Modulation of lung cytoskeletal remodeling, RXR based metabolic cascades and inflammation to achieve redox homeostasis during extended exposures to lowered pO2

Abstract

Extended exposure to low pO₂ has multiple effects on signaling cascades. Despite multiple exploratory studies, omics studies elucidating the signaling cascades essential for surviving extended low pO₂ exposures are lacking. In this study, we simulated low pO₂ (P_B = 40 kPa; 7620 m) exposure in male Sprague-Dawley rats for 3, 7 and 14 days. Redox stress assays and proteomics based network biology were performed using lungs and plasma. We observed that redox homeostasis was achieved after day 3 of exposure. We investigated the causative events for this. Proteo-bioinformatics analysis revealed STAT3 to be upstream of lung cytoskeletal processes and systemic lipid metabolism (RXR) derived inflammatory processes, which were the key events. Thus, during prolonged low pO₂ exposure, particularly those involving slowly decreasing pressures, redox homeostasis is achieved but energy metabolism is perturbed and this leads to an immune/inflammatory signaling impetus after third day of exposure. We found that an interplay of lung cytoskeletal elements, systemic energy metabolism and inflammatory proteins aid in achieving redox homeostasis and surviving extended low pO₂ exposures. Qualitative perturbations to cytoskeletal stability and innate immunity/inflammation were also observed during extended low pO₂ exposure in humans exposed to 14,000 ft for 7, 14 and 21 days.

Keywords: Energy metabolism; Hypoxia; Inflammation; Lung; Pathway analysis; Plasma; Proteome; Redox stress.