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The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension.

Church AC, Martin DH, Wadsworth R, Bryson G, Fisher AJ, Welsh DJ, Peacock AJ - Am. J. Physiol. Lung Cell Mol. Physiol. (2015)

Bottom Line: Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod).Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod.This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6.

View Article: PubMed Central - PubMed

Affiliation: Scottish Pulmonary Vascular Unit, University of Glasgow, Glasgow, United Kingdom; colinchurch@nhs.net.

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Related in: MedlinePlus

PH in a reversal strategy in 2 in vivo animal models by administration of PH-797804, a more selective p38 MAPKα inhibitor. A and B: animals were exposed to CH and after 2 wk p38 MAPK inhibition was commenced with daily injections. Hemodynamics and RV hypertrophy (RVH) were measured after 4 wk. Data represent mean values ± SE. *P < 0.05; **P < 0.01 for A. **P < 0.01; ***P < 0.001, for B. C: the lungs were removed after experiment and sections (5 mm) were cut. These were stained with α-smooth muscle actin and the vessels <80 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as completely, partially, or nonmuscularized. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. **P < 0.01; ■P < 0.05 for complete muscularized group in drug-treated vs. day 14 hypoxic control. D: lungs were removed after experiment and sections (5 mm) cut. These were stained with α-smooth muscle actin and the vessels <100 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as muscularized or nonmuscularized and the percentage of muscularized vessels calculated. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. ****P < 0.0001; ■P < 0.05 for hypoxic drug-treated vs. day 14 hypoxic control. E and F: animals were injected with MCT and after 2 wk p38 MAPK inhibition was commenced with daily injections. Hemodynamics and RVH were measured after 4 wk. Data represent mean values ± SE. Total animals n = 14–15 per group. ***P < 0.001 for E. *P < 0.05; **P < 0.01 for F. G: the lungs were removed after experiment and sections (5 mm) cut. These were stained with α-smooth muscle actin and the vessels <80 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as completely, partially or nonmuscularized. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. **P < 0.01; ■P < 0.05, for complete muscularized group in drug-treated vs. day 14 hypoxic control. H: lungs were removed after experiment and sections (5 mm) cut. These were stained with α-smooth muscle actin, and the vessels <100 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as muscularized or nonmuscularized, and the percentage of muscularized vessels was calculated. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. ****P < 0.0001; ■P < 0.05 for drug-treated vs. day 14 MCT control.
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Figure 5: PH in a reversal strategy in 2 in vivo animal models by administration of PH-797804, a more selective p38 MAPKα inhibitor. A and B: animals were exposed to CH and after 2 wk p38 MAPK inhibition was commenced with daily injections. Hemodynamics and RV hypertrophy (RVH) were measured after 4 wk. Data represent mean values ± SE. *P < 0.05; **P < 0.01 for A. **P < 0.01; ***P < 0.001, for B. C: the lungs were removed after experiment and sections (5 mm) were cut. These were stained with α-smooth muscle actin and the vessels <80 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as completely, partially, or nonmuscularized. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. **P < 0.01; ■P < 0.05 for complete muscularized group in drug-treated vs. day 14 hypoxic control. D: lungs were removed after experiment and sections (5 mm) cut. These were stained with α-smooth muscle actin and the vessels <100 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as muscularized or nonmuscularized and the percentage of muscularized vessels calculated. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. ****P < 0.0001; ■P < 0.05 for hypoxic drug-treated vs. day 14 hypoxic control. E and F: animals were injected with MCT and after 2 wk p38 MAPK inhibition was commenced with daily injections. Hemodynamics and RVH were measured after 4 wk. Data represent mean values ± SE. Total animals n = 14–15 per group. ***P < 0.001 for E. *P < 0.05; **P < 0.01 for F. G: the lungs were removed after experiment and sections (5 mm) cut. These were stained with α-smooth muscle actin and the vessels <80 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as completely, partially or nonmuscularized. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. **P < 0.01; ■P < 0.05, for complete muscularized group in drug-treated vs. day 14 hypoxic control. H: lungs were removed after experiment and sections (5 mm) cut. These were stained with α-smooth muscle actin, and the vessels <100 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as muscularized or nonmuscularized, and the percentage of muscularized vessels was calculated. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. ****P < 0.0001; ■P < 0.05 for drug-treated vs. day 14 MCT control.

Mentions: We adopted a reversal strategy whereby the animals were treated daily intraperitoneal injections of PH-797804 after 2 wk of chronic hypoxia. Similar to the study with SB203580 we found a significant reduction in the RVSP in the drug-treated animals after 2 wk of treatment (Fig. 5A) accompanied by a marked reduction in the degree of RVH compared with both 14- and 28-day time points (Fig. 5B), with no change in hematocrit (data not shown). The pulmonary vascular muscularization was reversed in the drug-treated group compared with the 28-day animal untreated group (Fig. 5, C and D). Systemic BP remained unchanged. (data not shown).


The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension.

