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Potential contribution of phenotypically modulated smooth muscle cells and related inflammation in the development of experimental obstructive pulmonary vasculopathy in rats.

Otsuki S, Sawada H, Yodoya N, Shinohara T, Kato T, Ohashi H, Zhang E, Imanaka-Yoshida K, Shimpo H, Maruyama K, Komada Y, Mitani Y - PLoS ONE (2015)

Bottom Line: Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages.Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals.We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

ABSTRACT
We tested the hypothesis that phenotypically modulated smooth muscle cells (SMCs) and related inflammation are associated with the progression of experimental occlusive pulmonary vascular disease (PVD). Occlusive PVD was induced by combined exposure to a vascular endothelial growth factor receptor tyrosine kinase inhibitor Sugen 5416 and hypobaric hypoxia for 3 weeks in rats, which were then returned to ambient air. Hemodynamic, morphometric, and immunohistochemical studies, as well as gene expression analyses, were performed at 3, 5, 8, and 13 weeks after the initial treatment (n = 78). Experimental animals developed pulmonary hypertension and right ventricular hypertrophy, and exhibited a progressive increase in indices of PVD, including cellular intimal thickening and intimal fibrosis. Cellular intimal lesions comprised α smooth muscle actin (α SMA)+, SM1+, SM2+/-, vimentin+ immature SMCs that were covered by endothelial monolayers, while fibrous intimal lesions typically included α SMA+, SM1+, SM2+, vimentin+/- mature SMCs. Plexiform lesions comprised α SMA+, vimentin+, SM1-, SM2- myofibroblasts covered by endothelial monolayers. Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages. Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals. We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD.

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Time course of PAH-related inflammatory gene expression in Sugen/hypoxia rats.Messenger RNA level of various genes at different time points and in controls was compared with a one-way analysis of variance followed by Tukey-Kramer multiple comparison test. Open square (control) indicates the control group 3 weeks after the vehicle treatment; closed square indicates Sugen/hypoxia rats at respective time points. IL6, interleukin 6; MCP1, monocyte chemotactic protein 1; MMP9, matrix metalloproteinase 9; TIMP1, tissue inhibitor of metalloproteinase 1; RANTES, Regulated on Activation, Normal T Cell Expressed and Secreted. Data are expressed as fold-change compared with the control group. Values are mean ± SD.
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pone.0118655.g008: Time course of PAH-related inflammatory gene expression in Sugen/hypoxia rats.Messenger RNA level of various genes at different time points and in controls was compared with a one-way analysis of variance followed by Tukey-Kramer multiple comparison test. Open square (control) indicates the control group 3 weeks after the vehicle treatment; closed square indicates Sugen/hypoxia rats at respective time points. IL6, interleukin 6; MCP1, monocyte chemotactic protein 1; MMP9, matrix metalloproteinase 9; TIMP1, tissue inhibitor of metalloproteinase 1; RANTES, Regulated on Activation, Normal T Cell Expressed and Secreted. Data are expressed as fold-change compared with the control group. Values are mean ± SD.

Mentions: In Sugen/hypoxia rats, mRNA expression of IL6, MCP1, MMP9, TIMP1 and cathepsin S was up-regulated at 3 weeks, which was progressively or persistently up-regulated during the experimental period in the lung, while that of RANTES was increased later at 8 and 13 weeks (Fig. 8). mRNA expression of other molecules, IL-1β, TNFα, VEGF-A, MMP2, and TIMP2 was not consistently up-regulated during the experimental period (S5 Fig.). Compared with in hypoxic or control rats at 3 and 5 weeks, the higher and persistent expression of IL6 and MCP1 and a distinct increase in MMP9 and cathepsin S expression was observed in Sugen/hypoxia rats (Fig. 9). Immunohistochemical and confocal microscopic analyses showed that these inflammatory molecules were expressed in vascular or perivascular inflammatory cells in vascular lesions in this model (S6 Fig.).


