title: Specific inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates vascular proliferation in monocrotaline-induced pulmonary hypertension in rats.
abstract: OBJECTIVE
  p38 mitogen-activated protein kinase is associated with many clinical entities characterized by inflammation. We postulated that inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates inflammation and the development of pulmonary hypertension in monocrotaline-treated rats.
  
  
  METHODS
  Rats were divided into 4 groups: (1) the control group (daily 0.9% saline), (2) the FR group (daily FR167653, 2 mg . kg(-1) . d(-1)), (3) the MCT group (daily 0.9% saline the day after a single monocrotaline dose, 60 mg/kg), and (4) the MCT+FR group (daily FR167653, 2 mg . kg(-1) . d(-1), the day after a single MCT dose). Body weight, pulmonary artery pressure, and morphometric changes of the pulmonary artery with the histopathologic method were observed weekly for 4 weeks. Also, p38 mitogen-activated protein kinase activity and inflammatory cytokine expression in the lung were measured.
  
  
  RESULTS
  Four weeks after monocrotaline administration, mean pulmonary artery pressure in the MCT+FR group was lower than in the MCT group (MCT+FR vs MCT: 24.7 +/- 1.9 vs 36.5 +/- 2.1 mm Hg; P < .05). In morphometric analysis the percentage of medial wall thickness and the percentage of muscularization in the MCT+FR group were reduced compared with those in the MCT group after 4 weeks (P < .05); however, the number of macrophages was not significantly different. p38 mitogen-activated protein kinase activity was significantly attenuated in the MCT+FR group compared with in the MCT group (7.2 +/- 0.52 vs 2.1 +/- 0.23 fold-increase, P < .05, at 1 week). Although mRNA levels of tumor necrosis factor alpha and interleukin 1beta were reduced in the MCT+FR group compared with in the MCT group (tumor necrosis factor alpha: 1.18 +/- 0.36 vs 3.05 +/- 1.12 fold-increase, P < .05, at 2 weeks; interleukin 1beta: 2.2 +/- 0.34 vs 4.4 +/- 1.09 fold-increase, P < .05, at 1 week), FR167653 did not suppress increased monocyte chemotactic protein 1 mRNA expression induced by monocrotaline (3.2 +/- 0.62 vs 3.1 +/- 0.42 fold-increase, at 1 week).
  
  
  CONCLUSIONS
  FR167653 significantly attenuates the expression of inflammatory cytokines, ultimately preventing the progression of pulmonary hypertension. These results suggest that p38 mitogen-activated protein kinase might play a central role in the molecular events that underlie the development and progression of pulmonary hypertension.
authors.affiliation: Departmrent of Thoracic and Cardiovascular Surgery, Mie University School of Medicine, Tsu, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Hideto
authors.initials: H
authors.lastname: Shimpo
authors.forename: Akira
authors.initials: A
authors.lastname: Shimamoto
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Chong
authors.forename: Craig R
authors.initials: CR
authors.lastname: Hampton
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Spring
authors.forename: Masaki
authors.initials: M
authors.lastname: Yada
authors.forename: Motoshi
authors.initials: M
authors.lastname: Takao
authors.forename: Koji
authors.initials: K
authors.lastname: Onoda
authors.forename: Isao
authors.initials: I
authors.lastname: Yada
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Pohlman
authors.forename: Edward D
authors.initials: ED
authors.lastname: Verrier
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology; D007150:Immunohistochemistry; D008168:Lung / Q000166:cytology; D008297:Male; D016686:Monocrotaline; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; C104334:FR 167653; D011720:Pyrazoles; D011725:Pyridines; D016686:Monocrotaline; D048051:p38 Mitogen-Activated Protein Kinases