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Gießen, Germany

Shi H.-X.,Wenzhou Medical College | Lin C.,Wenzhou Medical College | Lin B.-B.,Wenzhou Medical College | Wang Z.-G.,Wenzhou Medical College | And 11 more authors.
PLoS ONE | Year: 2013

Hypertrophic scars (HTS) and keloids are challenging problems. Their pathogenesis results from an overproduction of fibroblasts and excessive deposition of collagen. Studies suggest a possible anti-scarring effect of basic fibroblast growth factor (bFGF) during wound healing, but the precise mechanisms of bFGF are still unclear. In view of this, we investigated the therapeutic effects of bFGF on HTS animal model as well as human scar fibroblasts (HSF) model. We show that bFGF promoted wound healing and reduced the area of flattened non-pathological scars in rat skin wounds and HTS in the rabbit ear. We provide evidence of a new therapeutic strategy: bFGF administration for the treatment of HTS. The scar elevation index (SEI) and epidermal thickness index (ETI) was also significantly reduced. Histological reveal that bFGF exhibited significant amelioration of the collagen tissue. bFGF regulated extracellular matrix (ECM) synthesis and degradation via interference in the collagen distribution, the α-smooth muscle actin (α-SMA) and transforming growth factor-1 (TGF-β1) expression. In addition, bFGF reduced scarring and promoted wound healing by inhibiting TGFβ1/SMAD-dependent pathway. The levels of fibronectin (FN), tissue inhibitor of metalloproteinase-1 (TIMP-1) collagen I, and collagen III were evidently decreased, and matrix metalloproteinase-1 (MMP-1) and apoptosis cells were markedly increased. These results suggest that bFGF possesses favorable therapeutic effects on hypertrophic scars in vitro and in vivo, which may be an effective cure for human hypertrophic scars. © 2013 Shi et al. Source


Klinke A.,University of Cologne | Moller A.,University of Hamburg | Pekarova M.,Academy of Sciences of the Czech Republic | Ravekes T.,University of Cologne | And 15 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2014

Pulmonary arterial hypertension (PAH) is characterized by adverse remodeling of pulmonary arteries. Although the origin of the disease and its underlying pathophysiology remain incompletely understood, inflammation has been identified as a central mediator of disease progression. Oxidative inflammatory conditions support the formation of electrophilic fatty acid nitroalkene derivatives, which exert potent anti-inflammatory effects. The current study investigated the role of 10-nitro-oleic acid (OA-NO2) in modulating the pathophysiology of PAH in mice. Mice were kept for 28 days under normoxic or hypoxic conditions, and OA-NO2 was infused subcutaneously. Right ventricular systolic pressure (RVPsys) was determined, and right ventricular and lung tissue was analyzed. The effect of OA-NO2 on cultured pulmonary artery smooth muscle cells (PASMCs) and macrophages was also investigated. Changes in RVPsys revealed increased pulmonary hypertension in mice on hypoxia, which was significantly decreased by OA-NO2 administration. Right ventricular hypertrophy and fibrosis were also attenuated by OA-NO2 treatment. The infiltration of macrophages and the generation of reactive oxygen species were elevated in lung tissue of mice on hypoxia and were diminished by OA-NO2 treatment. Moreover, OA-NO2 decreased superoxide production of activated macrophages and PASMCs in vitro. Vascular structural remodeling was also limited by OA-NO2. In support of these findings, proliferation and activation of extracellular signal-regulated kinases 1/2 in cultured PASMCs was less pronounced on application of OA-NO2. Our results show that the oleic acid nitroalkene derivative OA-NO2 attenuates hypoxia-induced pulmonary hypertension in mice. Thus, OA-NO 2 represents a potential therapeutic agent for the treatment of PAH. Copyright © 2014 by the American Thoracic Society. Source


Tuder R.M.,Aurora University | Archer S.L.,Queens University | Dorfmuller P.,University Paris - Sud | Erzurum S.C.,Cleveland Clinic | And 6 more authors.
Journal of the American College of Cardiology | Year: 2013

