title: Indomethacin-induced small intestinal injury is ameliorated by cilostazol, a specific PDE-3 inhibitor.
abstract: BACKGROUND
  Neutrophil migration, one of the major factors predisposing to nonsteroidal anti-inflammatory drugs (NSAIDs)-induced intestinal lesions, consists of several steps, including interaction with P-selectin from platelets. Cilostazol, a specific phosphodiesterase (PDE)-3 inhibitor, suppresses the expression of P-selectin from platelets and reduces interaction between platelets and leukocytes, leading to inflammatory amelioration in several disease models. We tried to clarify the therapeutic effectiveness of cilostazol for NSAID-induced small intestinal lesions.
  
  
  METHODS
  1) Anti-PSGL-1 antibody (2 mg/kg) or cilostazol (100 mg/kg) was administered to mice one hour before Indomethacin (IND, 2.5 mg/kg) administration for 4 days to evaluate small intestinal lesions. 2) IND-induced migratory behaviors of neutrophils and platelets were evaluated in intestinal vessels by an intravital microscopy.
  
  
  RESULTS
  i) IND induced small intestinal lesions with an increase in MPO activity. Anti-PSGL-1 antibody and cilostazol ameliorated intestinal lesions along with suppression of MPO activity. ii) Intravital microscopy revealed that administration of IND increased migration of platelet-bearing neutrophils. Cilostazol treatment ameliorated neutrophil migration by blocking interaction between platelets and neutrophils.
  
  
  CONCLUSIONS
  Our results suggest that enhanced platelets-bearing neutrophil migration is critically involved in the pathogenesis of IND-induced small intestinal lesions and suggest a potential application of cilostazol for prevention of NSAID-induced small intestinal lesions.
authors.affiliation: Department of Internal Medicine, National Defense Medical College, Saitama, Japan. higashiyamala@gmail.com
authors.forename: Masaaki
authors.initials: M
authors.lastname: Higashiyama
authors.forename: Ryota
authors.initials: R
authors.lastname: Hokari
authors.forename: Chie
authors.initials: C
authors.lastname: Kurihara
authors.forename: Toshihide
authors.initials: T
authors.lastname: Ueda
authors.forename: Chikako
authors.initials: C
authors.lastname: Watanabe
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Komoto
authors.forename: Yoshikiyo
authors.initials: Y
authors.lastname: Okada
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawaguchi
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nagao
authors.forename: Soichiro
authors.initials: S
authors.lastname: Miura
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D002450:Cell Communication; D002465:Cell Movement / Q000187:drug effects; D000077407:Cilostazol; D007077:Ileal Diseases / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D007082:Ileum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D007213:Indomethacin / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D018709:Statistics, Nonparametric; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D009195:Peroxidase; D000077407:Cilostazol; D007213:Indomethacin