Effects of antifibrotic agents on TGF-β1, CTGF and IFN-γ expression in patients with idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a deadly disease, largely unresponsive to treatment with corticosteroids and immunosuppressives. The aim of this randomized, prospective, open-label study was to characterize the molecular effects of IFN-gamma-1b and colchicine, on biomarkers expression associated with fibrosis (TGF-beta, CTGF) and immunomodulatory/antimicrobial activity (IFN-gamma), in the lungs of patients with IPF. Fourteen (14) patients with an established diagnosis of IPF received either 200 microg of IFN-gamma-1b subcutaneously three times per week, or 1mg of oral colchicine per day, for 24 months. Using RT-PCR assay, we evaluated the transcription levels of transforming growth factor beta1 (TGF-beta1), connective-tissue growth factor (CTGF), and interferon-gamma (IFN-gamma) genes in lung tissue before and after treatment with IFN-gamma-1b or colchicine. Marked mRNA expression of TGF-beta1 and CTGF, but complete lack of interferon-gamma was detected in fibrotic lung tissue at entry. After treatment, both groups exhibited increased expression of IFN-gamma gene at 6 months that was sustained at 24 months. The expression of CTGF and TGF-beta1 remained almost stable before and after treatment, in the IFN-gamma-1b group, while TGF-beta1 was statistically decreased after therapy, in the colchicine group (p=0.0002). Significant difference in DLCO (% pred), was found between the two treatment groups in favor of IFN-gamma-1b group (p=0.04). In addition, the IFN-gamma-1b group showed stability in arterial PO2 while the colchicine group significantly deteriorated (p=0.02). In conclusion, we report the effect of antifibrotic agents (IFN-gamma-1b and colchicine) in TGF-beta, CTGF, and endogenous IFN-gamma gene expression, in human fibrosis. However, extended studies are needed to verify the pathophysiological consequences of these findings.

Increased Cell Surface Fas Expression Is Necessary and Sufficient To Sensitize Lung Fibroblasts to Fas Ligation-Induced Apoptosis: Implications for Fibroblast Accumulation in Idiopathic Pulmonary Fibrosis

“…Taken together, these findings suggest that fibroblast and myofibroblast accumulation in the lungs of IPF patients could occur as a result of impaired sensitization to Fas-induced apoptosis. They are also consistent with the developing notion that fibrosis can progress in the absence of a robust inflammatory response associated with reduced levels of proinflammatory sensitizing molecules such as TNF-a, IFN-g, and PGE 2 (1,(24)(25)(26).…”

“…Thus, it is plausible that the failure to activate NF-kB and increase Fas expression in fibroblast foci is due to the absence or reduced presence of the appropriate NF-kB-activating or other sensitizing stimuli within the fibroblastic foci. Consistent with this notion, previous studies have suggested relative deficiencies of key sensitizing molecules including TNF-a, IFN-g, and PGE 2 in lung tissues and bronchoalveolar lavage specimens from IPF patients (24,25,48,49).…”

Secretoglobin 3A2 Suppresses Bleomycin-induced Pulmonary Fibrosis by Transforming Growth Factor β Signaling Down-regulation

“…Damaged cells produce chemokines, which stimulate leukocytes to proliferate and produce profibrotic cytokines such as transforming growth factor ␤ (TGF␤), a major profibrotic growth factor, and interleukin-13 (IL-13), a major profibrotic mediator. TGF␤1 induces collagen type I transcription through the SMAD signaling, whereas IL-13 stimulates macrophages to produce TGF␤ (3)(4)(5)(6). On the other hand, interferon-␥ (IFN␥) inhibits collagen generation through STAT1 activation followed by sequestration of p300, which plays a pivotal role in the regulation of collagen synthesis by TGF␤ (7,8).…”

Effectiveness of Colchicine Therapy in 4 Cases of Retroperitoneal Fibrosis Associated with Autoinflammatory Diseases

“…It reduces adhesion of neutrophils to endothelium, inhibiting neutrophil migration, and blocks the in vitro release of fibronectin from alveolar macrophages 2,3 . It is approved by the US Food and Drug Administration for the treatment and prophylaxis of gout flares, but is used in the treatment of familial Mediterranean fever (FMF), recurrent pericarditis, primary biliary cirrhosis, Behçet's disease, relapsing polychondritis, Sweet's syndrome, scleroderma, amyloidosis, leukocytoclastic vasculitis, epidermolysis bullosa 4 , and idiopathic pulmonary fibrosis 5 .…”