Protective function of DJ-1/PARK7 in lipopolysaccharide and ventilator-induced acute lung injury

Amatullah, Hajera; Maron-Gutierrez, Tatiana; Shan, Yuexin; Gupta, Sahil; Tsoporis, James N.; Varkouhi, Amir K.; Teixeira Monteiro, Ana Paula; He, Xiaolin; Yin, Jun; Marshall, John C.; Rocco, Patricia R.M.; Zhang, Haibo; Kuebler, Wolfgang M.; dos Santos, Claudia C.

Oxidative stress is considered one of the early underlying contributors of acute lung injury (ALI) and ventilator-induced lung injury (VILI). DJ-1, also known as PARK7, has a well-established role as an antioxidant. We have previously shown maintaining oxidative balance via the ATF3-Nrf2 axis was important in protection from ALI. Here, we exclusively characterize the role of DJ-1 in sterile LPS-induced ALI and VILI. DJ-1 protein expression was increased after LPS treatment in human epithelial and endothelial cell lines and lungs of wild-type mice. DJ-1 deficient mice exhibited greater susceptibility to LPS-induced acute lung injury as demonstrated by increased cellular infiltration, augmented levels of pulmonary cytokines, enhanced ROS levels and oxidized by-products, increased pulmonary edema and cell death. In a two-hit model of LPS and mechanical ventilation (MV), DJ-1 deficient mice displayed enhanced susceptibility to inflammation and lung injury. Collectively, these results identify DJ-1 as a negative regulator of ROS and inflammation, and suggest its expression protects from sterile lung injury driven by high oxidative stress.