses on the functional role of HIF and its target genes during ARDS, as well as how HIF has evolved as a therapeutic target in current medical management.image Abstract figure legend Hypoxia-inducible factor (HIF) is a critical therapeutic target that can potentially improve acute respiratory distress syndrome (ARDS) outcomes. ARDS causes a significant burden on the healthcare system worldwide, with the sobering incidence of 23.4% of ARDS patients in intensive care units requiring mechanical ventilation, 66% of patients having a delayed diagnosis and 40% of cases being entirely unrecognized. The mortality risk was found to be 40%. In longitudinal studies, 40% of ARDS patients are readmitted by 1 year and 83% by 5 years. To date, we still do not have any direct treatment for ARDS besides supportive therapy. HIF has shown to be critical as an endogenous lung protective pathway, such that pharmacologic enhancement of HIF may improve ARDS outcomes via various mechanisms. Created with .image