title: Effects of a dual inhibitor of tumor necrosis factor-alpha and interleukin-1 on lipopolysaccharide-induced lung injury in rats: involvement of the p38 mitogen-activated protein kinase pathway.
abstract: OBJECTIVE
  Sepsis is a major cause of adult respiratory distress syndrome. In this study, we evaluated the effect of FR167653, which is a potent suppressant of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 production, on lipopolysaccharide (LPS)-induced lung injury and lethality in rats, and we examined the involvement of p38 mitogen-activated protein (MAP) kinase in the action of FR167653.
  
  
  METHODS
  Prospective, randomized study.
  
  
  METHODS
  Animal research facility in a university.
  
  
  METHODS
  Male Sprague-Dawley rats weighing 200-270 g.
  
  
  METHODS
  All the animals were assigned to one of the following four groups: control group, FR-only group, LPS-only group, and LPS/FR group. Animals in the LPS-only and LPS/FR groups received 6 mg/kg of LPS intravenously. The animals in the FR-only and LPS/FR groups also received an infusion of FR167653 at 0.2 mg x kg(-1) x hr(-1), commencing 30 mins before the LPS (or vehicle) injection and continuing for 5.5 hrs.
  
  
  RESULTS
  LPS significantly induced the accumulation of pulmonary neutrophils and lung edema, both of which were significantly attenuated by treatment with FR167653. FR167653 also significantly decreased the LPS-induced lethality. Histologically, tissue damage was milder in the LPS/FR group than in the LPS-only group. Serum concentrations of TNF-alpha and IL-1beta and plasma concentrations of thromboxane B2 were all suppressed in the LPS/FR group compared with the LPS-only group. Western blot analysis revealed that FR167653 inhibited the phosphorylation of p38 MAP kinase in lung tissues.
  
  
  CONCLUSIONS
  FR167653 administration decreased serum TNF-alpha and IL-1beta concentrations, which was associated with decreased lung injury and lethality. The mechanism responsible for the decreased TNF-alpha and IL-1 may be related to the inhibitory effect of FR167653 on p38 MAP kinase activation.
authors.affiliation: Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Yoshinari
authors.forename: I
authors.initials: I
authors.lastname: Takeyoshi
authors.forename: Y
authors.initials: Y
authors.lastname: Koibuchi
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Y
authors.initials: Y
authors.lastname: Kawashima
authors.forename: T
authors.initials: T
authors.lastname: Koyama
authors.forename: S
authors.initials: S
authors.lastname: Ohwada
authors.forename: Y
authors.initials: Y
authors.lastname: Morishita
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000150:complications*; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides; D008168:Lung / Q000737:chemistry; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000187:drug effects*; D011446:Prospective Studies; D011720:Pyrazoles / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D011725:Pyridines / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000401:mortality; D016019:Survival Analysis; D013929:Thromboxane B2 / Q000097:blood; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C104334:FR 167653; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D013929:Thromboxane B2; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases