Protective effect of nebivolol on bleomycin-induced lung fibrosis via suppressing TLR4/IL-1β/MMP-2 and TGF-β/HSP47 signaling pathways in rats.

Abstract

Background: Idiopathic pulmonary fibrosis (IPF), a potentially fatal illness, significantly alters normal lung structure and function, resulting in severe respiratory failure and death. As of yet, no curable remedy has been revealed. Nebivolol is a third-generation β-blocker that has numerous cytoprotective properties and is used to treat heart failure and hypertension. Its potential ability to prevent bleomycin-induced IPF has not been studied. The aim of the current study is to investigate the antifibrotic effect of nebivolol against bleomycin-induced lung fibrosis.

Methods: Twenty-four male Wistar rats were randomly divided into four groups (n = 6 per group): control, bleomycin, nebivolol, and nebivolol + bleomycin. Pulmonary fibrosis was induced by bleomycin administration, while nebivolol was given seven days prior to a single intratracheal injection of bleomycin, daily orally for 21 days. At the end of the study, lung injury and fibrosis were evaluated using histopathological analysis, lung wet/dry ratio, bronchoalveolar lavage fluid protein content, oxidative stress markers, inflammatory cytokines, and fibrosis-related signaling.

Results: Nebivolol significantly decreased the histopathological injuries demonstrated through lung tissue sections stained by hematoxylin/eosin and silver. It considerably decreased the lung wet/dry ratio, as well as the total protein level in bronchoalveolar lavage fluid. Further, nebivolol restored superoxide dismutase activity and suppressed elevated malondialdehyde levels, rebalancing the disrupted oxidative indicators. Nebivolol is additionally known to have anti-inflammatory effects, as demonstrated by a decrease in cytokine levels, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), while boosting the secretion of the anti-inflammatory mediator endothelial nitric oxide synthase. In addition, nebivolol's anti-inflammatory properties were obvious by its suppressing effect on Toll-like receptor 4 (TLR4) level and the matrix metalloproteinase-2 (MMP-2) expression. Finally, nebivolol mitigated the progression of the fibrotic cascade, as indicated by reducing the elevated levels of transforming growth factor beta (TGF-β) and heat shock protein 47 (HSP47).

Conclusion: Nebivolol treatment exhibited remarkable protective effects on bleomycin-mediated IPF in rats via suppressing TLR4/IL-1β/MMP-2 and TGF-β/HSP47 signaling pathways. This study might provide an innovative therapeutic approach to prevent the devastating lung scarring associated with IPF.