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Angiotensin II type 1 receptor antagonist attenuates lacrimal gland, lung, and liver fibrosis in a murine model of chronic graft-versus-host disease.

Yaguchi S, Ogawa Y, Shimmura S, Kawakita T, Hatou S, Satofuka S, Nakamura S, Imada T, Miyashita H, Yoshida S, Yaguchi T, Ozawa Y, Mori T, Okamoto S, Kawakami Y, Ishida S, Tsubota K - PLoS ONE (2013)

Bottom Line: Tissue RAS is present in the lacrimal gland, lung, and liver, and is known to be involved in the fibrotic pathogenesis of the lung and liver.First, we examined the localization and expression of RAS components in the lacrimal glands using immunohistochemistry and quantitative real-time polymerase chain reaction (PCR).We conclude that RAS is involved in fibrotic pathogenesis in the lacrimal gland and that AT1R antagonist has a therapeutic effect on lacrimal gland, lung, and liver fibrosis in cGVHD model mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

ABSTRACT
Chronic graft-versus-host disease (cGVHD), a serious complication following allogeneic HSCT (hematopoietic stem cell transplantation), is characterized by systemic fibrosis. The tissue renin-angiotensin system (RAS) is involved in the fibrotic pathogenesis, and an angiotensin II type 1 receptor (AT1R) antagonist can attenuate fibrosis. Tissue RAS is present in the lacrimal gland, lung, and liver, and is known to be involved in the fibrotic pathogenesis of the lung and liver. This study aimed to determine whether RAS is involved in fibrotic pathogenesis in the lacrimal gland and to assess the effect of an AT1R antagonist on preventing lacrimal gland, lung, and liver fibrosis in cGVHD model mice. We used the B10.D2→BALB/c (H-2(d)) MHC-compatible, multiple minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD. First, we examined the localization and expression of RAS components in the lacrimal glands using immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). Next, we administered an AT1R antagonist (valsartan; 10 mg/kg) or angiotensin II type 2 receptor (AT2R) antagonist (PD123319; 10 mg/kg) intraperitoneally into cGVHD model mice and assessed the fibrotic change in the lacrimal gland, lung, and liver. We demonstrated that fibroblasts expressed angiotensin II, AT1R, and AT2R, and that the mRNA expression of angiotensinogen was greater in the lacrimal glands of cGVHD model mice than in controls generated by syngeneic-HSCT. The inhibition experiment revealed that fibrosis of the lacrimal gland, lung, and liver was suppressed in mice treated with the AT1R antagonist, but not the AT2R antagonist. We conclude that RAS is involved in fibrotic pathogenesis in the lacrimal gland and that AT1R antagonist has a therapeutic effect on lacrimal gland, lung, and liver fibrosis in cGVHD model mice. Our findings point to AT1R antagonist as a possible target for therapeutic intervention in cGVHD.

