Cilostazol and pentoxifylline decrease angiogenesis, inflammation, and fibrosis in sponge-induced intraperitoneal adhesion in mice.
OBJECTIVE
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.


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.


RESULTS
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.


CONCLUSIONS
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.
Mendes
Juliana Barros
JB
Department 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.
Campos
Paula Peixoto
PP
Rocha
Monaliza Angela
MA
Andrade
Silvia Passos
SP
D000818:Animals; D000077407:Cilostazol; D004195:Disease Models, Animal; D005355:Fibrosis / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D010431:Pentoxifylline / Q000008:administration & dosage / Q000627:therapeutic use*; D010537:Peritoneum / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D015503:Surgical Sponges; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D000267:Tissue Adhesions / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000276:immunology / Q000473:pathology
D010726:Phosphodiesterase Inhibitors; D013777:Tetrazoles; D000077407:Cilostazol; D010431:Pentoxifylline