Abstract
Idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia (INSIP) are two related diseases involving varying degrees of pulmonary fibrosis with no effective cure. Bone morphogenetic protein 3 (BMP3) is a member of the transforming growth factor-β (TGF-β) super-family, which has not been implicated in pulmonary fibrosis previously. In this study, we aimed to investigate the potential role of BMP3 playing in pulmonary fibrosis from clinical diagnosis to molecular signaling regulation. RNA sequencing was performed to explore the potential biomarker of IIP patients. The expression of BMP3 was evaluated in 83 cases of IPF and INSIP by immunohistochemistry. The function of BMP3 was investigated in both fibroblast cells and a bleomycin-induced murine pulmonary fibrosis model. The clinical relevance of BMP3 expression were analyzed in 47 IIP patients, which were included in 83 cases and possess more than five-year follow-up data. Both RNA-sequencing and immunohistochemistry staining revealed that BMP3 was significantly down-regulated in lung tissues of patients with IPF and INSIP. Consistently, lower expression of BMP3 also was found in pulmonary fibrotic tissues of bleomycin-induced mice model. Up-regulation of BMP3 prevented pulmonary fibrosis processing through inhibiting cellular proliferation of fibroblasts as well as TGF-β1 signal transduction. Finally, the relatively higher expression of BMP3 in IPF patients was associated with less/worse mortality. Intravenous injection of recombinant BMP3. Taken together, our results suggested that the low expression level of BMP3 may indicate the unfavorable prognosis of IPF patients, targeting BMP3 may represent a novel potential therapeutic method for pulmonary fibrosis management.
Highlights
Idiopathic interstitial pneumonias (IIPs) are a group of interstitial lung diseases of unknown etiology that are characterized by varying degrees of chronic inflammation and progressive fibrosis of lung parenchyma [1, 2]
Identification of genes dysregulated in lung tissues from Idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia (INSIP) patients The illumina mRNA sequencing approach was used to determine the relative abundance of various genes in IIPs
In consistent with the outcome by SB431542 administration, rhBMP3 application reversed the TGF-β1 effect (Figure 5B). These results suggested that Bone morphogenetic protein 3 (BMP3) may alleviate the fibrotic processing by suppressing the activation of TGF-β1 signaling pathway and that the mutually antagonistic relationship between BMP3 and TGF-β1 plays a crucial role in the pathogenesis of pulmonary fibrosis (Figure 5C)
Summary
Idiopathic interstitial pneumonias (IIPs) are a group of interstitial lung diseases of unknown etiology that are characterized by varying degrees of chronic inflammation and progressive fibrosis of lung parenchyma [1, 2]. Idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia (INSIP) are two major sub-types of IIPs [3, 4]. IPF is histopathologically defined by the presence of the typical form of pulmonary fibrosis and often results in death within 3–5 years of diagnosis [1]. INSIP is universally associated with a more cellular interstitial pneumonia with or without accompanying fibrosis and occurs earlier in life with a better prognosis than IPF [5,6,7]. It has been suggested that efforts to combating IPF and INSIP should be aimed at exploring potential anti-fibrotic treatment strategies [8, 9]
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