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.
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http://dx.doi.org/10.1152/ajplung.00053.2017 | DOI Listing |
Front Immunol
January 2025
Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands.
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 PDFBMC Infect Dis
January 2025
Department of Health Promotion and Health Behavior, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia.
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 PDFEur J Med Chem
January 2025
School of Health Sciences, Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107, Reykjavik, Iceland. Electronic address:
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 PDFMicroorganisms
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 PDFBiomed Pharmacother
January 2025
Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea. Electronic address:
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.
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