[Show abstract][Hide abstract] ABSTRACT: Fibrosis involves an orchestrated cascade of events including activation of fibroblasts, increased production and deposition of extracellular matrix components, and differentiation of fibroblasts into myofibroblasts. Epithelial-mesenchymal cross-talk plays an important role in this process, and current hypotheses of organ fibrosis liken it to an aberrant wound healing response in which epithelial-mesenchymal transition (EMT) and cellular senescence may also contribute to disease pathogenesis. The fibrotic response is associated with altered expression of growth factors and cytokines, including increased levels of transforming growth factor-β1 (TGF-β1) and the more recent observation that increased levels of several insulin-like growth factor binding proteins (IGFBPs) are associated with a number of fibrotic conditions. IGFBPs have been implicated in virtually every cell type and process associated with the fibrotic response, making the IGFBPs attractive targets for the development of novel anti-fibrotic therapies. In this review, the current state of knowledge regarding the classical IGFBP family in organ fibrosis will be summarized and the clinical implications considered.
The Open Rheumatology Journal 06/2012; 6(1):140-5. DOI:10.2174/1874312901206010140
[Show abstract][Hide abstract] ABSTRACT: Fibroproliferative disorders such as idiopathic pulmonary fibrosis and systemic sclerosis have no effective therapies and result in significant morbidity and mortality due to progressive organ fibrosis. We examined the effect of peptides derived from endostatin on existing fibrosis and fibrosis triggered by two potent mediators, transforming growth factor-β (TGF-β) and bleomycin, in human and mouse tissues in vitro, ex vivo, and in vivo. We identified one peptide, E4, with potent antifibrotic activity. E4 prevented TGF-β-induced dermal fibrosis in vivo in a mouse model, ex vivo in human skin, and in bleomycin-induced dermal and pulmonary fibrosis in vivo, demonstrating that E4 exerts potent antifibrotic effects. In addition, E4 significantly reduced existing fibrosis in these preclinical models. E4 amelioration of fibrosis was accompanied by reduced cell apoptosis and lower levels of lysyl oxidase, an enzyme that cross-links collagen, and Egr-1 (early growth response gene-1), a transcription factor that mediates the effects of several fibrotic triggers. Our findings identify E4 as a peptide with potent antifibrotic activity and a possible therapeutic agent for organ fibrosis.
Science translational medicine 05/2012; 4(136):136ra71. DOI:10.1126/scitranslmed.3003421 · 15.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the role of insulin-like growth factor binding protein 3 (IGFBP-3) in mediating the effects of transforming growth factor β (TGFβ) on tenascin-C (TN-C) production and to assess the levels of TN-C in vivo in patients with systemic sclerosis (SSc)-associated pulmonary fibrosis.
Human primary lung fibroblasts were stimulated with TGFβ or IGFBP-3 in the presence or absence of specific small interfering RNAs and chemical inhibitors of the signaling cascade. TN-C levels in lung tissue specimens obtained from patients with SSc-associated pulmonary fibrosis were assessed using immunohistochemical analysis and were compared with the levels in specimens obtained from normal donors. TN-C levels were quantified in sera from normal donors and patients with SSc with or without pulmonary fibrosis, using an enzyme-linked immunosorbent assay.
IGFBP-3 mediated the induction of TN-C by TGFβ. Direct induction of TN-C by IGFBP-3 occurred in a p38 MAP kinase-dependent manner. TN-C levels were abundant in lung tissues from patients with SSc and were localized to subepithelial layers of the distal airways. No TN-C was detectable around the proximal airways. Patients with SSc-associated pulmonary fibrosis had significantly higher levels of circulating TN-C compared with SSc patients without pulmonary fibrosis. Longitudinal samples obtained from patients with SSc before and after the onset of pulmonary fibrosis showed increased levels of TN-C after the onset of pulmonary fibrosis.
IGFBP-3, which is overexpressed in fibrotic lungs, induces production of TN-C by subepithelial fibroblasts. The increased lung tissue levels of TN-C parallel the levels detected in the sera of SSc patients with pulmonary fibrosis, suggesting that TN-C may be a useful biomarker for SSc-related pulmonary fibrosis.
[Show abstract][Hide abstract] ABSTRACT: Interstitial lung disease is a frequent complication of systemic sclerosis and currently is the leading cause of death. Our ability to predict which individuals are at greatest risk of developing clinically significant, progressive interstitial lung disease remains inadequate. Identification of circulating autoantibodies and other biomarkers, as well as genetic polymorphisms and aberrant gene expression, all hold promise as diagnostic and prognostic tools, as well as therapeutic targets. Many practice patterns for the diagnosis and monitoring of connective tissue disease-associated interstitial lung disease are based upon published experience with idiopathic interstitial lung diseases. Although there are likely commonalities in the pathophysiologic mechanisms and clinical progression among all fibrosing lung diseases, a better understanding of features unique to systemic sclerosis-associated interstitial lung disease is essential to the development of more effective monitoring and treatment strategies.
Current Rheumatology Reports 02/2010; 12(1):19-25. DOI:10.1007/s11926-009-0071-8 · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The hallmarks of allergic asthma are airway inflammation, obstruction, and remodeling. Airway remodeling may lead to irreversible airflow obstruction with increased morbidity and mortality. Despite advances in the treatment of asthma, the mechanisms underlying airway remodeling are still poorly understood. We reported that insulin-like growth factor (IGF) binding proteins (IGFBPs) contribute to extracellular matrix deposition in idiopathic pulmonary fibrosis; however, their contribution to airway remodeling in asthma has not been established.
We hypothesized that IGFBP-3 is overexpressed in asthma and contributes to airway remodeling.
We evaluated levels of IGFBP-3 in tissues and bronchoalveolar lavage fluid from patients with asthma at baseline and 48 hours after allergen challenge, in reparative epithelium in an in vitro wounding assay, and in conditioned media from cytokine- and growth factor-stimulated primary epithelial cells.
IGFBP-3 levels and distribution were evaluated by Western blot, ELISA, and immunofluorescence. IGFBP-3 is increased in vivo in the airway epithelium of patients with asthma compared with normal control subjects. The concentration of IGFBP-3 is increased in the bronchoalveolar lavage fluid of patients with asthma after allergen challenge, its levels are increased in reparative epithelium in an in vitro wounding assay and in the conditioned medium of primary airway epithelial cell cultures stimulated with IGF-I.
Our results suggest that one mechanism of allergic airway remodeling is through the secretion of the profibrotic IGFBP-3 from IGF-I-stimulated airway epithelial cells during allergic inflammation.
American Journal of Respiratory and Critical Care Medicine 08/2009; 180(7):611-7. DOI:10.1164/rccm.200810-1555OC · 13.00 Impact Factor