Transient Transgene Expression of Decorin in the Lung Reduces the Fibrotic Response to Bleomycin

Department of Pathology and Molecular Medicine and Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 04/2001; 163(3 Pt 1):770-7. DOI: 10.1164/ajrccm.163.3.2006084
Source: PubMed


Pulmonary fibrosis is a chronic progressive disease with no effective therapy. Transforming growth factor beta (TGF-beta) is thought to be a key profibrotic mediator and blocking its activity is therefore one of the targets of new treatment strategies for fibrosis. Decorin is an endogenous proteoglycan and one of the known inhibitors of TGF-beta. The short half-life of peptide-based therapeutics makes gene transfer a promising approach to achieve prolonged protein levels in the lung. Replication-deficient adenovirus was used to deliver decorin transgene (AdDec) to the airways by a single intranasal injection in a murine bleomycin model of lung fibrosis. The ability of vector-derived decorin to inhibit TGF-beta was examined in a bioassay and its effect on bleomycin-induced pulmonary fibrosis was determined by histomorphology and lung hydroxyproline. In vitro, supernatant from cells infected with AdDec abrogated the bioactivity of TGF-beta in a dose-dependent manner whereas control virus (AdDL70) had no effect. In vivo, treatment of bleomycin-injected mice with AdDec substantially reduced the fibrogenic response compared with control virus (hydroxyproline: bleomycin/AdDec, 1.96 microg/mg; bleomycin/AdDL70, 3.05 microg/mg; p = 0.0005). These results suggest that a single administration of AdDec was able to generate a local pulmonary environment that effectively blocked the fibrogenic response to bleomycin by inhibition of TGF-beta.

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    • "Decorin directly interacts with TGFβ and inhibits its profibrotic biological activity. Recombinant expression of decorin in the lung airways of mice inhibits bleomycin-induced pulmonary fibrosis (Kolb et al., 2001). In addition to the secreted proteoglycans of the ECM, there are also a number of cell membrane proteoglycans that can interact with chemical signals and function as co-receptors. "
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    ABSTRACT: Fibroblasts are the most common cell type of the connective tissues found throughout the body and the principal source of the extensive extracellular matrix (ECM) characteristic of these tissues. They are also the central mediators of the pathological fibrotic accumulation of ECM and the cellular proliferation and differentiation that occurs in response to prolonged tissue injury and chronic inflammation. The transformation of the fibroblast cell lineage involves classical developmental signaling programs and includes a surprisingly diverse range of precursor cell types-most notably, myofibroblasts that are the apex of the fibrotic phenotype. Myofibroblasts display exaggerated ECM production; constitutively secrete and are hypersensitive to chemical signals such as cytokines, chemokines, and growth factors; and are endowed with a contractile apparatus allowing them to manipulate the ECM fibers physically to close open wounds. In addition to ECM production, fibroblasts have multiple concomitant biological roles, such as in wound healing, inflammation, and angiogenesis, which are each interwoven with the process of fibrosis. We now recognize many common fibroblast-related features across various physiological and pathological protracted processes. Indeed, a new appreciation has emerged for the role of non-cancerous fibroblast interactions with tumors in cancer progression. Although the predominant current clinical treatments of fibrosis involve non-specific immunosuppressive and anti-proliferative drugs, a variety of potential therapies under investigation specifically target fibroblast biology.
    Frontiers in Pharmacology 05/2014; 5:123. DOI:10.3389/fphar.2014.00123 · 3.80 Impact Factor
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    • "Decorin binds to the epidermal growth factor receptor , the Met receptor and the toll-like receptors, suppressing growth (Moscatello et al., 1998; Csordá s et al., 2000), inhibiting angiogenesis (Neill et al., 2012b) and modulating inflammatory responses (Moreth et al., 2012) in tumour and lesion microenvironments . Although in some particular circumstances decorin binding to TGF-b enhances growth factor activity (Takeuchi et al., 1994), inhibition of TGF-b activity after decorin binding is more widely reported and through this mechanism decorin indirectly suppresses inflammatory scarring in fibrotic diseases (Yamaguchi et al., 1990; Border et al 1992; Kolb et al., 2001). Accordingly, in CNS lesions, decorin reduces the deposition of chondroitin sulphate proteoglycans, fibronectin and laminin, and suppresses astrocytic, microglial and macrophage reactions in and around the wound (Logan et al., 1999a; Davies et al., 2004). "
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    ABSTRACT: In post-haemorrhagic and other forms of communicating hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-β has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-β antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile communicating hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-β/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-β1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of hydrocephalus in juvenile rats by blocking transforming growth factor-β-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic communicating hydrocephalus.
    Brain 09/2013; 136(Pt 9):2842-58. DOI:10.1093/brain/awt203 · 9.20 Impact Factor
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    • "In our cultures basal decorin expression is much higher in PF compared to airway fibroblasts. Decorin is a matrix proteoglycan that appears to play a role in mediating TGFβ signaling by binding TGFβ and sequestering it in the matrix [12]–[14], and transient expression of decorin using an adenoviral vector reduces bleomycin-induced fibrosis [15]. The dramatic decrease in decorin gene expression in PF from smoke-exposed animals might also be important in allowing TGFβ release. "
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    ABSTRACT: Chronic obstructive lung disease (COPD) is characterized by matrix deposition in the small airways but matrix loss from the parenchyma, phenomena which must depend on the ability of local fibroblasts to produce matrix after smoke exposure. To investigate this idea, we exposed C57Bl/6 mice once to cigarette smoke or to air (control) and prepared primary cultures of lung fibroblasts by microdissecting large airways (trachea, LAF), medium size airways (major bronchi, MAF) and parenchyma (PF). Control PF showed the lowest rate of wound closure and wound closure was depressed in all lines by a single in vivo smoke exposure. Gene expression of matrix proteins differed considerably among the sites; decorin, which may sequester TGFβ, was markedly higher in PF. PF showed higher intrinsic ratios of pSmad2/Smad2. Smoke caused much greater increases in secreted and matrix deposited collagens 1 and 3 in PF than in LAF or MAF. Expression of Thy-1, a gene that suppresses myofibroblast differentiation, was increased by smoke in PF. We conclude that there is considerable regional heterogeneity in murine lung fibroblasts in terms of matrix production, either basally or after in vivo smoke exposure; that PF have lower ability to repair wounds and higher intrinsic TGFβ signaling; and that a single exposure to smoke produces lasting changes in the pattern of matrix production and wound repair, changes that may be mediated in part by smoke-induced release of TGFβ. However, PF still retain the ability to repair by producing new matrix after a single in vivo smoke exposure.
    PLoS ONE 06/2012; 7(6):e39761. DOI:10.1371/journal.pone.0039761 · 3.23 Impact Factor
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