Potential contribution of phenotypically modulated smooth muscle cells and related inflammation in the development of experimental obstructive pulmonary vasculopathy in rats.

Otsuki S, Sawada H, Yodoya N, Shinohara T, Kato T, Ohashi H, Zhang E, Imanaka-Yoshida K, Shimpo H, Maruyama K, Komada Y, Mitani Y - PLoS ONE (2015)

Time course of PAH-related inflammatory gene expression in Sugen/hypoxia rats.Messenger RNA level of various genes at different time points and in controls was compared with a one-way analysis of variance followed by Tukey-Kramer multiple comparison test. Open square (control) indicates the control group 3 weeks after the vehicle treatment; closed square indicates Sugen/hypoxia rats at respective time points. IL6, interleukin 6; MCP1, monocyte chemotactic protein 1; MMP9, matrix metalloproteinase 9; TIMP1, tissue inhibitor of metalloproteinase 1; RANTES, Regulated on Activation, Normal T Cell Expressed and Secreted. Data are expressed as fold-change compared with the control group. Values are mean ± SD.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4340876&req=5

pone.0118655.g008: Time course of PAH-related inflammatory gene expression in Sugen/hypoxia rats.Messenger RNA level of various genes at different time points and in controls was compared with a one-way analysis of variance followed by Tukey-Kramer multiple comparison test. Open square (control) indicates the control group 3 weeks after the vehicle treatment; closed square indicates Sugen/hypoxia rats at respective time points. IL6, interleukin 6; MCP1, monocyte chemotactic protein 1; MMP9, matrix metalloproteinase 9; TIMP1, tissue inhibitor of metalloproteinase 1; RANTES, Regulated on Activation, Normal T Cell Expressed and Secreted. Data are expressed as fold-change compared with the control group. Values are mean ± SD.
Mentions: In Sugen/hypoxia rats, mRNA expression of IL6, MCP1, MMP9, TIMP1 and cathepsin S was up-regulated at 3 weeks, which was progressively or persistently up-regulated during the experimental period in the lung, while that of RANTES was increased later at 8 and 13 weeks (Fig. 8). mRNA expression of other molecules, IL-1β, TNFα, VEGF-A, MMP2, and TIMP2 was not consistently up-regulated during the experimental period (S5 Fig.). Compared with in hypoxic or control rats at 3 and 5 weeks, the higher and persistent expression of IL6 and MCP1 and a distinct increase in MMP9 and cathepsin S expression was observed in Sugen/hypoxia rats (Fig. 9). Immunohistochemical and confocal microscopic analyses showed that these inflammatory molecules were expressed in vascular or perivascular inflammatory cells in vascular lesions in this model (S6 Fig.).

Bottom Line: Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages.Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals.We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

ABSTRACT
We tested the hypothesis that phenotypically modulated smooth muscle cells (SMCs) and related inflammation are associated with the progression of experimental occlusive pulmonary vascular disease (PVD). Occlusive PVD was induced by combined exposure to a vascular endothelial growth factor receptor tyrosine kinase inhibitor Sugen 5416 and hypobaric hypoxia for 3 weeks in rats, which were then returned to ambient air. Hemodynamic, morphometric, and immunohistochemical studies, as well as gene expression analyses, were performed at 3, 5, 8, and 13 weeks after the initial treatment (n = 78). Experimental animals developed pulmonary hypertension and right ventricular hypertrophy, and exhibited a progressive increase in indices of PVD, including cellular intimal thickening and intimal fibrosis. Cellular intimal lesions comprised α smooth muscle actin (α SMA)+, SM1+, SM2+/-, vimentin+ immature SMCs that were covered by endothelial monolayers, while fibrous intimal lesions typically included α SMA+, SM1+, SM2+, vimentin+/- mature SMCs. Plexiform lesions comprised α SMA+, vimentin+, SM1-, SM2- myofibroblasts covered by endothelial monolayers. Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages. Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals. We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD.

Show MeSH
Related in: MedlinePlus