Church AC, Martin DH, Wadsworth R, Bryson G, Fisher AJ, Welsh DJ, Peacock AJ - Am. J. Physiol. Lung Cell Mol. Physiol. (2015)

PH in a reversal strategy in 2 in vivo animal models by administration of PH-797804, a more selective p38 MAPKα inhibitor. A and B: animals were exposed to CH and after 2 wk p38 MAPK inhibition was commenced with daily injections. Hemodynamics and RV hypertrophy (RVH) were measured after 4 wk. Data represent mean values ± SE. *P < 0.05; **P < 0.01 for A. **P < 0.01; ***P < 0.001, for B. C: the lungs were removed after experiment and sections (5 mm) were cut. These were stained with α-smooth muscle actin and the vessels <80 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as completely, partially, or nonmuscularized. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. **P < 0.01; ■P < 0.05 for complete muscularized group in drug-treated vs. day 14 hypoxic control. D: lungs were removed after experiment and sections (5 mm) cut. These were stained with α-smooth muscle actin and the vessels <100 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as muscularized or nonmuscularized and the percentage of muscularized vessels calculated. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. ****P < 0.0001; ■P < 0.05 for hypoxic drug-treated vs. day 14 hypoxic control. E and F: animals were injected with MCT and after 2 wk p38 MAPK inhibition was commenced with daily injections. Hemodynamics and RVH were measured after 4 wk. Data represent mean values ± SE. Total animals n = 14–15 per group. ***P < 0.001 for E. *P < 0.05; **P < 0.01 for F. G: the lungs were removed after experiment and sections (5 mm) cut. These were stained with α-smooth muscle actin and the vessels <80 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as completely, partially or nonmuscularized. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. **P < 0.01; ■P < 0.05, for complete muscularized group in drug-treated vs. day 14 hypoxic control. H: lungs were removed after experiment and sections (5 mm) cut. These were stained with α-smooth muscle actin, and the vessels <100 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as muscularized or nonmuscularized, and the percentage of muscularized vessels was calculated. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. ****P < 0.0001; ■P < 0.05 for drug-treated vs. day 14 MCT control.
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Figure 5: PH in a reversal strategy in 2 in vivo animal models by administration of PH-797804, a more selective p38 MAPKα inhibitor. A and B: animals were exposed to CH and after 2 wk p38 MAPK inhibition was commenced with daily injections. Hemodynamics and RV hypertrophy (RVH) were measured after 4 wk. Data represent mean values ± SE. *P < 0.05; **P < 0.01 for A. **P < 0.01; ***P < 0.001, for B. C: the lungs were removed after experiment and sections (5 mm) were cut. These were stained with α-smooth muscle actin and the vessels <80 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as completely, partially, or nonmuscularized. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. **P < 0.01; ■P < 0.05 for complete muscularized group in drug-treated vs. day 14 hypoxic control. D: lungs were removed after experiment and sections (5 mm) cut. These were stained with α-smooth muscle actin and the vessels <100 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as muscularized or nonmuscularized and the percentage of muscularized vessels calculated. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. ****P < 0.0001; ■P < 0.05 for hypoxic drug-treated vs. day 14 hypoxic control. E and F: animals were injected with MCT and after 2 wk p38 MAPK inhibition was commenced with daily injections. Hemodynamics and RVH were measured after 4 wk. Data represent mean values ± SE. Total animals n = 14–15 per group. ***P < 0.001 for E. *P < 0.05; **P < 0.01 for F. G: the lungs were removed after experiment and sections (5 mm) cut. These were stained with α-smooth muscle actin and the vessels <80 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as completely, partially or nonmuscularized. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. **P < 0.01; ■P < 0.05, for complete muscularized group in drug-treated vs. day 14 hypoxic control. H: lungs were removed after experiment and sections (5 mm) cut. These were stained with α-smooth muscle actin, and the vessels <100 mm were analyzed for degree of muscularization. Five to 10 random fields (×40) were analyzed with 3 slides per animal. The vessels were categorized as muscularized or nonmuscularized, and the percentage of muscularized vessels was calculated. Groups analyzed by ANOVA for overall change with posttest analysis; n = 10 animals. ****P < 0.0001; ■P < 0.05 for drug-treated vs. day 14 MCT control.
Mentions: We adopted a reversal strategy whereby the animals were treated daily intraperitoneal injections of PH-797804 after 2 wk of chronic hypoxia. Similar to the study with SB203580 we found a significant reduction in the RVSP in the drug-treated animals after 2 wk of treatment (Fig. 5A) accompanied by a marked reduction in the degree of RVH compared with both 14- and 28-day time points (Fig. 5B), with no change in hematocrit (data not shown). The pulmonary vascular muscularization was reversed in the drug-treated group compared with the 28-day animal untreated group (Fig. 5, C and D). Systemic BP remained unchanged. (data not shown).

Bottom Line: Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod).Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod.This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6.

View Article: PubMed Central - PubMed

Affiliation: Scottish Pulmonary Vascular Unit, University of Glasgow, Glasgow, United Kingdom; colinchurch@nhs.net.

Show MeSH
Related in: MedlinePlus