P-Rex1 is a potential novel therapeutic target for pulmonary fibrosis (PF), according to the results of a new study, “Identification of P-Rex1 as an anti-inflammatory and anti-fibrogenic target for pulmonary fibrosis,” published in Scientific Reports.
Because little is understood about factors that promote the transition of PF from the inflammatory phase to the fibrogenic phase, establishing effective therapies against the disease is difficult. In the recent study, researchers investigated the potential role of P-Rex1, previously identified as a functional regulator of the inflammatory response, in the biological mechanisms that lead to PF.
To this end, researchers administered bleomycin sulfateto both control (wild-type) and p-rex1 knockout mice (mice with the p-rex1 gene removed) in order to induce the development of PF. Bleomycin-induced lung injury is an established method to study the underlying mechanisms of PF.
Control mice exhibited features of PF that included lungs showing destruction of alveolar architecture, massive collagen deposit, and a marked increase in the number of fibroblasts. On the contrary, p-rex1 knockout mice lungs showed well-preserved alveolar structure, fewer fibroblasts and less collagen deposition around capillary vessels. Additionally, the knockout mice survival was significantly improved compared to wild-type controls.
Since bleomycin leads to an interstitial inflammatory response (as a result of damage to the alveolar epithelial cells), authors compared the expression of selected inflammatory cytokines and chemokines in lung tissue homogenates and bronchoalveolar lavage fluid (BALF) of both controls and p-rex1 knockout mice. The team measured cytokines expression profile at days 0, 3 and 7 after bleomycin challenge. P-Rex1 knockout mice were found to express significantly less proinflammatory cytokines and chemokines; additionally, theP-Rex1 mice showed lower leukocyte infiltration in the lung tissue when compared to wild-type controls.
Further investigation of the mechanisms responsible for these phenotypes, revealed that P-Rex1 expression is detected in lung fibroblasts of control mice; and that its deletion lessened fibroblast migration to the lungs, via a TGFβ-1-dependent mechanism. The study results suggested that P-Rex1 is a downstream mediator of TGFβ-1 signaling.
In conclusion, results identified P-Rex1 as a novel player in PF. Future studies targeting P-Rex1 may block the inflammatory and fibrogenic processes of PF.
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