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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 lungs and livers of the DMSO, valsartan, and PD123319 groups.A: Mallory staining of the murine cGVHD lungs showing severe fibrosis of the interstitial space. The interstitial space fibrosis was decreased in the valsartan group. Mallory staining of the murine cGVHD livers showed periductal fibrosis in the bile duct; this fibrosis was decreased in the valsartan group. B: The alveolar space was quantified as the ratio of the alveolar space to the total area in the Mallory staining. The alveolar space was smaller in the cGVHD compared with control lungs (p = 0.0001). C: The alveolar space was largest in the valsartan group (p<0.01). D: The periductal fibrosis was quantified as the mean thickness of blue-stained area around the intrahepatic bile ducts. The fibrosis was thicker in the cGVHD compared with the control livers (p = 0.0003). E: The fibrosis was thinnest in the valsartan group (p<0.01). Magnification, A: X200. Scale bar, A: 50 µm. The results represent the mean ± SD. B, D: Control n = 5, cGVHD n = 5; C, E: DMSO n = 6, valsartan n = 8, PD123319 n = 8. B, D: **p<0.01 by Student's-t test; C, E: **p<0.01 by Bonferroni/Dunn test.
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pone-0064724-g004: Fibrotic changes in the murine lungs and livers of the DMSO, valsartan, and PD123319 groups.A: Mallory staining of the murine cGVHD lungs showing severe fibrosis of the interstitial space. The interstitial space fibrosis was decreased in the valsartan group. Mallory staining of the murine cGVHD livers showed periductal fibrosis in the bile duct; this fibrosis was decreased in the valsartan group. B: The alveolar space was quantified as the ratio of the alveolar space to the total area in the Mallory staining. The alveolar space was smaller in the cGVHD compared with control lungs (p = 0.0001). C: The alveolar space was largest in the valsartan group (p<0.01). D: The periductal fibrosis was quantified as the mean thickness of blue-stained area around the intrahepatic bile ducts. The fibrosis was thicker in the cGVHD compared with the control livers (p = 0.0003). E: The fibrosis was thinnest in the valsartan group (p<0.01). Magnification, A: X200. Scale bar, A: 50 µm. The results represent the mean ± SD. B, D: Control n = 5, cGVHD n = 5; C, E: DMSO n = 6, valsartan n = 8, PD123319 n = 8. B, D: **p<0.01 by Student's-t test; C, E: **p<0.01 by Bonferroni/Dunn test.

Mentions: In the lung, the cGVHD model mice showed interstitial space fibrosis with a loss of the normal lacy alveolar pattern (Figure 4A). The alveolar space was smaller in the cGVHD compared with the control lungs (p = 0.0001) (Figure 4B). In the inhibition experiment, valsartan prevented the interstitial space fibrosis (Figure 4A), and the alveolar space was largest in the valsartan group (p<0.01) (Figure 4C). In the liver, the cGVHD model mice showed periductal fibrosis in the bile duct (Figure 4A). The periductal fibrosis was thicker in the cGVHD compared with the control livers (p = 0.0003) (Figure 4D). In the inhibition experiment, valsartan prevented periductal fibrosis in the bile duct (Figure 4A), and the periductal fibrosis was thinnest in the valsartan group (p<0.01) (Figure 4E). These results suggest that fibrosis in cGVHD lung and liver was inhibited by AT1R antagonist (valsartan) administration like that in the lacrimal gland.


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 lungs and livers of the DMSO, valsartan, and PD123319 groups.A: Mallory staining of the murine cGVHD lungs showing severe fibrosis of the interstitial space. The interstitial space fibrosis was decreased in the valsartan group. Mallory staining of the murine cGVHD livers showed periductal fibrosis in the bile duct; this fibrosis was decreased in the valsartan group. B: The alveolar space was quantified as the ratio of the alveolar space to the total area in the Mallory staining. The alveolar space was smaller in the cGVHD compared with control lungs (p = 0.0001). C: The alveolar space was largest in the valsartan group (p<0.01). D: The periductal fibrosis was quantified as the mean thickness of blue-stained area around the intrahepatic bile ducts. The fibrosis was thicker in the cGVHD compared with the control livers (p = 0.0003). E: The fibrosis was thinnest in the valsartan group (p<0.01). Magnification, A: X200. Scale bar, A: 50 µm. The results represent the mean ± SD. B, D: Control n = 5, cGVHD n = 5; C, E: DMSO n = 6, valsartan n = 8, PD123319 n = 8. B, D: **p<0.01 by Student's-t test; C, E: **p<0.01 by Bonferroni/Dunn test.
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pone-0064724-g004: Fibrotic changes in the murine lungs and livers of the DMSO, valsartan, and PD123319 groups.A: Mallory staining of the murine cGVHD lungs showing severe fibrosis of the interstitial space. The interstitial space fibrosis was decreased in the valsartan group. Mallory staining of the murine cGVHD livers showed periductal fibrosis in the bile duct; this fibrosis was decreased in the valsartan group. B: The alveolar space was quantified as the ratio of the alveolar space to the total area in the Mallory staining. The alveolar space was smaller in the cGVHD compared with control lungs (p = 0.0001). C: The alveolar space was largest in the valsartan group (p<0.01). D: The periductal fibrosis was quantified as the mean thickness of blue-stained area around the intrahepatic bile ducts. The fibrosis was thicker in the cGVHD compared with the control livers (p = 0.0003). E: The fibrosis was thinnest in the valsartan group (p<0.01). Magnification, A: X200. Scale bar, A: 50 µm. The results represent the mean ± SD. B, D: Control n = 5, cGVHD n = 5; C, E: DMSO n = 6, valsartan n = 8, PD123319 n = 8. B, D: **p<0.01 by Student's-t test; C, E: **p<0.01 by Bonferroni/Dunn test.
Mentions: In the lung, the cGVHD model mice showed interstitial space fibrosis with a loss of the normal lacy alveolar pattern (Figure 4A). The alveolar space was smaller in the cGVHD compared with the control lungs (p = 0.0001) (Figure 4B). In the inhibition experiment, valsartan prevented the interstitial space fibrosis (Figure 4A), and the alveolar space was largest in the valsartan group (p<0.01) (Figure 4C). In the liver, the cGVHD model mice showed periductal fibrosis in the bile duct (Figure 4A). The periductal fibrosis was thicker in the cGVHD compared with the control livers (p = 0.0003) (Figure 4D). In the inhibition experiment, valsartan prevented periductal fibrosis in the bile duct (Figure 4A), and the periductal fibrosis was thinnest in the valsartan group (p<0.01) (Figure 4E). These results suggest that fibrosis in cGVHD lung and liver was inhibited by AT1R antagonist (valsartan) administration like that in the lacrimal gland.

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