title: Pretreatment with olprinone hydrochloride, a phosphodiesterase III inhibitor, attenuates lipopolysaccharide-induced lung injury via an anti-inflammatory effect.
abstract: OBJECTIVE
  Acute respiratory distress syndrome is characterized by neutrophil accumulation in the lungs and the activation of several cytokines produced by macrophages. Olprinone hydrochloride, a specific phosphodiesterase III inhibitor, has anti-inflammatory effects and inhibits the activation of macrophages, in addition to its inotropic and vasodilatory effects. The purpose of this study was to examine the beneficial effects of olprinone on lipopolysaccharide (LPS)-induced pulmonary inflammation.
  
  
  METHODS
  Lung inflammation was produced by intravenous LPS injection into rats. The rats were divided into four groups: a vehicle group in which normal saline was injected, an olprinone group in which olprinone was injected at a dose of 0.2mg/kg, a dexamethasone group in which dexamethasone was injected at a dose of 5mg/kg, and a control group. In each group, drug was injected intraperitoneally 30 min before the intravenous administration of LPS. The blood was obtained at 1h and then animals were sacrificed at 6h and blood and lung specimen were obtained for cytokine analysis and pathological examination. On another set of experiment, bronchioloalveolar lavage (BAL) was performed for cytokine analysis of BAL fluid. The macrophages isolated from normal rat by BAL were cultured in vitro with the presence of LPS and olprinone or dexamethasone, and supernatant was collected. The levels of several cytokines in the serum, in the BAL fluid, and in the culture supernatant were determined.
  
  
  RESULTS
  The animals injected with LPS were found to have an influx of neutrophils in the lungs, and inflammatory cytokines, such as TNF-alpha and IL-6, and anti-inflammatory cytokine IL-10 were produced. Pretreatment with olprinone or dexamethasone significantly inhibited the LPS-induced neutrophil influx into the lungs, suppressed inflammatory cytokines TNF-alpha and IL-6. The level of anti-inflammatory cytokine IL-10 increased in an olprinone group. The inhibition of TNF-alpha and IL-6, and the augmentation of IL-10 release were also observed in in vitro culture of isolated rat alveolar macrophages when olprinone (10(-5)mol/ml) and LPS (10 microg/ml) were cultured together. However, the level of IL-10 in serum and culture supernatant was suppressed in a dexamesathone group.
  
  
  CONCLUSIONS
  LPS-induced lung inflammation is strongly inhibited by olprinone accompanying the enhancement of IL-10 and the inhibition of inflammatory cytokines. Results of the in vitro experiment suggest that alveolar macrophages may play an important role in ameliorating LPS-induced lung inflammation and the mechanism of its effect is different from that of steroid.
authors: Division of Thoracic and Cardiovascular Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata 951-8510, Japan.
authors: Terumoto
authors: T
authors: Koike
authors: Muhammad
authors: M
authors: Nadeen Qutab
authors: Masanori
authors: M
authors: Tsuchida
authors: Masaru
authors: M
authors: Takekubo
authors: Masayuki
authors: M
authors: Saito
authors: Jun-ichi
authors: J
authors: Hayashi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018929:Cell Culture Techniques; D003907:Dexamethasone / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D058987:Phosphodiesterase 3 Inhibitors; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012128:Respiratory Distress Syndrome / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D058987:Phosphodiesterase 3 Inhibitors; D011728:Pyridones; C059498:olprinone; D003907:Dexamethasone