Resolution Of Pulmonary Fibrosis Research Articles

Targeting the pentraxin 3/CD44 axis: A potential treatment for pulmonary fibrosis

Targeting the pentraxin 3/CD44 axis: A potential treatment for pulmonary fibrosis

Multi-Modal Analysis of Cell Populations and Architectural States Mediating the Progression and Resolution of Pulmonary Fibrosis

Multi-Modal Analysis of Cell Populations and Architectural States Mediating the Progression and Resolution of Pulmonary Fibrosis

TRAIL-Dependent Resolution of Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease characterized by the persistence of activated myofibroblasts resulting in excessive deposition of extracellular matrix proteins and profound tissue remodeling. In the present study, the expression of tumor necrosis factor- (TNF-) related apoptosis-inducing ligand (TRAIL) was key to the resolution of bleomycin-induced pulmonary fibrosis. Both in vivo and in vitro studies demonstrated that Gr-1+TRAIL+ bone marrow-derived myeloid cells blocked the activation of lung myofibroblasts. Although soluble TRAIL was increased in plasma from IPF patients, the presence of TRAIL+ myeloid cells was markedly reduced in IPF lung biopsies, and primary lung fibroblasts from this patient group expressed little of the TRAIL receptor-2 (DR5) when compared with appropriate normal samples. IL-13 was a potent inhibitor of DR5 expression in normal fibroblasts. Together, these results identified TRAIL+ myeloid cells as a critical mechanism in the resolution of pulmonary fibrosis, and strategies directed at promoting its function might have therapeutic potential in IPF.

Tumor Necrosis Factor-α–Induced Myofibroblast Plasticity as a Mechanism of Repair after Fibrotic Lung Injury

Idiopathic pulmonary fibrosis is a fibrotic interstitial lung disease of unknown cause that is associated with a poor clinical prognosis. Occurring within a transforming growth factor-β–driven antiinflammatory lung microenvironment, there is a significant accumulation of apoptosis-resistant myofibroblasts resulting in excess collagen deposition, an aberrant injury repair process, and progressive disease. Decreasing the number and profibrotic phenotype of myofibroblasts through their dedifferentiation to lipofibroblasts (resident pulmonary fibroblasts), may be important for the repair of the lung during fibrosis resolution. Therefore, we hypothesized that delivering the proinflammatory cytokine tumor necrosis factor (TNF)-α to fibrotic mice would accelerate resolution by (1) reducing the profibrotic phenotype of myofibroblasts by inducing their dedifferentiation to lipofibroblasts and (2) sensitizing them to undergo Fas-mediated apoptosis. We investigated this by accelerating the resolution of established pulmonary fibrosis in bleomycin-instilled wild-type mice by intratracheal delivery of recombinant mouse TNF-α. This resulted in a reduction in the fibrotic burden, improved lung function and architecture as quantified by hydroxyproline levels, static compliance, Masson’s trichrome staining, and decreased α-smooth muscle actin staining. Fibroblasts isolated from resolving lungs had increased Fas surface levels and an enhanced sensitivity to Fas-mediated apoptosis compared with fibroblasts from a fibrotic lung. In vitro stimulation of lung myofibroblasts with TNF-α led to decreased α-smooth muscle actin staining and an acquisition of Nile red–positive lipid droplets, indicating their dedifferentiation to lipofibroblasts. Our results support the conclusion that TNF-α–induced accelerated resolution of pulmonary fibrosis occurs via a mechanism involving reduced numbers and profibrotic phenotype of myofibroblasts and an increased sensitivity of these cells to undergo Fas-mediated apoptosis through their dedifferentiation to lipofibroblasts. Understanding how TNF-α reduces the pathogenic nature of myofibroblasts by inducing their dedifferentiation to lipofibroblasts may be critical for promoting the resolution and repair of the injured lung, leading to restoration of normal architecture and function.