Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis

Lasky, Joseph A.; Ortiz, Luis A.; Tonthat, Boihoang; Hoyle, Gary W.; Corti, Miriam; Athas, Grace; Lungarella, Giuseppe; Brody, Arnold R.; Friedman, Mitchell

doi:10.1152/ajplung.1998.275.2.l365

Cited by 182 publications

(168 citation statements)

References 20 publications

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“…This may be the reason why we found an association between VEGF expression and von Willebrand factor in this model in contrast to the results of Fehrenbach et al Recently, Inoki et al (22) demonstrated that connective tissue growth factor (CTGF) binds to VEGF and inhibits VEGF-induced angiogenesis. CTGF and VEGF are downstream effectors of TGF-␤, and these growth factors are known to be up-regulated in this model (23). At the advanced phase of fibrosis at 28 days, angiogenesis may be effected by other factors such as CTGF.…”

Section: Discussionmentioning

confidence: 84%

Anti-Vascular Endothelial Growth Factor Gene Therapy Attenuates Lung Injury and Fibrosis in Mice

Hamada

Kuwano

Yamada

et al. 2005

The Journal of Immunology

160

110

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Vascular endothelial growth factor (VEGF) is an angiogenesis factor with proinflammatory roles. Flt-1 is one of the specific receptors for VEGF, and soluble flt-1 (sflt-1) binds to VEGF and competitively inhibits it from binding to the receptors. We examined the role of VEGF in the pathophysiology of bleomycin-induced pneumopathy in mice, using a new therapeutic strategy that comprises transfection of the sflt-1 gene into skeletal muscles as a biofactory for anti-VEGF therapy. The serum levels of sflt-1 were significantly increased at 3–14 days after the gene transfer. Transfection of the sflt-1 gene at 3 days before or 7 days after the intratracheal instillation of bleomycin decreased the number of inflammatory cells, the protein concentration in the bronchoalveolar lavage fluid and with von Willebrand factor expression at 14 days. Transfection of the sflt-1 gene also attenuated pulmonary fibrosis and apoptosis at 14 days. Since the inflammatory cell infiltration begins at 3 days and is followed by interstitial fibrosis, it is likely that VEGF has important roles as a proinflammatory, a permeability-inducing, and an angiogenesis factor not only in the early inflammatory phase but also in the late fibrotic phase. Furthermore, this method may be beneficial for treating lung injury and fibrosis from the viewpoint of clinical application, since it does not require the use of a viral vector or neutralizing Ab.

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Section: Discussionmentioning

confidence: 84%

Anti-Vascular Endothelial Growth Factor Gene Therapy Attenuates Lung Injury and Fibrosis in Mice

Hamada

Kuwano

Yamada

et al. 2005

The Journal of Immunology

160

110

View full text Add to dashboard Cite

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“…There, CTGF can stimulate fibroblast proliferation in an autocrine and paracrine manner as has been suggested with other models. 31 As with TGF-␤1, CTGF was further noted in allografts from Smad3-deficient recipients. Together with others' findings in cultured Smad3-deficient fibroblasts showing no increased production of CTGF after treatment with TGF-␤1, 14 we conclude that this up-regulation in experimental OB is independent not only of Smad3, but of TGF-␤1 itself.…”

Section: Discussionmentioning

confidence: 94%

Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model

Ramirez

Takagawa

Sekosan

et al. 2004

The American Journal of Pathology

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Chronic allograft rejection manifested as obliterative bronchiolitis (OB) remains the single greatest impediment to long-term survival after lung transplantation. Transforming growth factor-␤1 (TGF-␤1) has been implicated in the tissue remodeling response associated with OB. Therefore, its intracellular signal transducer, Smad3, is a prime target of investigation. Herein, we examine the role of TGF-␤1, through Smad3, in the development of OB using heterotopic tracheal transplantation in wild-type and Smad3-null mice. TGF-␤1 was detectable within infiltrating mononuclear cells early after transplantation. Throughout the last 20 years, lung transplantation has evolved into an accepted treatment option for patients with end-stage lung disease because of emphysema, pulmonary fibrosis, pulmonary hypertension, and cystic fibrosis. 1 However, chronic allograft rejection manifested as obliterative bronchiolitis (OB) remains the major obstacle to long-term survival after lung transplantation. 2 Clinically, OB is characterized by airflow limitation, defined by a 20% decline in forced expiratory volume in 1 second (FEV 1 ), and is often complicated by recurrent lower respiratory tract infections. The histological hallmark of OB is the presence of obstructing intraluminal polyps comprised of fibromyxoid granulation tissue and plaques of dense submucosal eosinophilic scar on lung biopsy. OB can complicate up to 60% of lung allografts and becomes increasingly prevalent the further removed from the transplant operation. 3 Progressive OB ultimately results in worsening hypoxemia and death.Many studies on the pathogenesis of OB have concentrated on the role of cellular allogenic immune responses during OB development. However, fibroproliferation and tissue remodeling clearly play an important role in its pathogenesis because OB is characterized by the accumulation of fibroblasts and the excessive deposition of connective tissue matrix within the lumen of the affected bronchioles. The factors that initiate and maintain fibroproliferation and tissue remodeling within the airway lumen in OB have not been fully elucidated. One candidate factor is transforming growth factor (TGF)-␤, a pleiotropic cytokine with potent profibrotic activities. 4 Extensively studied in solid organ transplantation, TGF-␤ has been found to have beneficial effects on alloimmunity. For instance, overexpression of a TGF-␤ transgene leads to marked reductions in acute rejection and prolongation of graft survival in experimental heart and

