Biapenem as a Novel Insight into Drug Repositioning against Particulate Matter-Induced Lung Injury

The screening of biologically active chemical compound libraries can be an efficient way to reposition Food and Drug Adminstration (FDA)-approved drugs or to discover new therapies for human diseases. Particulate matter with an aerodynamic diameter equal to or less than 2.5 μm (PM_2.5) is a form of air pollutant that causes significant lung damage when inhaled. This study illustrates drug repositioning with biapenem (BIPM) for the modulation of PM-induced lung injury. Biapenem was used for the treatment of severe infections. Mice were treated with BIPM via tail-vein injection after the intratracheal instillation of PM_2.5. Alterations in the lung wet/dry weight, total protein/total cell count and lymphocyte count, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were monitored in the PM_2.5-treated mice. BIPM effectively reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM_2.5. Enhanced myeloperoxidase (MPO) activity by PM_2.5 in the pulmonary tissue was inhibited by BIPM. Moreover, increased levels of inflammatory cytokines and total protein by PM_2.5 in the BALF were also decreased by BIPM treatment. In addition, BIPM markedly suppressed PM_2.5-induced increases in the number of lymphocytes in the BALF. Additionally, the activity of mammalian target of rapamycin (mTOR) was increased by BIPM. Administration of PM_2.5 increased the expression levels of toll-like receptor 4 (TLR4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1, which were suppressed by BIPM. In conclusion, these findings indicate that BIPM has a critical anti-inflammatory effect due to its ability to regulate both the TLR4-MyD88 and mTOR-autophagy pathways, and may thus be a potential therapeutic agent against diesel PM_2.5-induced pulmonary injury.