Abstract
The goals of this study were to investigate the role of the Notch1/PDGFRβ/ROCK1 signaling pathway in the pathogenesis of pulmonary fibrosis and to explore the possibility of treating fibrosis by targeting Notch1. Lung tissues from patients with pulmonary fibrosis were examined for the expression of Notch1/PDGFRβ/ROCK1 using RT-qPCR, western blotting, and immunostaining. Cultured mouse lung pericytes were transfected with Notch1-overexpressed vectors or shRNA targeting PDGFRβ/ROCK1 to examine cell behaviors, including proliferation, cell cycle arrest, and differentiation toward myofibroblasts. Finally, a mouse pulmonary fibrosis model was prepared, and a Notch1 inhibitor was administered to observe tissue morphology and pericyte cell behaviors. Human pulmonary fibrotic tissues presented with overexpression of Notch1, PDGFRβ, and ROCK1, in addition to a prominent transition of pericytes into myofibroblasts. In cultured mouse lung pericytes, overexpression of Notch1 led to the accelerated proliferation and differentiation of cells, and it also increased the expression of the PDGFRβ and ROCK1 proteins. The knockdown of PDGFRβ/ROCK1 in pericytes remarkably suppressed pericyte proliferation and differentiation. As further substantiation, the administration of a Notch1 inhibitor in a mouse model of lung fibrosis inhibited the PDGFRβ/ROCK1 pathway, suppressed pericyte proliferation and differentiation, and alleviated the severity of fibrosis. Our results showed that the Notch1 signaling pathway was aberrantly activated in pulmonary fibrosis, and this pathway may facilitate disease progression via mediating pericyte proliferation and differentiation. The inhibition of the Notch1 pathway may provide one promising treatment strategy for pulmonary fibrosis.
Highlights
Idiopathic pulmonary fibrosis (IPF) is characterized as interstitial pneumonia in adults with an unknown etiology[1]
We first examined the expression of Notch[1] and platelet-derived growth factor receptor β (PDGFRβ) in the lung tissues of IPF patients
Using HE staining, we found that tissues in the pulmonary fibrosis (PF) model presented with prominent tissue fibrosis, and this could be partially alleviated by the Notch[1] inhibitor (Fig. 5a)
Summary
Idiopathic pulmonary fibrosis (IPF) is characterized as interstitial pneumonia in adults with an unknown etiology[1]. The estimated prevalence of IPF is 50 cases per 100,000 people in the US, and the incidence rises sharply with age, especially in those older than 70 years[2]. IPF usually has an unfavorable prognosis and is unresponsive to classical medicines that treat fibrosis[3]. It is reported that the IPF patient population has only a 3-year median survival period, and the disease usually ends with respiratory failure[4]. IPF patients may experience acute episodes of disease exacerbation for unknown reasons[5], significantly elevating the death rate. It is important to further reveal the underlying cellular and molecular mechanisms of IPF for the diagnosis and development of medication. The pericyte-myofibroblast transition (PMT) is characterized by the detachment of pericytes from endothelial
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