Pulmonary fibrosis is occurred by unknown causes during repairing damaged tissues, and often untreatable situation (Wynn, 2011). Idiopathic pulmonary fibrosis (IPF) is the severe form of interstitial pneumonia, irreversible, and progressive, and unknown etiology, with a significant high mortality rate. Alveolar parenchymal fibrosis and infiltration of inflammatory cells are observed. Antifibrotic drugs such as pirfenidone and nintedanib are used for treatment of IPF in the clinical field to slow its progression, but it still continues to progress. Acute exacerbation (AE) of IPF was first reported in 1993 and identified as the onset of acute lung injury/acute respiratory distress syndrome of unknown cause in IPF patients (Kondoh et al., 1993). The incidence of AE in IPF patients ranges from 7 to 32% (Kreuter et al., 2019) and more than 45% of cause of deaths in IPF patients is due to AE (Natsuizaka et al., 2014). However, there is currently no effective treatment for AE of IPF, and the physiological and molecular mechanisms of AE of IPF remain unclear.

Animal models provide a bridge between patients and the laboratory bench and have been contributed to understand IPF (Kimura et al., 2015). The mouse model of bleomycin (BLM)-induced IPF has been widely utilized. BLM was primarily used for treatment of Hodgkin's lymphoma and testicular germ cell tumors. However, it causes pulmonary fibrosis as a serious side effect. Conversely, it is often used to investigate IPF (Gul et al., 2023). The BLM-administered mice show several important features of IPF, including alveolar epithelial cell injury, epithelial-mesenchymal transition, differentiation of fibroblasts into myofibroblasts, and collagen deposition (Yan et al., 2018). Although BLM induced fibrosis in the lungs of animal models, excessive inflammation seen in AE of IPF is not observed during the fibrotic phase (Liu et al., 2013). Moreover, pro-inflammatory cytokine levels in serums of AE of IPF patients are elevated (Drakopanagiotakis et al., 2023; Lee et al., 2021; Papiris et al., 2018), suggesting that the inflammatory response is involved in the progression of AE of IPF. Thus, BLM-induced IPF is not necessarily a suitable model for analyzing the characteristics of AE of IPF. Lipopolysaccharide (LPS) is derived from the cell walls of gram-negative bacteria, induces rapidly inflammatory response, and is well-used to generate the models of ALI (Li et al., 2021; Reutershan et al., 2005). Recently, combined administration of BLM and LPS (BLM + LPS) has been utilized the model of AE of IPF (Kimura et al., 2015; Kurniawan et al., 2023; Miyamoto et al., 2022), because severe inflammatory response, excessive fibrosis, and inflammation, which are often seen in AE of IPF in humans are observed in the lungs of BLM + LPS-administered mice. Therefore, the BLM + LPS-administered mice are more appropriate to investigate the features of AE of IPF. The aim of current study is to elucidate the mechanism underlying the progression of BLM + LPS-induced AE of IPF in mice.