A Peptide Derived from Endostatin Ameliorates Organ Fibrosis

Yamaguchi, Yukie; Takihara, Takahisa; Chambers, Roger; Veraldi, Kristen L.; Larregina, Adriana T.; Feghali‐Bostwick, Carol

doi:10.1126/scitranslmed.3003421

Cited by 115 publications

(129 citation statements)

References 36 publications

Supporting

Mentioning

123

Contrasting

Order By: Relevance

“…Our previous study confirmed that systemic application of endostatin could prevent hypertrophic scar formation in the rabbit ear model (Ren et al, 2013). Yamaguchi et al (2012) found that endostatin-derived peptide ameliorates organ fibrosis that is triggered by transforming growth factor-β (TGF-β) and bleomycin in human and mouse tissues. However, the molecular mechanisms by which endostatin mediates fibrosis in fibroblasts remain poorly understood.…”

Section: Introductionsupporting

confidence: 71%

Endostatin inhibits fibrosis by modulating the PDGFR/ERK signal pathway: an in vitro study

Ren

2017

J. Zhejiang Univ. Sci. B

View full text Add to dashboard Cite

Accumulating evidence indicates that endostatin inhibits fibrosis. However, the mechanism is yet to be clarified. The aim of this study is to evaluate the effect of endostatin on platelet-derived growth factor-BB (PDGF-BB)-or transforming growth factor β1 (TGF-β1)-induced fibrosis in cultured human skin fibroblasts, and to further examine the molecular mechanisms involved. Human dermal fibroblasts were cultured in Dulbecco's modified Eagle's medium (DMEM) and serum-starved for 48 h before treatment. Cells were grouped as follows: "PDGF-BB", "PDGF-BB+ endostatin", "TGF-β1", "TGF-β1+endostatin", "endostatin", and "blank control". The fibroblasts were stimulated with either TGF-β1 or PDGF-BB for 72 h in order to set up the fibrosis model in vitro. The cells were co-cultured with either TGF-β1 or PDGF-BB and endostatin and were used to check the inhibiting effect of endostatin. A blank control group and an endostatin group were used as negative control groups. The biomarkers of fibrosis, including the expression of collagen I, hydroxyproline, and α-smooth muscle actin (α-SMA), were evaluated using an enzyme-linked immunosorbent assay (ELISA) and Western blot. The expression of phosphorylated PDGF receptor β (p-PDGFRβ), PDGFRβ, phosphorylated extracellular signal-regulated kinase (p-ERK), and ERK was detected using Western blot and immunofluorescent staining was used to explore the mechanisms. Both PDGF-BB and TGF-β1 significantly up-regulated the expression of collagen I, hydroxyproline, and α-SMA. Endostatin significantly attenuated both the PDGF-BB-and TGF-β1-induced over-expression of collagen I, hydroxyproline, and α-SMA. PDGF-BB and TGF-β1 both promoted the expression of PDGFR, ERK, and p-ERK. Endostatin inhibited the expression of PDGFR and p-ERK but did not affect the expression of total ERK. Endostatin inhibited hypertrophic scar by modulating the PDGFRβ/ERK pathway. Endostatin could be a promising multi-target drug in future fibrosis therapy.

show abstract

Section: Introductionsupporting

confidence: 71%

Endostatin inhibits fibrosis by modulating the PDGFR/ERK signal pathway: an in vitro study

Ren

2017

J. Zhejiang Univ. Sci. B

View full text Add to dashboard Cite

show abstract

“…Increased concentrations of lysyl oxidase (LOX), an amine oxidase critical for the initiation of collagen and elastin crosslinking (32), and increased mRNA concentrations of collagen Types I and III have also been reported in murine models of lung fibrosis (33). In this report, MK2i treatment markedly reduced TGF-b-induced fibronectin and collagen expression.…”

Section: Discussionmentioning

confidence: 53%

Peptide-Mediated Inhibition of Mitogen-Activated Protein Kinase–Activated Protein Kinase–2 Ameliorates Bleomycin-Induced Pulmonary Fibrosis

