Therapies For Fibrotic Diseases Research Articles

MicroRNA-34a: A Novel Therapeutic Target in Fibrosis.

Fibrosis can occur in many organs, and severe cases leading to organ failure and death. No specific treatment for fibrosis so far. In recent years, microRNA-34a (miR-34a) has been found to play a role in fibrotic diseases. MiR-34a is involved in the apoptosis, autophagy and cellular senescence, also regulates TGF-β1/Smad signal pathway, and negatively regulates the expression of multiple target genes to affect the deposition of extracellular matrix and regulate the process of fibrosis. Some studies have explored the efficacy of miR-34a-targeted therapies for fibrotic diseases. Therefore, miR-34a has specific potential for the treatment of fibrosis. This article reviews the important roles of miR-34a in fibrosis and provides the possibility for miR-34a as a novel therapeutic target in fibrosis.

Evaluation of the Effects of Human Dental Pulp Stem Cells on the Biological Phenotype of Hypertrophic Keloid Fibroblasts.

Objective: Despite numerous existing treatments for keloids, the responses in the clinic have been disappointing, due to either low efficacy or side effects. Numerous studies dealing with preclinical and clinical trials have been published about effective therapies for fibrotic diseases using mesenchymal stem cells; however, no research has yet been reported to scientifically investigate the effect of human dental pulp stem cells (HDPSCs) on the treatment of keloids. The objective is to provide an experimental basis for the application of stem cells in the treatment of keloids. Methods: Human normal fibroblasts (HNFs) and human keloid fibroblasts (HKFs) were cultured alone and in combination with HDPSCs using a transwell cell-contact-independent cell culture system. The effects of HDPSCs on HKFs were tested using a CCK-8 assay, live/dead staining assay, quantitative polymerase chain reaction, Western blot and immunofluorescence microscopy. Results: HDPSCs did not inhibit the proliferation nor the apoptosis of HKFs and HNFs. HDPSCs did, however, inhibit their migration. Furthermore, HDPSCs significantly decreased the expression of profibrotic genes (CTGF, TGF-β1 and TGF-β2) in HKFs and KNFs (p < 0.05), except for CTGF in HNFs. Moreover, HDPSCs suppressed the extracellular matrix (ECM) synthesis in HKFs, as indicated by the decreased expression of collagen I as well as the low levels of hydroxyproline in the cell culture supernatant (p < 0.05). Conclusions: The co-culture of HDPSCs inhibits the migration of HKFs and the expression of pro-fibrotic genes, while promoting the expression of anti-fibrotic genes. HDPSCs’ co-culture also inhibits the synthesis of the extracellular matrix by HKFs, whereas it does not affect the proliferation and apoptosis of HKFs. Therefore, it can be concluded that HDPSCs can themselves be used as a tool for restraining/hindering the initiation or progression of fibrotic tissue.

Detection of substrate binding of a collagen-specific molecular chaperone HSP47 in solution using fluorescence correlation spectroscopy

Heat shock protein 47 kDa (HSP47), an ER-resident and collagen-specific molecular chaperone, recognizes collagenous hydrophobic amino acid sequences (Gly-Pro-Hyp) and assists in secretion of correctly folded collagen. Elevated collagen production is correlated with HSP47 expression in various diseases, including fibrosis and keloid. HSP47 knockdown ameliorates liver fibrosis by inhibiting collagen secretion, and inhibition of the interaction of HSP47 with procollagen also prevents collagen secretion. Therefore, a high-throughput system for screening of drugs capable of inhibiting the interaction between HSP47 and collagen would aid the development of novel therapies for fibrotic diseases. In this study, we established a straightforward method for rapidly and quantitatively measuring the interaction between HSP47 and collagen in solution using fluorescence correlation spectroscopy (FCS). The diffusion rate of HSP47 labeled with Alexa Fluor 488 (HSP47-AF), a green fluorescent dye, decreased upon addition of type I or III collagen, whereas that of dye-labeled protein disulfide isomerase (PDI) or bovine serum albumin (BSA) did not, indicating that specific binding of HSP47 to collagen could be detected using FCS. Using this method, we calculated the dissociation constant of the interaction between HSP47 and collagen. The binding ratio between HSP47-AF and collagen did not change in the presence of sodium chloride, confirming that the interaction was hydrophobic in nature. In addition, we observed dissociation of collagen from HSP47 at low pH and re-association after recovery to neutral pH. These observations indicate that this system is appropriate for detecting the interaction between HSP47 and collagen, and could be applied to high-throughput screening for drugs capable of suppressing and/or curing fibrosis.