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Fibrotic changes in the murine lacrimal glands of cGVHD mice treated with DMSO, valsartan, and PD123319.A: Mallory staining of the DMSO, valsartan, and PD23319 lacrimal glands showing that the fibrosis around the medium-sized interlobular ducts was decreased in the valsartan group. B: Collagen deposition was mildest in the valsartan group (p<0.01). C: The mean densities of CD45+ inflammatory cells and HSP47+ fibroblasts in the lacrimal glands were decreased in the valsartan group compared with the DMSO and PD123319 groups (both CD45+ inflammatory cells and HSP47+ fibroblasts: p<0.01). D: Quantitative real-time PCR revealed that the HSP47, collagen type I alpha 1, collagen type I alpha 2, and collagen type III alpha 1 expression in the valsartan group were significantly lower than those in the DMSO group (HSP47; p<0.05, collage type I alpha 1; p<0.01, collagen type I alpha 2; p<0.05, collagen type III alpha 1; p<0.01). Magnification, A: X200. Scale bar, A: 50 µm. The results represent the mean ± SD. B, C, D: DMSO n = 6, valsartan n = 8, PD123319 n = 8. D: The vertical axis shows the expression ratio of mRNAs. Fold change shows the expression ratio of mRNAs in the DMSO, valsartan, and PD123319 group. The expression level in the DMSO group was defined as 1. *p<0.05, **p<0.01 by Bonferroni/Dunn test.
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pone-0064724-g003: Fibrotic changes in the murine lacrimal glands of cGVHD mice treated with DMSO, valsartan, and PD123319.A: Mallory staining of the DMSO, valsartan, and PD23319 lacrimal glands showing that the fibrosis around the medium-sized interlobular ducts was decreased in the valsartan group. B: Collagen deposition was mildest in the valsartan group (p<0.01). C: The mean densities of CD45+ inflammatory cells and HSP47+ fibroblasts in the lacrimal glands were decreased in the valsartan group compared with the DMSO and PD123319 groups (both CD45+ inflammatory cells and HSP47+ fibroblasts: p<0.01). D: Quantitative real-time PCR revealed that the HSP47, collagen type I alpha 1, collagen type I alpha 2, and collagen type III alpha 1 expression in the valsartan group were significantly lower than those in the DMSO group (HSP47; p<0.05, collage type I alpha 1; p<0.01, collagen type I alpha 2; p<0.05, collagen type III alpha 1; p<0.01). Magnification, A: X200. Scale bar, A: 50 µm. The results represent the mean ± SD. B, C, D: DMSO n = 6, valsartan n = 8, PD123319 n = 8. D: The vertical axis shows the expression ratio of mRNAs. Fold change shows the expression ratio of mRNAs in the DMSO, valsartan, and PD123319 group. The expression level in the DMSO group was defined as 1. *p<0.05, **p<0.01 by Bonferroni/Dunn test.

Mentions: Mallory staining of the lacrimal glands of cGVHD mice treated with DMSO, the AT1R antagonist valsartan, and the AT2R antagonist PD123319 revealed that the periductal fibrosis was decreased in the valsartan group compared with the DMSO or PD123319 group (Figure 3A). Similarly, collagen deposition was mildest in the valsartan group (p<0.01) (Figure 3B). The mean CD45+ inflammatory cell and HSP47+ fibroblast densities were significantly decreased in the valsartan group compared with the DMSO or PD123319 group (both CD45+ inflammatory cells and HSP47+ fibroblasts: p<0.01) (Figure 3C).


Angiotensin II type 1 receptor antagonist attenuates lacrimal gland, lung, and liver fibrosis in a murine model of chronic graft-versus-host disease.

Yaguchi S, Ogawa Y, Shimmura S, Kawakita T, Hatou S, Satofuka S, Nakamura S, Imada T, Miyashita H, Yoshida S, Yaguchi T, Ozawa Y, Mori T, Okamoto S, Kawakami Y, Ishida S, Tsubota K - PLoS ONE (2013)

