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Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been shown to ameliorate a number of vascular diseases. We evaluated the inflammatory and angiogenic components of the fibrovascular tissue induced by subcutaneous implants in mice and their modulation by fluvastatin. Our results showed that the statin (0.6 and 6 mg/kg/day) inhibited hemoglobin (Hb) content (51%) and vascular endothelial growth factor (VEGF) levels (71%) in the treated group compared with the control group. The inflammatory component, as assessed by N-acetyl-β-D-glucosaminidase activity and tumor necrosis factor-α (TNF-α) level was also decreased by the compound. In the treated group; the inhibition of the enzyme activity was 33% and the cytokine was 67% relative to the control. In these implants the statin was also able to decrease nitric oxide (NO) production, detected with an NO-sensitive electrode. To our knowledge this is the first study demonstrating an inhibitory role of fluvastatin on the production of NO in inflammatory angiogenesis of newly formed fibrovascular tissue., (© 2012 The Authors APMIS © 2012 APMIS.)

1. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitors, exert anti-inflammatory, anti-oxidant and anti-angiogenic effects. These effects are associated with downregulation of pro-inflammatory/pro-angiogenic molecules and upregulation of endothelial nitric oxide synthase (e-NOS) expression/nitric oxide (NO) production. 2. Using the murine sponge model to induce chronic intraperitoneal inflammatory response, we evaluated the inflammatory components, angiogenic and NO production of the fibrovascular tissue, and their modulation by fluvastatin. 3. Our results showed that fluvastatin (0.6 and 6 mg/kg per day) inhibited haemoglobin (Hb) content 4.9±0.4 (n=15; control) vs 2.2±0.2 (n=6; fluvastatin 0.6) and 1.8±0.2 (n=6; fluvastatin 6.0) and the number of vessels in the treated group when compared with the control group. The inflammatory component, as assessed by myeloperoxidase and N-acetyl-β-d-glucosaminidase activities and by the pro-inflammatory cytokines, tumour necrosis factor-α (TNF-α) and Monocyte chemotactic protein-1 (MCP-1)/CCL2/JE levels, was also decreased by the compound. In the treated group, inhibition of both enzyme activities was 54% and 57%, respectively. The levels of the cytokines (TNF-α and CCL2/JE) intra-implant were decreased relative to the control. In these implants, fluvastatin was also able to increase NO production, as detected with an NO-sensitive electrode. 4. The inhibitory function of fluvastatin on key components of intraperitoneal inflammatory angiogenesis shown in the present study is clearly associated with the modulatory effects of this statin on vascular endothelial growth factor, TNF-α and NO production., (© 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.)

To investigate the effects of metformin on angiogenesis, on inflammatory cell accumulation and on production of endogenous cytokines in sponge implant in mice. Polyester-polyurethane sponges were implanted in Swiss mice and metformin (40 or 400mg/kg/day) was given orally for six days. The implants collected at day 7 postimplantation were processed for the assessment of hemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) e collagen used as indexes for angiogenesis, neutrophil and macrophage accumulation and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic and fibrogenic cytokines were also determined. Metformin treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition and the levels of transforming growth factor (TGF-beta1) intraimplant. A regulatory function of metformin on multiple parameters of main components of inflammatory angiogenesis has been revealed giving insight into the potential therapeutic underlying the actions of metformin., (Copyright (c) 2009. Published by Elsevier SAS.)

