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J Thorac Cardiovasc Surg 2004;128:850-859
© 2004 The American Association for Thoracic Surgery

Cardiopulmonary Support And Physiology

Specific inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates vascular proliferation in monocrotaline-induced pulmonary hypertension in rats

^a Department of Thoracic and Cardiovascular Surgery, Mie University School of Medicine, Tsu, Japan
^b Division of Cardiothoracic Surgery, Department of Surgery, University of Washington School of Medicine, Seattle, Wash, USA

Received for publication December 17, 2003; revisions received February 18, 2004; accepted for publication March 3, 2004.

^* Address for reprints: Akira Shimamoto, MD, PhD, Division of Cardiothoracic Surgery, Department of Surgery, University of Washington School of Medicine, 1959 NE Pacific St, Box 356310, Seattle, WA 98195-6310, USA
jj6jdv{at}u.washington.edu

OBJECTIVES: 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 and interleukin 1ß were reduced in the MCT+FR group compared with in the MCT group (tumor necrosis factor : 1.18 ± 0.36 vs 3.05 ± 1.12 fold-increase, P < .05, at 2 weeks; interleukin 1ß: 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).

CONCLUSION: 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.

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