Interferon-β Inhibits Bleomycin-Induced Lung Fibrosis by Decreasing Transforming Growth Factor-β and Thrombospondin

Abstract

Pulmonary fibrosis is the result of abnormal processes of repair that occur after lung injury. Transforming growth factor (TGF)-beta is a key molecule in the progression of pulmonary fibrosis. Although clinical use of interferon (IFN)-beta did not improve survival in patients with idiopathic pulmonary fibrosis, because some preclinical studies have suggested that IFN-beta is a potent inhibitor of fibrogenesis, beneficial effects of IFN-beta have been expected. We therefore attempted to determine effects of IFN-beta and investigated the mechanism of action of IFN-beta in bleomycin-induced pulmonary fibrosis. Bleomycin at Day 0 and IFN-beta for 4 wk were administered intravenously to ICR mice. At 28 d after bleomycin injection, histologic and chemical analysis was performed for evaluation of effects of IFN-beta. Tissue distribution and amounts of TGF-beta1 and thrombospondin (TSP)-1/2 were analyzed. IFN-beta attenuated prolylhydroxylase activity, resulting in inhibition of pulmonary fibrosis. Bleomycin-induced increase in TGF-beta1 in epithelial cells and extracellular matrix was attenuated by IFN-beta. TSP-1/2 was limited in platelets of control mice, but was present in foamy cells in fibrotic regions induced by bleomycin. These findings suggest that the antifibrotic effect of IFN-beta is inhibition of TGF-beta and its activation via decrease in TSP-1/2 in lung tissue and change in location of TSP-1/2 from platelets to foamy cells.

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

“…Li, Azuma, Takahashi et al, 2002) etc. ), Cytokines (Interferon-β (Azuma, Li et al, 2005), Interferon-γ (Gurujeyalakshmi & Giri, 1995;Hyde, Henderson, Giri, Tyler, & Stovall, 1988;Okada, Sugie, & Aisaka, 1993), Interleukin (IL)-1beta (M. Yasui et al, 1991), IL-10 (Arai et al, 2000), IL-18 (Nakatani-Okuda et al, 2005), Keratinocyte growth factor (Deterding et al, 1997;Sugahara, Iyama, Kuroda, & Sano, 1998;Yi et al, 1996), Hepatocyte growth factor (Dohi, Hasegawa, Yamamoto, & Marshall, 2000;Mizuno, Matsumoto, Li, & Nakamura, 2005;Umeda et al, 2004;Yaekashiwa et al, 1997), Chemokine ligand (CXCL)-10 (Tager et al, 2004),CXCL11 (Burdick et al, 2005), CD (cluster of differentiation)-36 (Yehualaeshet et al, 2000) etc. ), Cytokine antibodies (Transforming growth factor-β (Giri, Hyde, & Hollinger, 1993), Tumor necrosis factor-α (Fichtner-Feigl, Strober, Kawakami, Puri, & Kitani, 2006;Fujita et al, 2003;Piguet & Vesin, 1994), Connective tissue growth factor (Matsuoka et al, 2002), IL-12 , IL-13 (Fichtner-Feigl, Strober, Kawakami, Puri, & Kitani, 2006), Platelet derived growth factor (Aono et al, 2005;Chaudhary, Schnapp, & Park, 2006;Daniels et al, 2004;Yoshida et al, 1999), Vascular endothelial growth factor (Hamada et al, 2005), CCR-1 (Tokuda et al, 2000), CCR-3 (Huaux et al, 2005), CCL-11 (Huaux et al, 2005), CD-11 (Piguet, Rosen, Vesin, & Grau, 1993), MCP-1 etc.…”

“…They speculated that this might be based on inhibition of heat shock protein 47 positive cells and α−smooth muscle actin positive myofibroblasts (Kakugawa et al, 2004). Pirfenidone has recently been tested in multiple clinical trials, showing some promising results such as improvement of vital capacity and reduction of acute exacerbations (Azuma, Li et al, 2005). To further clarify the safety of this drug, a large phase III clinical trial (CAPACITY) has been initiated in 2006.…”

A Pneumocyte–Macrophage Paracrine Lipid Axis Drives the Lung toward Fibrosis

“…Lipid clearance is ordinarily mediated by ATII cells and, to a lesser extent, AMs (12,13). Lipid-laden AMs, also called "foam cells," are common pathological features in animals models of lung fibrosis (14,15) and in histological specimens from patients with various chronic fibrotic lung diseases (16,17). Although foam cells are thought to be a consequence, rather than cause, of fibrotic lung disease, their very presence signifies a disruption in surfactant lipid homeostasis.…”

Interferon-β Reduces Proteinuria in Experimental Glomerulonephritis

“…9 In vivo, IFN-␤ inhibited fibrosis in a mouse model of bleomycin-induced pulmonary fibrosis. 10 In view of the potential benefits of IFN-␤ on glomerular injury and fibrosis, we examined its effects in three distinct models of glomerular injury in rats: Nephrotoxic nephritis (NTN), Thy-1 nephritis, and puromycin aminonucleoside nephrosis (PAN). Our results show a striking reduction of proteinuria in all three models, but this was not accompanied by major effects on glomerular inflammation.…”