Impaired BCAA Catabolism Contributes To Acute Lung Injury By Triggering Oxidative Stress and Inflammatory Response Via the MAPK Pathway

Acute lung injury (ALI) is a severe respiratory failure characterized by rapid alveolar injury, severe hypoxemia, and an uncontrolled inflammatory response. Branched-chain amino acids (BCAAs) are a group of essential amino acids, including valine, leucine, and isoleucine. Accumulating evidence shows that BCAA metabolism has long been implicated in the etiology of type 2 diabetes, myocardial ischemia/reperfusion, heart failure, cancer, and other conditions. However, the contribution of BCAA metabolism regulation in ALI remains largely elusive. Here, we found that branched-chain α-keto acids (BCKAs), intermediate metabolites of BCAAs, were increased in the lungs of ALI mice induced by lipopolysaccharide (LPS) and positively correlated with ALI. Accordingly, promoting BCKA degradation by BT2 alleviates the LPS-induced ALI by suppressing inflammation and oxidative stress in mice with ALI. In addition, we found that BCKA supplements exacerbated the LPS-induced inflammation, oxidative stress, and ALI in mice. Mechanistic studies revealed that BCKAs exacerbate the LPS-induced ALI by activating the mitogen-activated protein kinase (MAPK) pathway in macrophages. Collectively, we demonstrate the causal role of defective BCAA catabolism in the development of ALI. Targeting BCAA catabolism might be a promising therapeutic strategy for ALI.