Fibrotic changes in the murine lacrimal glands of cGVHD mice treated with DMSO, valsartan, and PD123319.A: Mallory staining of the DMSO, valsartan, and PD23319 lacrimal glands showing that the fibrosis around the medium-sized interlobular ducts was decreased in the valsartan group. B: Collagen deposition was mildest in the valsartan group (p<0.01). C: The mean densities of CD45+ inflammatory cells and HSP47+ fibroblasts in the lacrimal glands were decreased in the valsartan group compared with the DMSO and PD123319 groups (both CD45+ inflammatory cells and HSP47+ fibroblasts: p<0.01). D: Quantitative real-time PCR revealed that the HSP47, collagen type I alpha 1, collagen type I alpha 2, and collagen type III alpha 1 expression in the valsartan group were significantly lower than those in the DMSO group (HSP47; p<0.05, collage type I alpha 1; p<0.01, collagen type I alpha 2; p<0.05, collagen type III alpha 1; p<0.01). Magnification, A: X200. Scale bar, A: 50 µm. The results represent the mean ± SD. B, C, D: DMSO n = 6, valsartan n = 8, PD123319 n = 8. D: The vertical axis shows the expression ratio of mRNAs. Fold change shows the expression ratio of mRNAs in the DMSO, valsartan, and PD123319 group. The expression level in the DMSO group was defined as 1. *p<0.05, **p<0.01 by Bonferroni/Dunn test.
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pone-0064724-g003: Fibrotic changes in the murine lacrimal glands of cGVHD mice treated with DMSO, valsartan, and PD123319.A: Mallory staining of the DMSO, valsartan, and PD23319 lacrimal glands showing that the fibrosis around the medium-sized interlobular ducts was decreased in the valsartan group. B: Collagen deposition was mildest in the valsartan group (p<0.01). C: The mean densities of CD45+ inflammatory cells and HSP47+ fibroblasts in the lacrimal glands were decreased in the valsartan group compared with the DMSO and PD123319 groups (both CD45+ inflammatory cells and HSP47+ fibroblasts: p<0.01). D: Quantitative real-time PCR revealed that the HSP47, collagen type I alpha 1, collagen type I alpha 2, and collagen type III alpha 1 expression in the valsartan group were significantly lower than those in the DMSO group (HSP47; p<0.05, collage type I alpha 1; p<0.01, collagen type I alpha 2; p<0.05, collagen type III alpha 1; p<0.01). Magnification, A: X200. Scale bar, A: 50 µm. The results represent the mean ± SD. B, C, D: DMSO n = 6, valsartan n = 8, PD123319 n = 8. D: The vertical axis shows the expression ratio of mRNAs. Fold change shows the expression ratio of mRNAs in the DMSO, valsartan, and PD123319 group. The expression level in the DMSO group was defined as 1. *p<0.05, **p<0.01 by Bonferroni/Dunn test.
Mentions: Mallory staining of the lacrimal glands of cGVHD mice treated with DMSO, the AT1R antagonist valsartan, and the AT2R antagonist PD123319 revealed that the periductal fibrosis was decreased in the valsartan group compared with the DMSO or PD123319 group (Figure 3A). Similarly, collagen deposition was mildest in the valsartan group (p<0.01) (Figure 3B). The mean CD45+ inflammatory cell and HSP47+ fibroblast densities were significantly decreased in the valsartan group compared with the DMSO or PD123319 group (both CD45+ inflammatory cells and HSP47+ fibroblasts: p<0.01) (Figure 3C).

Bottom Line: Tissue RAS is present in the lacrimal gland, lung, and liver, and is known to be involved in the fibrotic pathogenesis of the lung and liver.First, we examined the localization and expression of RAS components in the lacrimal glands using immunohistochemistry and quantitative real-time polymerase chain reaction (PCR).We conclude that RAS is involved in fibrotic pathogenesis in the lacrimal gland and that AT1R antagonist has a therapeutic effect on lacrimal gland, lung, and liver fibrosis in cGVHD model mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

ABSTRACT
Chronic graft-versus-host disease (cGVHD), a serious complication following allogeneic HSCT (hematopoietic stem cell transplantation), is characterized by systemic fibrosis. The tissue renin-angiotensin system (RAS) is involved in the fibrotic pathogenesis, and an angiotensin II type 1 receptor (AT1R) antagonist can attenuate fibrosis. Tissue RAS is present in the lacrimal gland, lung, and liver, and is known to be involved in the fibrotic pathogenesis of the lung and liver. This study aimed to determine whether RAS is involved in fibrotic pathogenesis in the lacrimal gland and to assess the effect of an AT1R antagonist on preventing lacrimal gland, lung, and liver fibrosis in cGVHD model mice. We used the B10.D2→BALB/c (H-2(d)) MHC-compatible, multiple minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD. First, we examined the localization and expression of RAS components in the lacrimal glands using immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). Next, we administered an AT1R antagonist (valsartan; 10 mg/kg) or angiotensin II type 2 receptor (AT2R) antagonist (PD123319; 10 mg/kg) intraperitoneally into cGVHD model mice and assessed the fibrotic change in the lacrimal gland, lung, and liver. We demonstrated that fibroblasts expressed angiotensin II, AT1R, and AT2R, and that the mRNA expression of angiotensinogen was greater in the lacrimal glands of cGVHD model mice than in controls generated by syngeneic-HSCT. The inhibition experiment revealed that fibrosis of the lacrimal gland, lung, and liver was suppressed in mice treated with the AT1R antagonist, but not the AT2R antagonist. We conclude that RAS is involved in fibrotic pathogenesis in the lacrimal gland and that AT1R antagonist has a therapeutic effect on lacrimal gland, lung, and liver fibrosis in cGVHD model mice. Our findings point to AT1R antagonist as a possible target for therapeutic intervention in cGVHD.

Show MeSH
Related in: MedlinePlus