Angiotensin II Type 1 Receptor Antagonist Attenuates Lacrimal Gland, Lung, and Liver Fibrosis in a Murine Model of Chronic Graft-Versus-Host Disease

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-2d) 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.

Tissue Renin–Angiotensin System in Lacrimal Gland Fibrosis in a Murine Model of Chronic Graft-Versus-Host Disease

“…Its features include skin fibrosis with increased collagen deposition, 29,31 pulmonary fibrosis, 31 inflammation and destruction of the salivary gland, 32 hepatic disease characterized by intrahepatic and extrahepatic bile duct mononuclear cell infiltration followed by fibrous thickening and sclerosis of the bile duct wall, 33,34 and lacrimal gland fibrosis. 35 We previously characterized the inflammatory and fibrotic changes in the lacrimal glands of B10.D2/BALB/c (H-2 d ) cGVHD mice. 35 Allogeneic transplantation, in which female BALB/c recipient mice received male B10.D2 donor bone marrow (1 · 10 6 /mouse) and spleen cells (2 · 10 6 /mouse), was used to generate the cGVHD model.…”

“…35 We previously characterized the inflammatory and fibrotic changes in the lacrimal glands of B10.D2/BALB/c (H-2 d ) cGVHD mice. 35 Allogeneic transplantation, in which female BALB/c recipient mice received male B10.D2 donor bone marrow (1 · 10 6 /mouse) and spleen cells (2 · 10 6 /mouse), was used to generate the cGVHD model. For controls, syngeneic transplantation was used, in which female BALB/c recipient mice received male BALB/c donor bone marrow and spleen cells.…”

“…*P , 0.05, **P , 0.01 by the Student t test. Reproduced in a modified format from Yaguchi et al 35 tissue. 51 Immunohistochemical analysis revealed that prorenin/ renin and ACE were localized in myoepithelial cells around ducts and acini (Figs.…”

“…D2/BALB/c (H-2 d ) murine model of cGVHD. 35 Lacrimal gland specimens from the control group, generated by syngeneic transplantation, and the cGVHD model, generated by allogeneic transplantation, were taken 3 weeks after bone marrow transplantation.…”

Xia-Yu-Xue Decoction Inhibits Intestinal Epithelial Cell Apoptosis in CCl4-Induced Liver Fibrosis

“…We have also reported that macrophage infiltration and apoptosis in the kidney of fibrotic and cirrhotic rats [18, 19]. The pathological changes in extrahepatic organs, such as spleen, lung [20], and heart [21] associated with liver fibrosis have also been reported. However, the pathological changes in the intestine during the development of liver fibrosis were poorly understood.…”