Hepatocyte Growth Factor Attenuates Collagen Accumulation in a Murine Model of Pulmonary Fibrosis

Abstract

We investigated the in vivo effects of recombinant human hepatocyte growth factor (HGF) on epithelial cell proliferation in normal mouse lung and on the repair process that follows bleomycin-induced lung injury. Intratracheal administration of 100 micrograms of rhHGF to C57BL/6 mice led to proliferation of bronchial and alveolar epithelial cells as indicated by an increased number of cells staining for proliferating cell nuclear antigen (PCNA). The effect of HGF on the lung repair process was examined by administration of 100 micrograms of rhHGF on Day 3 and Day 6 after intratracheal injection of bleomycin to mice. We found that HGF significantly attenuated collagen accumulation induced by bleomycin as determined by quantitation of hydroxyproline content and by scoring of the extent of fibrosis. To explore the potential mechanisms involved in the beneficial effects of HGF, we performed in vitro studies with A549 pulmonary epithelial cells and found that HGF enhanced cell surface plasmin generation, expression of u-PA activity, and cell migration. In summary, HGF has potent in vivo and in vitro effects on epithelial cells, which suggests it may have a role in the therapy of pulmonary fibrosis.

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.…”

“…HGF acts on epithelial cells as a mitogen, stimulating migration and morphogenesis (Dohi, Hasegawa, Yamamoto, & Marshall, 2000;Yaekashiwa et al, 1997). It is described as potent inducer of matrix metalloproteinases (MMPs), which degrade extracellular matrix and are overexpressed during progression of myofibroblast apoptosis (Mizuno, Matsumoto, Li, & Nakamura, 2005).…”

“…It is described as potent inducer of matrix metalloproteinases (MMPs), which degrade extracellular matrix and are overexpressed during progression of myofibroblast apoptosis (Mizuno, Matsumoto, Li, & Nakamura, 2005). HGF levels are increased in the BALF of IPF patients (Dohi, Hasegawa, Yamamoto, & Marshall, 2000) and evidence exists that its function is protective against lung damage, preventing subsequent fibrogenesis (Mizuno, Matsumoto, Li, & Nakamura, 2005). Similar antifibrotic properties were demonstrated in an animal study, where bleomycin was administered by intraperitoneal infusion from day 0 to day 7, followed by infusion of recombinant HGF from day 7 to day 14, day 14 to day 21, or day 21 to day 28.…”

Plasminogen-Mediated Activation and Release of Hepatocyte Growth Factor from Extracellular Matrix

“…These increases are significant because inhibition of HGF activity in the lung in animal models worsens lung fibrosis (14). Conversely, interventions designed to increase HGF reduce scarring (22)(23)(24). For HGF to have its effect on target cells, it must undergo several extracellular processing events (15,16).…”

Association of hepatocyte growth factor promoter polymorphism with severity of interstitial lung disease in Japanese patients with systemic sclerosis

“…Numerous studies have shown HGF to be an endogenous antifibrotic factor in the lungs, ameliorating fibrotic lesions and preserving lung function in experimental animal models of pulmonary fibrosis (22)(23)(24)(25). HGF exerts its antifibrotic effects on pulmonary function by reducing the production of type I collagen and CTGF, and increasing the production of matrix metalloproteinase 1 in lung fibroblasts (12,26).…”