Hepatocyte Growth Factor Gene Transfer to Alveolar Septa for Effective Suppression of Lung Fibrosis

Watanabe, Masaki; Ebina, Masahito; Orson, Frank M.; Nakamura, Akira; Kubota, Kazuo; Koinuma, Daizo; Akiyama, Ken; Maemondo, Makoto; Okouchi, Shinya; Tahara, Masaki; Matsumoto, Kunio; Nakamura, Toshikazu; Nukiwa, Toshihiro

doi:10.1016/j.ymthe.2005.02.019

Cited by 72 publications

(58 citation statements)

References 38 publications

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“…The role of HGF as a potent antifibrotic factor has recently been established in several animal models of pulmonary fibrosis (21)(22)(23)(24). However, the therapeutic potential of HGF in the treatment of pulmonary fibrosis in humans has yet to be explored.…”

Section: Discussionmentioning

confidence: 99%

“…In the lung, HGF acts as an important mediator of mesenchymal-epithelial interactions during development, inflammation, and repair (18,22). Recently, HGF was shown to reverse fibrogenic processes in a bleomycin-induced model of pulmonary fibrosis (21)(22)(23)(24). HGF inhibits collagen deposition and attenuates the amount of already deposited extracellular matrix proteins (21,23).…”

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confidence: 99%

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Impairment of the antifibrotic effect of hepatocyte growth factor in lung fibroblasts from African Americans: Possible role in systemic sclerosis

Bogatkevich¹,

Ludwicka-Bradley²,

Highland³

et al. 2007

Arthritis & Rheumatism

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Objective. To compare the composition of cytokines in African American and Caucasian patients with systemic sclerosis (SSc; scleroderma) and in healthy individuals, particularly the expression and function of hepatocyte growth factor (HGF).Methods. Bronchoalveolar lavage (BAL) fluid samples were analyzed using cytokine array techniques. HGF in plasma and cell culture medium samples was measured by enzyme-linked immunosorbent assay. Connective tissue growth factor (CTGF), type I collagen expression, and c-Met receptor phosphorylation were studied by immunoblotting.Results Conclusion. Ethnic differences exist in terms of antifibrotic HGF expression in lung fibroblasts derived from Caucasian and African American subjects. Reduced levels of HGF as well as a deficiency in c-Met receptor function appear to be present in African American patients with SSc. These findings may explain in part the greater disease severity and worse prognosis observed in African Americans with SSc.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Impairment of the antifibrotic effect of hepatocyte growth factor in lung fibroblasts from African Americans: Possible role in systemic sclerosis

Bogatkevich¹,

Ludwicka-Bradley²,

Highland³

et al. 2007

Arthritis & Rheumatism

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“…Blocking HGF by inhibitory antibodies worsens lung fibrosis after bleomycin administration (14). Elevation of HGF levels by its exogenous delivery (22,23) or by gene transfer (24) reduces the amount of fibrosis that occurs after lung injury. This antifibrotic effect is not unique to the lung, but occurs in other organs, including liver (51), kidney (52,53), skin (54), and heart (55).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

Matsuoka

Sisson

Nishiuma

et al. 2006

Am J Respir Cell Mol Biol

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Interventions that enhance plasminogen activation within the lung consistently limit the fibrosis that follows alveolar injury. However, this protective effect cannot be attributed solely to accelerated clearance of fibrin that forms as a provisional matrix after lung injury. To explore other mechanisms, we considered interactions between the plasminogen activation system and hepatocyte growth factor (HGF). HGF is known to have antifibrotic activity, but to do so, it must be both released from its sites of sequestration within extracellular matrix (ECM) and activated by proteolytic cleavage. A recent study using bleomycin-exposed mice showed that manipulations of the plasminogen activation system influenced the amount of free HGF within bronchoalveolar lavage fluid without affecting total lung HGF mRNA or protein. To elucidate the mechanisms, we studied the role of plasminogen activation in fibroblastmediated HGF release and activation. We found that NIH3T3 and mouse lung fibroblasts release ECM-bound HGF in a plasminogendependent fashion. The plasminogen effect was lost when lung fibroblasts from urokinase-type plasminogen activator (uPA)-deficient mice were used, and was increased by fibroblasts from plasminogen activator inhibitor (PAI)-1-deficient mice. Plasminogen addition to NIH3T3 or mouse lung fibroblasts increased conversion of pro-HGF to its active form. The plasminogen effect on activation was lost when uPA-deficient fibroblasts were used and accentuated by PAI-1-deficient fibroblasts. In conjunction with the previous in vivo study, these results suggest that plasminogen activation can protect the lung against fibrosis by increasing the availability of active HGF.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Hoshino¹,

Satoh²,

Kawaguchi³

et al. 2011

Arthritis & Rheumatism

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Objective. To examine associations of singlenucleotide polymorphisms (SNPs) within genes for hepatocyte growth factor (HGF) and its receptor c-met with disease susceptibility and organ involvement in Japanese patients with systemic sclerosis (SSc).Methods. Four SNPs (HGF -1652 C/T, ؉44222 C/T, and ؉63555 G/T, and c-met -980 T/A) were analyzed in 159 SSc patients and 103 healthy control subjects with the use of a polymerase chain reactionbased assay. The influence of the HGF -1652 SNP on transcription activity was evaluated with a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA).Results. There was no difference in the distribution of HGF/c-met SNPs between SSc patients and controls. HGF -1652 TT was found much more frequently in SSc patients with end-stage lung disease (ESLD) than in those without (41% versus 8%; P ‫؍‬ 0.0004). This association was confirmed by a replication study involving a separate cohort of 155 SSc patients. Kaplan-Meyer analysis revealed that HGF -1652 TT carriers had a higher probability of developing ESLD than did CT or CC carriers. The HGF promoter carrying the HGF -1652 T allele had lower transcription activity than did the promoter carrying the C allele. EMSA showed the presence of a potential negative transcription regulator that binds specifically to the HGF promoter carrying a T allele at position -1652. Finally, TT carriers had a relative inability to increase circulating HGF levels even in the presence of advanced interstitial lung disease.Conclusion. A SNP in the HGF promoter region may modulate the severity of interstitial lung disease by controlling the transcriptional efficiency of the HGF gene.

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Hepatocyte Growth Factor Gene Transfer to Alveolar Septa for Effective Suppression of Lung Fibrosis

Cited by 72 publications

References 38 publications

Impairment of the antifibrotic effect of hepatocyte growth factor in lung fibroblasts from African Americans: Possible role in systemic sclerosis

Impairment of the antifibrotic effect of hepatocyte growth factor in lung fibroblasts from African Americans: Possible role in systemic sclerosis

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

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

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