**1. Introduction**

Pulmonary fibrosis is the result of the end-stage pathological development of existing lung diseases caused by infection, autoimmunity, chronic inflammation, and idiopathy. Idiopathic pulmonary fibrosis (IPF), one of the most common causes of interstitial pneumonia, is characterized by progressive and irreversible fibrotic scar formation in the gas exchange regions of the lung, resulting in organ malfunction. IPF is a devastating lung disease as patients show poor prognosis, with a median survival of 2–5 years as well as increased risks of pulmonary hypertension and lung cancer [1]. A chronic inflammatory process of the lung has long been considered a main potential mechanism underlying IPF [2]. Moreover, innate and adaptive inflammation may contribute to determining the rate of disease progression in patients with IPF [3]. However, the mortality of patients with IPF is correlated with the extent of fibrotic focus formation, which results from the abnormal and excessive accumulation of extracellular matrix (ECM) components, including collagen, fibronectin, and elastin [4]. Hence, recent studies focusing on the behaviors of ECM-producing myofibroblasts in pulmonary fibrosis may also inform the identification of therapeutic options for IPF [5–8]. In terms of current pharmacological therapies for IPF, while nintedanib and pirfenidone have been approved by the Food and Drug Administration, neither can improve the survival of patients with IPF [9]. Indeed, new beneficial strategies that enable patients with IPF to survive longer and with improved quality of life have been long-awaited.

Among mitogen-activated protein kinases (MAPKs), members of the p38 MAPK family are activated in response to environmental stresses such as inflammatory stimuli by cytokines and Toll-like receptor ligands, osmolality shock, ultraviolet irradiation, oxidative stress, chemotherapeutic drugs, etc. Of the four isoforms ( α, β2, γ, and δ) of p38, p38 α is ubiquitously expressed in adult tissues and its physiological and pathological roles have been well investigated [10]. p38 MAPKs are activated by dual phosphorylation of the TGY motif within their activation loop by two upstream MAPK kinases (MAP2Ks)—mitogen-activated protein kinase kinase (MKK)-3 and MKK6—that are activated by various types of MAPKK kinases (MAP3Ks) [11]. In addition to this canonical activation pathway, specific binding of transforming growth factor (TGF)-β-activated kinase 1-binding protein 1 to p38 α leads to p38 α autophosphorylation and activation [12]. TGF-β signaling is one of the most crucial factors in the murine pulmonary fibrosis model and may be potentiated in the pathogenesis of IPF [13,14]. These findings strongly sugges<sup>t</sup> the involvement of p38 signaling in the development of pulmonary fibrosis. In fact, several studies have reported that p38 inhibitors, SB239063 and FR-167653, can ameliorate bleomycin (BLM)-induced pulmonary fibrosis [15,16]. Lipopolysaccharide-induced epithelial-mesenchymal transition (EMT), in the early pulmonary fibrosis process, may be associated with p38 and TGF-β/smad3 signaling pathways [17]. Additionally, macrophage-specific loss of function of forkhead box M1, which inhibits the p38 signaling pathway, exacerbates BLM-induced pulmonary fibrosis [18]. Furthermore, pirfenidone was originally recognized as a small molecule p38 γ inhibitor that blocks the synthesis of TGF-β [19]. Hence, the involvement of p38 signaling in the pathogenesis of pulmonary fibrosis is indubitable.

Here, we designed the study to elucidate new therapeutic target genes for IPF based on the notion that p38 positively regulates the development of pulmonary fibrosis. Mice with stepwise changes in the intrinsic activity of p38, specifically in alveolar epithelial type II cells (AEC II), were subjected to the pulmonary fibrosis model by BLM because AEC II could play a critical role in the progression of IPF [20]. RNA sequencing of total RNA derived from the lungs followed by transcriptome analysis was performed.