Stem Cells, Inflammation, and Fibrosis.

Stem Cells, Inflammation, and Fibrosis.

Therapy for Fibrotic Diseases: Nearing the Starting Line

Fibrosis, or the accumulation of extracellular matrix molecules that make up scar tissue, is a common feature of chronic tissue injury. Pulmonary fibrosis, renal fibrosis, and hepatic cirrhosis are among the more common fibrotic diseases, which in aggregate represent a huge unmet clinical need. New appreciation of the common features of fibrosis that are conserved among tissues has led to a clearer understanding of how epithelial injury provokes dysregulation of cell differentiation, signaling, and protein secretion. At the same time, discovery of tissue-specific features of fibrogenesis, combined with insights about genetic regulation of fibrosis, has laid the groundwork for biomarker discovery and validation, and the rational identification of mechanism-based antifibrotic drugs. Together, these advances herald an era of sustained focus on translating the biology of fibrosis into meaningful improvements in quality and length of life in patients with chronic fibrosing diseases.

Sphingolipid Regulation of Tissue Fibrosis

Bioactive sphingolipids, such as sphingosine 1-phosphate (S1P), dihydrosphingosine 1-phosphate (dhS1P) and ceramide, regulate a diverse array of cellular processes. Many of these processes are important components of wound-healing responses to tissue injury, including cellular apoptosis, vascular leak, fibroblast migration, and TGF-β signaling. Since over-exuberant or aberrant wound-healing responses to repetitive injury have been implicated in the pathogenesis of tissue fibrosis, these signaling sphingolipids have the potential to influence the development and progression of fibrotic diseases. Here we review accumulating in vitro and in vivo data indicating that these lipid mediators can in fact influence fibrogenesis in numerous organ systems, including the lungs, skin, liver, heart, and eye. Targeting these lipids, their receptors, or the enzymes involved in their metabolism consequently now appears to hold great promise for the development of novel therapies for fibrotic diseases.

CCN2 is required for bleomycin‐induced skin fibrosis in mice

No therapy for fibrotic disease is available. The proadhesive matricellular protein connective tissue growth factor CCN2 is a marker of fibrotic cells; however, the specific role of CCN2 in connective tissue biology in general and in fibrogenesis in particular is unclear. The aim of this study was to assess whether adult mice bearing a smooth muscle cell/fibroblast-specific deletion of CCN2 are resistant to bleomycin-induced skin scleroderma. Cutaneous fibrosis was induced in mice by subcutaneous injection of bleomycin. Untreated control groups were injected with phosphate buffered saline. Mice bearing a fibroblast/smooth muscle cell-specific deletion of CCN2 were investigated for changes in dermal thickness, collagen content, and the number of α-smooth muscle actin (α-SMA)-positive cells. Dermal fibroblasts were isolated to assess whether the induction of collagen and α-SMA messenger RNA in response to transforming growth factor β (TGFβ) was impaired. The loss of CCN2 resulted in resistance to bleomycin-induced skin fibrosis. In response to bleomycin, wild-type mice possessed, but CCN2-deficient mice lacked, abundant α-SMA-expressing myofibroblasts within fibrotic lesions. Fibroblast responses to TGFβ, a potent inducer of myofibroblast differentiation, were not affected. Collectively, these results indicate that CCN2 is essential for bleomycin-induced skin fibrosis, likely due to a defect in myofibroblast recruitment. These data indicate that therapeutic strategies that involve blocking CCN2 in vivo may be of benefit in combating fibrotic skin disease.

SMP-534 inhibits TGF-β-induced ECM production in fibroblast cells and reduces mesangial matrix accumulation in experimental glomerulonephritis

Transforming growth factor-beta (TGF-beta) is a potent fibrotic factor responsible for the synthesis of extracellular matrix (ECM) and is implicated as the major determinant in pathogenesis of chronic fibroses, including kidney. The novel small compound SMP-534 reduced ECM production induced by TGF-beta in fibroblast cells. SMP-534 inhibited TGF-beta-induced p38 mitogen-activated protein kinase (p38) activation but did not inhibit epidermal growth factor (EGF)-induced extracellular signal-related kinase (ERK) activation. We also found that oral administration of SMP-534 dose dependently lowered hydroxyproline contents in the cortical region of the kidney in rat anti-Thy-1 nephritis models. In periodic acid-Schiff staining of kidney sections, ECM accumulation was reduced by SMP-534 treatment. These data indicate that SMP-534 has potential in therapy for fibrotic diseases, including nephropathy.