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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.

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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.