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

Abstract

Background Pulmonary 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 results In 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. 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.

Vinpocetine alleviated alveolar epithelial cells injury in experimental pulmonary fibrosis by targeting PPAR-γ/NLRP3/NF-κB and TGF-β1/Smad2/3 pathways

“…Additionally, it is an important pathway in activating the nuclear transcriptional factor NF-κB 78 . NF-κB activation can induce the expression of pro-inflammatory cytokines, chemokines, adhesion molecules, and matrix metalloproteinases, which contribute to the recruitment of inflammatory cells, tissue damage, and remodeling in PF 18 .…”

“…This study will focus on some molecular targets, including Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulatory nuclear factor that influences the activity and cellular response of the antioxidant system 17 , NF-κB, and the inflammasome NLRP3 which are closely related to one another and influence the level of inflammatory and pro-fibrotic cytokines in the microenvironment as well as the apoptosis and senescence of alveolar epithelial cells especially for NF-κB 18 . As for peroxisome proliferator-activated receptor gamma (PPAR-γ), studies have suggested its important role in modulating the inflammatory and fibrotic responses in the lung 19 .…”

Exploratory analysis to predict pneumonitis during durvalumab consolidation therapy for patients with locally advanced non‐small cell lung cancer from proteomic profiling of circulating extracellular vesicles

“…These cytokines damage lung tissue by activating signaling pathways, such as the NF‐κB pathway. RELA is associated with acute lung injury and pulmonary fibrosis in human and mouse models 39,40 . ICI may also induce inflammation and immune responses in lung tissue, as they convert exhausted T cell phenotypes to active effector phenotypes, promoting cytokine production via T cell activation 41 .…”

“…RELA is associated with acute lung injury and pulmonary fibrosis in human and mouse models. 39 , 40 ICI may also induce inflammation and immune responses in lung tissue, as they convert exhausted T cell phenotypes to active effector phenotypes, promoting cytokine production via T cell activation. 41 The proinflammatory cytokine interleukin‐6, which is induced by the NF‐κB pathway, is reported to be an important mediator of irAEs in patients with NSCLC receiving ICIs.…”

3D pulmonary fibrosis model for anti-fibrotic drug discovery by inkjet-bioprinting

“…TGF-β1 activates multiple kinases to stimulate nuclear translocation and phosphorylation of NF-κB p65, thereby activating NF-κB signaling and affecting its downstream targets [33]. NF-κB is a significant regulator of EMT and PF [34], and a recent study suggested a novel strategy whereby the blockade of NF-κB could alleviate PF [35]. We observed a slight increase in NF-κB p65 in PF-induced model by TGF-β1 (figure 3(b, ii)), and confirmed that it was lowered after treatment with nintedanib and pirfenidone (figure 3(b, iv and v)).…”