Knowledge of the pathobiology of pulmonary hypertension (PH) continues to accelerate. However, fundamental gaps remain in our understanding of the underlying pathological changes in pulmonary arteries and veins in the different forms of this syndrome. Although PH primarily affects the arteries, venous disease is increasingly recognized as an important entity. Moreover, prognosis in PH is determined largely by the status of the right ventricle, rather than the levels of pulmonary artery pressures. It is increasingly clear that although vasospasm plays a role, PH is an obstructive lung panvasculopathy. Disordered metabolism and mitochondrial structure, inflammation, and dysregulation of growth factors lead to a proliferative, apoptosis-resistant state. These abnormalities may be acquired, genetically mediated as a result of mutations in bone morphogenetic protein receptor-2 or activin-like kinase-1, or epigenetically inherited (as a result of epigenetic silencing of genes such as superoxide dismutase-2). There is a pressing need to better understand how the pathobiology leads to severe disease in some patients versus mild PH in others. Recent recognition of a potential role of acquired abnormalities of mitochondrial metabolism in the right ventricular myocytes and pulmonary vascular cells suggests new therapeutic approaches, diagnostic modalities, and biomarkers. Finally, dissection of the role of pulmonary inflammation in the initiation and promotion of PH has revealed a complex yet fascinating interplay with pulmonary vascular remodeling, promising to lead to novel therapeutics and diagnostics. Emerging concepts are also relevant to the pathobiology of PH, including a role for bone marrow and circulating progenitor cells and microribonucleic acids. Continued interest in the interface of the genetic basis of PH and cellular and molecular pathogenetic links should further expand our understanding of the disease. © 2013 by the American College of Cardiology Foundation. Published by Elsevier Inc. Source


Ishizaki T.,University of Fukui | Mizuno S.,Kanazawa Medical University | Sakai A.,Matsumoto University | Matsukawa S.,University of Fukui | And 8 more authors.
BioMed Research International | Year: 2015

Yaks have adapted to high altitude and they do not develop hypoxic pulmonary hypertension. Although we previously identified the important role of augmented nitric oxide synthase activity in the yak pulmonary circulatory system, evidence of the direct involvement of Rho-kinase as a basal vascular tone regulator is lacking. Four domesticated male pure-bred yaks and four bulls that were born and raised at an altitude of 3000 m in the Tien-Shan mountains were studied at an altitude of 3,100 m. Mean pulmonary artery pressure (mPAP) was measured before and after fasudil (60 mg in 20 mL of saline) was intravenously administered using a Swan-Ganz catheter at a rate of 3.3 mL/min for 30 min. Fasudil decreased mPAP in bulls from 67.8 ± 14.9 to 32.3 ± 5.3 mmHg (P < 0.05) after 15 min and the level was maintained for 30 min, but it merely blunted mPAP in yaks from 28.2 ± 4.5 to 25.1 ± 11.1 and 23.2 ± 2.7 mmHg after 5 and 30 min, respectively. These findings comprise the first evidence of a modest role of Rho-kinase in the maintenance of pulmonary artery pressure in the yak. © 2015 Takeshi Ishizaki et al. Source


Mikulski Z.,Universities of Giessen | Zaslona Z.,Universities of Giessen | Cakarova L.,Universities of Giessen | Hartmann P.,Universities of Giessen | And 4 more authors.
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2010

Serotonin (5-HT), known as neuromodulator, regulates immune responses and inflammatory cascades. The expression and function of 5-HT receptors on alveolar macrophages (AM), which are the major fraction of pulmonary immune cells, remain elusive. Therefore, we determined the expression of 5-HT type 2 receptors and investigated the effects evoked by stimulation with 5-HT in AM compared with alveolar epithelial cells (AEC). Quantitative PCR (qPCR) analysis revealed expression of the receptors 5-HT2A and 5-HT2B in AEC and of 5-HT2C in AM. In AM, 5-HT (10-5 M) induced a rise in intracellular calcium concentration ([Ca2+]i) that was initiated by release of Ca2+ from intracellular stores and depended on extracellular Ca2+ in a sustained phase. This 5-HT-induced increase in [Ca2+]i was not observed in AM treated with the 5-HT2C-selective inhibitor RS-102221 and in AM derived from 5-HT 2C-deficient mice. AM stimulated with 5-HT (10-5 M) showed increased expression of CCL2 (MCP-1) mRNA as assayed by qPCR at 4 h and augmented production of CCL2 protein as determined by dot-blot assay and ELISA at 24 h. Notably, in 5-HT2C-deficient AM, CCL2 production was not induced by 5-HT treatment. Moreover, transcriptional responses to 5-HT exposure assayed by microarray experiments were only observed in AM from wild-type animals and not in AM derived from 5-HT2C-deficient mice. Taken together, these data demonstrate the presence of functional 5-HT2C receptors on AM and suggest a role of 5-HT as novel modulator of AM function. These effects are exclusively driven by the 5-HT2C receptor, thereby providing the potential for selective intervention. Copyright © 2010 the American Physiological Society. Source

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