Oleic acid-induced acute lung injury in Ob/Ob mice fed with high-fat-diet exacerbate bile acid uptake and liver injury that was reversed by antagonizing their entry

ABSTRACT

Background and aims: Acute respiratory distress syndrome (ARDS) is a serious complication of COVID-19 and present in a large percentage of COVID-19 deaths. Many studies suggest that people with obesity are at increased risk of severe COVID-19, however, mechanism on liver-lung axis remains unknown. We aimed to evaluate whether bile acid (BAs) trafficking interfere with acute lung injury (ALI) in animal model with obesity. Method: Leptin deficient (ob/ob) mice fed with high-fat-diet (Ob/Ob HFD) were i.p injected with oleic acid (OA) to induce ALI. To modulate BAs uptake, mice were i.p treated with neutralizing antibody for sodium taurocholate co-transporting polypeptide (NTCP;BAs-transporter). Broncho-alveolar lavage fluid (BALF), lungs, livers and serum were obtained from mice and assessed for inflammatory (HandE staining, ALT and pro-inflammatory panel of cytokines), fibrosis (Sirius red staining, a-smooth muscle actin, collagen and fibronectin) and metabolic (BAs, cholesterol, triglyceride, glucose tolerance test (GTT) and fasting blood sugar (FBS)) profiles. In addition, alveolarcapillary membrane injury of surfactant D (SP-D) and the receptor for advanced glycation end-products (RAGE). BAs trafficking were assessed in primary lung cells and their impact on proliferation and apoptosis were evaluated. Results: Compared to WT-littermates, OA-induced lung injury and was worsened in the in the Ob/Ob HFD in the histopathology outcome. In addition, BALF of the Ob/Ob HFD showed elevated levels of BAs (3- fold;P = 0.002) associated with increased GM-CSF, INF-g, IL-1, IL-6 and IL-8 (p < 0.01). Moreover, Ob/Ob HFD with OA showed elevated serum levels in liver enzymes, lipids, glucose and metabolic markers (p < 0.01). In addition, Ob/Ob HFD livers showed an exacerbated fibrosis profile. NTCP neutralizing antibody in Ob/Ob HFD while inhibited BAs uptake/trafficking in both primary alveolar type II (BALF showed 4-fold increase in BAs) and primary hepatocytes (serum showed 3-fold increase in BAs). SP-D, RAGE and serum metabolic markers were suppressed to normal in line with enhance lung and liver histology and maintaining cell viability. Conclusion: Modulation of BAs trafficking from the liver of obese mice to the lungs could be an important step in the pathogenesis of ALI. Antagonizing BAs uptake may suggest a therapeutic strategy in improving liver-lung axis.