Epithelial cells have been suggested as potential drivers of lung fibrosis, although the epithelial-dependent pathways that promote fibrogenesis remain unknown. Extracellular matrix is increasingly recognized as an environment that can drive cellular responses in various pulmonary diseases. In this study, we demonstrate that transforming growth factor-β1 (TGF-β1)-stimulated mouse tracheal basal (MTB) cells produce provisional matrix proteins in vitro, which initiate mesenchymal changes in subsequently freshly plated MTB cells via Rho kinase- and c-Jun NH-terminal kinase (JNK1)-dependent processes. Repopulation of decellularized lung scaffolds, derived from mice with bleomycin-induced fibrosis or from patients with idiopathic pulmonary fibrosis, with wild-type MTB cells resulted in a loss of epithelial gene expression and augmentation of mesenchymal gene expression compared with cells seeded into decellularized normal lungs. In contrast, Jnk1 basal cells seeded into fibrotic lung scaffolds retained a robust epithelial expression profile, failed to induce mesenchymal genes, and differentiated into club cell secretory protein-expressing cells. This new paradigm wherein TGF-β1-induced extracellular matrix derived from MTB cells activates a JNK1-dependent mesenchymal program, which impedes subsequent normal epithelial cell homeostasis, provides a plausible scenario of chronic aberrant epithelial repair, thought to be critical in lung fibrogenesis. This study identifies JNK1 as a possible target for inhibition in settings wherein reepithelialization is desired.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032072PMC
http://dx.doi.org/10.1152/ajplung.00053.2017DOI Listing

Publication Analysis

Top Keywords

mtb cells
16
extracellular matrix
12
cells
9
tracheal basal
8
basal cells
8
c-jun nh-terminal
8
lung scaffolds
8
gene expression
8
cells seeded
8
epithelial
5

Similar Publications

Introduction: Tuberculosis (TB) is the deadliest infectious disease worldwide and novel vaccines are urgently needed. HLA-E is a virtually monomorphic antigen presentation molecule and is not downregulated upon HIV co-infection. HLA-E restricted specific CD8 T cells are present in the circulation of individuals with active TB (aTB) and infection (TBI) with or without HIV co-infection, making HLA-E restricted T cells interesting vaccination targets for TB.

View Article and Find Full Text PDF

Background: Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a global health crisis, especially in sub-Saharan Africa, where high human immune virus (HIV) prevalence exacerbates the problem. The co-infection of TB and HIV creates a deadly combination, increasing susceptibility and complicating disease progression and treatment. Ethiopia, classified as a high-burden country, faces significant challenges despite efforts to reduce co-infection rates.

View Article and Find Full Text PDF

The natural bioactive products myxin and iodinin are phenazine 5,10-dioxides possessing potent anti-bacterial and anti-cancer activity in vitro. This work describes the synthesis and derivatization of new myxin and iodinin regioisomers, developed from 1,3-dihydroxyphenazine 5,10-dioxide. Compounds were evaluated for activity towards M.

View Article and Find Full Text PDF

Impact of H37Rv Infection on Extracellular Vesicle Cargo in Macrophages: Implications for Host-Pathogen Interaction.

Microorganisms

November 2024

Department of Microbiology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico.

Tuberculosis (TB) is one of the most common respiratory infections worldwide, and it is caused by (). employs immune evasion mechanisms that allow the disease to become chronic. Despite extensive research, the host-pathogen interaction remains incompletely understood.

View Article and Find Full Text PDF

Granulomas, dense clusters of immune cells and bacteria, are critical barriers in tuberculosis (TB) treatment. Recent advancements in TB management have highlighted granuloma control as a potential host-directed therapy (HDT) strategy. Although isoniazid (INH) is the first-line drug for TB therapy, its efficacy is limited to non-replicating Mycobacterium tuberculosis (Mtb) under granulomatous conditions, necessitating the development of more effective derivatives.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!