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

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Manuel J. Antunes, MD, PhD, DSc

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Presentation transcript:

Specific inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates vascular proliferation in monocrotaline-induced pulmonary hypertension in rats Jun Lu, MD, Hideto Shimpo, MD, PhD, Akira Shimamoto, MD, PhD, Albert J. Chong, MD, Craig R. Hampton, MD, Denise J. Spring, MD, Masaki Yada, MD, PhD, Motoshi Takao, MD, PhD, Koji Onoda, MD, PhD, Isao Yada, MD, PhD, Timothy H. Pohlman, MD, Edward D. Verrier, MD The Journal of Thoracic and Cardiovascular Surgery Volume 128, Issue 6, Pages 850-859 (December 2004) DOI: 10.1016/j.jtcvs.2004.03.003

Figure 1 Effects of FR167653 on hemodynamic assessments in rats with MCT-induced PH. Shown are measurements of percentage BW gain (%BWG; A), mean PAP (B), and RV/(LV+S) ratio as RVH (C) in the control, FR, MCT, and MCT+FR groups at 4 weeks after MCT or saline administration. Values represent means ± SD of 5 animals: *P < .05 versus control group at 4 weeks; †P < .05 versus MCT group at 4 weeks. The Journal of Thoracic and Cardiovascular Surgery 2004 128, 850-859DOI: (10.1016/j.jtcvs.2004.03.003)

Figure 2 Effects of FR167653 on morphometric analysis of PA in rats with MCT-induced PH. Shown are histopathologic findings of PAs with external diameters of less than 50 μm and greater than 101 μm (elastica van Gieson, original magnification 400×; A); measurements of percentage of medial wall thickness of muscular PA (%MWT) with external diameters of less than 50 μm, 51 to 100 μm, and greater than 101 μm (B); and percentage of muscularized PA (% Muscularization) in normally nonmuscular peripheral PA at the alveolar duct and alveolar wall levels (C) in the control, FR, MCT, and MCT+FR groups at 4 weeks after MCT administration. Values represent means ± SD of 4 animals: *P < .05 versus period-matched control animals; †P < .05 versus period-matched MCT-treated animals. The Journal of Thoracic and Cardiovascular Surgery 2004 128, 850-859DOI: (10.1016/j.jtcvs.2004.03.003)

Figure 3 Effects of FR167653 on p38 MAPK activity in the lungs of rats with MCT-induced PH: A, Western blotting analysis of phospho-ATF-2 expression after immunoprecipitation and kinase assay as p38 MAPK activity; B, p38 MAPK activities denoted as fold activation over those of a period-matched control animal. Values represent means ± SD of 8 animals: *P < .01 versus period-matched control animals; †P < .05 versus period-matched MCT-treated animals. The Journal of Thoracic and Cardiovascular Surgery 2004 128, 850-859DOI: (10.1016/j.jtcvs.2004.03.003)

Figure 4 Immunohistochemical analyses for phospho-p38 MAPK localization (dark brown) in large and small PAs at 1 week after initial treatment (A; original magnification 400×). High-power resolution in small (B) and large (C) PAs in MCT-treated rats (original magnification 800×). Phospho-p38 MAPK–positive macrophages surrounding the intra-acinar PA in MCT-treated rats. PA, Pulmonary artery; Br, bronchiole. The Journal of Thoracic and Cardiovascular Surgery 2004 128, 850-859DOI: (10.1016/j.jtcvs.2004.03.003)

Figure 5 Effects of FR167653 on quantitative reverse transcriptase–polymerase chain reaction analysis of TNF-α (A), IL-1β (B), and MCP-1 (C) mRNA in the lungs of rats with MCT-induced PH. The vertical axis denotes a fold increase over values in period-matched control animals after the amount of mRNA for each cytokine was normalized to that of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA. Values represent means ± SD of 8 animals: *P < .05 versus period-matched control animals; †P < .05 versus period-matched MCT-treated animals. The Journal of Thoracic and Cardiovascular Surgery 2004 128, 850-859DOI: (10.1016/j.jtcvs.2004.03.003)

Figure 6 Effects of FR167653 on numbers of interstitial macrophages in the lungs of rats with MCT-induced PH. Values represent means ± SD of 8 animals: *P < .05 versus period-matched control animals. The Journal of Thoracic and Cardiovascular Surgery 2004 128, 850-859DOI: (10.1016/j.jtcvs.2004.03.003)