While compelling evidence indicates beneficial effects of statins on inflammatory processes, besides their cholesterol-lowering activities, the actions on angiogenesis are less clear-cut. Our aim was to investigate the effects of atorvastatin on key components of inflammatory angiogenesis in the murine sponge model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss mice. Atorvastatin (0.6, 3 mg/kg/day) was given orally for 8 days in drinking water. The implants collected at day 9 postimplantation were processed for the assessment of hemoglobin, myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) and collagen. Relevant inflammatory, angiogenic and fibrogenic cytokines were also determined. Atorvastatin treatment resulted in significant decrease in sponge vascularization (Hb content) and in VEGF levels at both doses. Neutrophil influx (MPO activity) was not affected by the compound whereas macrophage recruitment (NAG activity) was inhibited, suggesting a degree of selectivity by atorvastatin for this cell population. The level of CCL2 (MCP1-JE) was decreased only with 0.6 mg/kg. Atorvastatin was also able to reduce collagen deposition and the levels of transforming growth factor (TGF-beta1) intraimplant, dose-dependently. The inhibitory function of atorvastatin on multiple parameters of main components of inflammatory angiogenesis revealed in this study is clearly associated with the modulatory effects of HMG-CoA reductase on VEGF, TNF-alpha and TGF-beta1 production., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

The specific PDE4 inhibitor (rolipram) has been shown to attenuate excessive accumulation/activation of inflammatory cells and fibroblasts and cytokine production in several pathological conditions through cyclic nucleotide modulation. Here, using the murine sponge model to induce chronic subcutaneous inflammatory response and to elicit the formation of intraperitoneal adhesions we explored the hypothesis that rolipram would exert beneficial effects on decreasing key components of both processes (inflammatory cell recruitment, angiogenesis, and deposition of extracellular matrix component). Two doses of rolipram (0.2 or 2 mg/kg/day) were administered orally for 7 days in groups of mice bearing either subcutaneous or intraperitoneal polyether-polyurethane implants. Rolipram was effective in inhibiting angiogenesis as assessed by hemoglobin content and VEGF levels in subcutaneous implants (about 40% with both doses) but failed to exert this activity in intraperitoneal implants. Conversely, accumulation of neutrophils and macrophages determined by measuring myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) activities intraimplant, respectively, was attenuated only in intraperitoneal implants by the treatment. Levels of TNF-alpha and MCP-1 were also determined and rolipram at both doses decreased the production of both cytokines in intraperitoneal implants. The levels of MCP-1 in the subcutaneous implants were not affected by the treatment. Fibrosis was evaluated by determining the amount of collagen and production of TGF-beta1 intraimplant. Both parameters were attenuated by rolipram. These results have shown differential sensitivity of proliferating tissues to PDE4 inhibitor indicating that this agent may be used to target inflammatory angiogenesis selectively.

Aims: Adhesion formation following abdominal intervention is an abnormal peritoneal healing process. Our aim was to investigate the effects of controlling adhesion development by inhibiting its key components (angiogenesis, inflammation and fibrosis) using phosphodiesterase (PDE) inhibitors., Main Methods: Two PDE inhibitors including cilostazol a PDE3 inhibitor (40 and 400 mg/kg), and pentoxifylline (PTX), a PDE 1-5 inhibitor (50 and 500 mg/kg) were used for a period of 7 days to inhibit angiogenesis, inflammation, and fibrosis in a murine model of sponge-induced peritoneal adhesion. Angiogenesis was assessed by hemoglobin content, vascular endothelial growth factor (VEGF) levels, and morphometric analysis. Accumulation of neutrophils and macrophages was determined by measuring myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) activities, respectively. Levels of TNF-alpha were also determined. Fibrosis was assessed by determining the amount of collagen in the implant; TGF-beta1 levels in the implant were also measured., Key Findings: Our results show that the treatments attenuated the main components of the adhesion tissue by reducing the amount of fibrovascular tissue that infiltrated the sponge matrix (wet weight). Hemoglobin content and VEGF levels were also decreased by approximately 40%. Neutrophil accumulation was unaffected by the compounds. However, NAG activity was reduced by pentoxifylline, but not by cilostazol. These compounds also decreased the levels of the pro-inflammatory and pro-fibrogenic cytokines TNF-alpha and TGF-beta1, respectively, and collagen synthesis., Significance: Our results suggest that cilostazol and PTX decreased the development of peritoneal adhesions in the model, which might be associated with cyclic nucleotide modulation. Therapies to intervene in these pathways may be beneficial for the prevention of these lesions.