Inhibition of nuclear factor κB in the lungs protect bleomycin-induced lung fibrosis in mice

Devaang Thakur,Sudhiranjan Gupta,Madeleine Atkinson,Olivia Taliaferro,Rakeshwar S Guleria,Ryan Stoffel

doi:10.1007/s11033-022-07185-8

Abstract

BackgroundPulmonary fibrosis is a debilitating condition with limited therapeutic avenues. The pathogenicity of pulmonary fibrosis constitutes involvement of cellular proliferation, activation, and transformational changes of fibroblast to myofibroblasts. It is a progressive lung disease and is primarily characterized by aberrant accumulation of extracellular matrix proteins in the lungs with poor prognosis. The inflammatory response in the pathogenesis of lung fibrosis is suggested because of release of several cytokines; however, the underlying mechanism remains undefined. A genetic model is the appropriate way to delineate the underlying mechanism of pulmonary fibrosis.Methods and resultsIn this report, we have used cc-10 promoter based IκBα mutant mice (IKBM, an inhibitor of NF-κB) which were challenged with bleomycin (BLM). Compared to wild-type (WT) mice, the IKBM mice showed significant reduction in several fibrotic, vascular, and inflammatory genes. Moreover, we have identified a new set of dysregulated microRNAs (miRNAs) by miRNA array analysis in BLM-induced WT mice. Among these miRNAs, let-7a-5p and miR-503-5p were further analyzed. Our data showed that these two miRNAs were upregulated in WT-BLM and were reduced in IKBM-BLM mice. Bioinformatic analyses showed that let-7a-5p and miR-503-5p target for endothelin1 and bone morphogenic receptor 1A (BMPR1A), respectively, and were downregulated in WT-BLM mice indicating a link in pulmonary fibrosis.ConclusionWe concluded that inhibition of NF-κB and modulation of let-7a-5p and miR-503-5p contribute a pivotal role in pulmonary fibrosis and may be considered as possible therapeutic target for the clinical management of lung fibrosis.

Highlights

Pulmonary fibrosis, a severe condition resulting from an injury to the lung parenchyma, causes increased proliferation and migration of fibroblasts and excessive accumulation of matrix proteins in the lung [1,2,3]
We report for the first time that BLMinduced pulmonary fibrosis is associated with NF-κB activation (RelA), upregulation of fibrotic genes, enhanced inflammatory response and altered expression of bone morphogenic protein receptor A (BMPR1A) in WT mice; and all these alterations were prevented in IKBM mice treated with BLM
Our results demonstrate for the first time that inhibition of NF-κB in the lungs attenuated BLM-induced lung fibrosis

Summary

Introduction

A severe condition resulting from an injury to the lung parenchyma, causes increased proliferation and migration of fibroblasts and excessive accumulation of matrix proteins in the lung [1,2,3]. It is a progressive lung disease and primarily characterized by deposition of uncontrolled extracellular matrix (ECM) components including collagens, matrix metalloproteinases (MMPs) and tissue inhibitor of matrix proteinases (TIMPS) [4,5,6]. The pathogenicity of pulmonary fibrosis constitutes involvement of cellular proliferation, activation, and transformational changes of fibroblast to myofibroblasts It is a progressive lung disease and is primarily characterized by aberrant accumulation of extracellular matrix proteins in the lungs with poor prognosis. Conclusion We concluded that inhibition of NF-κB and modulation of let-7a-5p and miR-503-5p contribute a pivotal role in pulmonary fibrosis and may be considered as possible therapeutic target for the clinical management of lung fibrosis

Methods

Results

Conclusion