Vittal¹,

Fisher²,

Gu³

et al. 2013

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2, or MK2), a serine/threonine kinase downstream of p38 mitogen-activated protein kinase, has been implicated in inflammation and fibrosis. Compared with pathologically normal lung tissue, significantly higher concentrations of activated MK2 are evident in lung biopsies of patients with idiopathic pulmonary fibrosis (IPF). Expression is localized to fibroblasts and epithelial cells. In the murine bleomycin model of pulmonary fibrosis, we observed robust, activated MK2 expression on Day 7 (prefibrotic stage) and Day 14 (postfibrotic stage). To determine the effects of MK2 inhibition during the postinflammatory/prefibrotic and postfibrotic stages, C57BL/6 mice received intratracheal bleomycin instillation (0.025 U; Day 0), followed by PBS or the MK2 inhibitor (MK2i; 37.5 mg/kg), administered via either local (nebulized) or systemic (intraperitoneal) routes. MK2i or PBS was dosed daily for 14 days subsequent to bleomycin injury, beginning on either Day 7 or Day 14. Regardless of mode of administration or stage of intervention, MK2i significantly abrogated collagen deposition, myofibroblast differentiation and activated MK2 expression. MK2i also decreased circulating TNF-a and IL-6 concentrations, and modulated the local mRNA expression of profibrotic cytokine il-1b, matrix-related genes col1a2, col3a1, and lox, and transforming growth factor-b family members, including smad3, serpine1 (pai1), and smad6/7. In vitro, MK2i dosedependently attenuated total MK2, myofibroblast differentiation, the secretion of collagen Type I, fibronectin, and the activation of focal adhesion kinase, whereas activated MK2 was attenuated at optimal doses. The peptide-mediated inhibition of MK2 affects both inflammatory and fibrotic responses, and thus may offer a promising therapeutic target for IPF.Keywords: MK2; IPF; established fibrosis; transforming growth factor-b; SMAD Idiopathic pulmonary fibrosis (IPF) is a fatal scarring disease of the lung with no known etiology or definite treatment modality, and a survival rate of 3 to 5 years. Although the onset of IPF symptoms (breathlessness and cough) is usually insidious, significant fibrotic damage is already present at the time of diagnosis. IPF afflicts approximately 128,100 people in the United States, with 48,000 new cases occurring annually (1). Although lung transplantation is considered the definitive therapy for IPF, the 5-year survival after lung transplantation is only 50%. Accordingly, even lung transplantation cannot be considered a "cure" for IPF.Histopathologically, IPF can be described as an accumulation of activated myofibroblasts in fibroblastic foci (2). The impaired apoptosis of myofibroblasts may result in a persistent and dysregulated repair process that culminates in tissue fibrosis. Arguably, inflammation also plays a critical role in IPF, perhaps through the cyclic acute stimulation of fibroblasts in response to epithelial injury. Therefore, effective lung-tissue repair and matrix remodeling subse...

show abstract

“…This may at first seem counterintuitive as proteins up-regulated in disease tend to serve a pathologic role. However, the scientific literature catalogues a growing number of proteins up-regulated in disease that work to counter the disease process, reestablish homeostasis, and return the body to its original state of health (61)(62)(63), and we have found that FAP behaves in such a fashion in pulmonary fibrosis. This study is the first to demonstrate that the absence of FAP worsens the development of pulmonary fibrosis after lung injury, establishing a protective role for FAP in the lung.…”

Section: Discussionmentioning

confidence: 94%

“…Previous work by others has shown significant biological activity of peptides generated from proteolytic degradation of collagens, for example the chemotactic properties of the matrikine, PGP, or the antifibrotic actions of endostatin, a product of proteolytic degradation of collagen XVIII (61,74,75). Indeed, we did identify increased neutrophilic inflammation in BAL fluid from FAP-null mice compared with wild type in our bleomycin model as well as a more prominent inflammatory infiltrate overall in the BAL from FAP-null mice versus wild type after thoracic FIGURE 11.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice

Fan

Zhu

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2-4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury. In two different models of pulmonary fibrosis, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAPdeficient mouse lungs, consistent with in vitro studies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP participates directly, in concert with MMPs, in collagen catabolism and clearance and is an important factor in resolving scar after injury and restoring lung homeostasis. Our study identifies FAP as a novel endogenous regulator of fibrosis and is the first to show FAP's protective effects in the lung.Idiopathic pulmonary fibrosis, the most common of the idiopathic interstitial pneumonias, is characterized by inexorable progressive lung injury and scarring, with eventual death within 2-4 years from the time of diagnosis in the absence of lung transplantation (1). The etiology of the disease is poorly understood, and current Food and Drug Administration-approved treatments have only limited impact on the course of the disease (2-4).Fibroblast activation protein (FAP, 2 also known as seprase) is a 95-kDa cell surface, type II integral serine protease belonging to the post-proline dipeptidyl aminopeptidase (DPP) family (5) that is specifically induced on lung fibroblasts in patients with idiopathic pulmonary fibrosis, in particular at the leading edge of fibrosis (6). The DPP family of serine proteases cleaves amino-terminal dipeptides from polypeptides with L-proline or L-alanine at the penultimate position. FAP is unique in that it displays additional in vitro endopeptidase (7), gelatinase, and potentially collagenase activity (8,9). FAP expression is restricted, occurring at high levels on mesenchymal cells during embryogenesis (10) and then is repressed shortly after birth. In conditions associated with matrix remodeling...

show abstract

A Peptide Derived from Endostatin Ameliorates Organ Fibrosis

Cited by 115 publications

References 36 publications

Endostatin inhibits fibrosis by modulating the PDGFR/ERK signal pathway: an in vitro study

Endostatin inhibits fibrosis by modulating the PDGFR/ERK signal pathway: an in vitro study

Peptide-Mediated Inhibition of Mitogen-Activated Protein Kinase–Activated Protein Kinase–2 Ameliorates Bleomycin-Induced Pulmonary Fibrosis

Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice

Contact Info

Product

Resources

About