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Cilostazol and pentoxifylline decrease angiogenesis, inflammation, and fibrosis in sponge-induced intraperitoneal
Juliana Barros Mendes1, Paula Peixoto Campos, Monaliza Angela Rocha
1Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte/MG, Brazil, Av. Antônio Carlos 6627; Campus Pampulha, CEP: 31270-901; Cx Post 486, Brazil.
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.
Insights
Phosphodiesterase (PDE) inhibitors, cilostazol and pentoxifylline, reduced peritoneal adhesion development in a murine model by inhibiting key components like angiogenesis and fibrosis. These findings suggest potential therapeutic benefits for preventing adhesions.
Area of Science:
- Peritoneal healing
- Inflammation and fibrosis research
- Vascular biology
Background:
- Abdominal surgery can lead to abnormal peritoneal healing, forming adhesions.
- Adhesion formation involves complex processes including angiogenesis, inflammation, and fibrosis.
- Current therapeutic strategies for adhesion prevention are limited.
Purpose of the Study:
- To investigate the efficacy of phosphodiesterase (PDE) inhibitors in controlling peritoneal adhesion development.
- To assess the impact of PDE inhibitors on key adhesion components: angiogenesis, inflammation, and fibrosis.
Main Methods:
- A murine model of sponge-induced peritoneal adhesion was utilized.
- Two PDE inhibitors, cilostazol (PDE3) and pentoxifylline (PDE 1-5), were administered for 7 days.
- Assays included hemoglobin content, VEGF, MPO, NAG, TNF-alpha, TGF-beta1, and collagen levels to evaluate angiogenesis, inflammation, and fibrosis.
Main Results:
- Both cilostazol and pentoxifylline significantly reduced fibrovascular tissue, hemoglobin, and VEGF levels, indicating inhibition of angiogenesis.
- Pentoxifylline, but not cilostazol, reduced neutrophil-associated NAG activity.
- Both compounds decreased pro-inflammatory (TNF-alpha) and pro-fibrogenic (TGF-beta1) cytokines, and collagen synthesis.
Conclusions:
- Cilostazol and pentoxifylline demonstrated efficacy in decreasing peritoneal adhesion development in a murine model.
- The anti-adhesion effects are likely linked to cyclic nucleotide modulation via PDE inhibition.
- Targeting these pathways with PDE inhibitors may offer a novel therapeutic approach for preventing peritoneal adhesions.
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