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“…The fibroblasts present in bleomycin-induced fibrotic lesions show activated Smad3 (21), and bleomycin-induced lung fibrosis is reversed by application of an adenovirus encoding Smad7 (22) and is known to be less severe in Smad3-deficient mice (23). Increased CTGF expression has been observed in this mouse model (4,6). However, the contribution of CTGF to bleomycin-induced pulmonary fibrosis and the mechanisms underlying the action of CTGF have yet to be elucidated.…”

mentioning

confidence: 91%

“…However, CTGF is consistently overexpressed in fibrotic lesions in patients with SSc and in those with other connective tissue diseases, affecting organs including the dermis, liver, kidney, heart, and lung (6,7). Elevated CTGF expression also correlates with, and contributes to, expression of ␣-smooth muscle actin (␣-SMA) and the myofibroblast phenotype in, for example, repair and development of connective tissue (8,9).…”

mentioning

confidence: 99%

Pivotal role of connective tissue growth factor in lung fibrosis: MAPK‐dependent transcriptional activation of type I collagen

Ponticos

Holmes

et al. 2009

Arthritis & Rheumatism

214

151

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Objective. Connective tissue growth factor (CTGF; CCN2) is overexpressed in systemic sclerosis (SSc) and has been hypothesized to be a key mediator of the pulmonary fibrosis frequently observed in this disease. CTGF is induced by transforming growth factor ␤ (TGF␤) and is a mediator of some profibrotic effects of TGF␤ in vitro. This study was undertaken to investigate the role of CTGF in enhanced expression of type I collagen in bleomycin-induced lung fibrosis, and to delineate the mechanisms of action underlying the effects of CTGF on Col1a2 (collagen gene type I ␣2) in this mouse model and in human pulmonary fibroblasts.Methods. Transgenic mice that were carrying luciferase and ␤-galactosidase reporter genes driven by the Col1a2 enhancer/promoter and the CTGF promoter, respectively, were injected with bleomycin to induce lung fibrosis (or saline as control), and the extracted pulmonary fibroblasts were incubated with CTGF blocking agents. In vitro, transient transfection, promoter/ reporter constructs, and electrophoretic mobility shift assays were used to determine the mechanisms of action of CTGF in pulmonary fibroblasts.Results. In the mouse lung tissue, CTGF expression and promoter activity peaked 1 week after bleomycin challenge, whereas type I collagen expression and Col1a2 promoter activity peaked 2 weeks postchallenge. Fibroblasts isolated from the mouse lungs 14 days after bleomycin treatment retained a profibrotic expression pattern, characterized by greatly elevated levels of type I collagen and CTGF protein and increased promoter activity. In vitro, inhibition of CTGF by specific small interfering RNA and neutralizing antibodies reduced the collagen protein expression and Col1a2 promoter activity. Moreover, in vivo, anti-CTGF antibodies applied after bleomycin challenge significantly reduced the Col1a2 promoter activity by ϳ25%. The enhanced Col1a2 promoter activity in fibroblasts from bleomycintreated lungs was partly dependent on Smad signaling, whereas CTGF acted on the Col1a2 promoter by a mechanism that was independent of the Smad binding site, but was, instead, dependent on the ERK-1/2 and JNK MAPK pathways. The CTGF effect was mapped to the proximal promoter region surrounding the inverted CCAAT box, possibly involving CREB and c-Jun. In human lung fibroblasts, the human COL1A2 promoter responded in a similar manner, and the mechanisms of action also involved ERK-1/2 and JNK signaling.Conclusion. Our results clearly define a direct profibrotic effect of CTGF and demonstrate its contribution to lung fibrosis through transcriptional activation

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Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis

Cited by 182 publications

References 20 publications

Anti-Vascular Endothelial Growth Factor Gene Therapy Attenuates Lung Injury and Fibrosis in Mice

Anti-Vascular Endothelial Growth Factor Gene Therapy Attenuates Lung Injury and Fibrosis in Mice

Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model

Pivotal role of connective tissue growth factor in lung fibrosis: MAPK‐dependent transcriptional activation of type I collagen

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