DTAI ameliorated acute lung injury and pulmonary fibrosis by suppressing the TGF-β/Smad signaling pathway in mice

Idiopathic pulmonary fibrosis (IPF), an interstitial lung disease, is a chronic and progressive disorder manifesting lung scarring and fibrosis, affecting 3 million people worldwide. Risk factors for IPF include smoking, pollutants, age, and infectious agents, such as SARS-CoV-2. Pathologically, IPF is potentiated by persistent inflammation, aberrant repair process, myofibroblast activation, and unregulated extracellular matrix (ECM) deposition. Approved by the FDA for IPF treatment, pirfenidone and nintedanib slow disease progression with minimal improvement in patient survival. Here, we discovered a novel compound DTAI that ameliorated lipopolysaccharide (LPS)-induced lung injury and bleomycin (BLM)-induced pulmonary fibrosis in C57BL/6 male mice. Specifically, DTAI reduced inflammatory cell infiltration into the lungs and the cell number of neutrophils and macrophages in bronchoalveolar lavage fluid (BALF), where the cytokine levels decreased accordingly. Besides, DTAI improved aberrant ECM deposition in the lungs and downregulated the levels of pulmonary hydroxyproline and several fibrotic factors. As for the clinical features of IPF, high-resolution CT scans were performed to identify the pathological features of interstitial pneumonias. Notably, DTAI improved pulmonary consolidation with less ground-glass opacification in BLM-induced pulmonary fibrotic mice. Interestingly, DTAI attenuated myofibroblast activation in TGF-β1-induced human LL29 fibroblasts, along with reduced Smad2/3 phosphorylation and ROS production. In conclusion, DTAI mitigated acute lung injuries and pulmonary fibrosis by modulating the activation of fibroblasts and TGF-β/Smad signaling.