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ABCC transporter inhibition reduces zymosan-induced peritonitis.

Abstract
Inflammatory mediators are released from injured tissues being responsible for the first steps of inflammatory processes. Multidrug efflux transporters, members of the ATP-binding cassette (ABC) family, are ubiquitously expressed. ABCC molecules transport several endogenous substances, including leukotriene C4 (LTC4) and PGE2, which are involved in zymosan-induced inflammation. The present study investigated the role played by ABCC transporters on zymosan-induced peritonitis in mice. Most of the resident peritoneal cells were macrophages, based on their morphology and membrane-activated complex 3 expression. RT-PCR demonstrated that these cells expressed ABCC, and ABCC activity was analyzed in vivo via the s.c. injection of ABCC inhibitors [probenecid (PROB) 200 mg/kg or MK571 20 mg/kg], followed by an i.v. injection of carboxyfluorescein diacetate (CFDA), an ABCC fluorescent substrate. Both inhibitors increased CFDA accumulation, suggesting ABCC impairment. Moreover, ABCC reversors decreased zymosan-induced plasma exudation by 86.6 +/- 7.4 and 97.6 +/- 2.3%, a feature related to a diminished secretion of LTC(4) (65.1+/-11 and 47.8+/-9.9%) and PGE(2) (under basal levels). Cell migration was inhibited similarly. Furthermore, PROB and MK571 inhibited IL-1ss by 83.4 +/- 13 and 71.2 +/- 13.4% and TNF-alpha content by 47 +/- 4.5 and 28.9 +/- 0.8%, respectively. NO metabolites and reactive oxygen species production were also reduced. The present results suggest that ABCC molecules have a relevant role in the acute inflammatory response produced by zymosan in mice.
AuthorsDaniela F P Leite, Juliana Echevarria-Lima, Samira Cardoso Ferreira, João B Calixto, Vivian M Rumjanek
JournalJournal of leukocyte biology (J Leukoc Biol) Vol. 82 Issue 3 Pg. 630-7 (Sep 2007) ISSN: 0741-5400 [Print] United States
PMID17576824 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, Differentiation
  • Bronchodilator Agents
  • Eicosanoids
  • Interleukin-1beta
  • Lipopolysaccharides
  • Multidrug Resistance-Associated Proteins
  • Propionates
  • Quinolines
  • Tumor Necrosis Factor-alpha
  • monocyte-macrophage differentiation antigen
  • verlukast
  • Zymosan
  • multidrug resistance-associated protein 1
Topics
  • Animals
  • Antigens, Differentiation (metabolism)
  • Bronchodilator Agents (pharmacology)
  • Cell Movement
  • Chemotaxis, Leukocyte
  • Edema (prevention & control)
  • Eicosanoids (antagonists & inhibitors, metabolism)
  • Inflammation
  • Interleukin-1beta (metabolism)
  • Lipopolysaccharides (pharmacology)
  • Luminescence
  • Macrophage Activation
  • Macrophages, Peritoneal (cytology, drug effects, metabolism)
  • Male
  • Mice
  • Monocytes (cytology, metabolism)
  • Multidrug Resistance-Associated Proteins (antagonists & inhibitors, genetics, metabolism)
  • Peritonitis (chemically induced, prevention & control)
  • Propionates (pharmacology)
  • Quinolines (pharmacology)
  • Respiratory Burst
  • Tumor Necrosis Factor-alpha (metabolism)
  • Zymosan (toxicity)

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