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.
Highlights
IntroductionChronic graft-versus-host disease (cGVHD), a multisystem chronic allo-immune and auto-immune disorder, is a serious and potentially life-threatening long-term complication of allogeneic HSCT (hematopoietic stem cell transplantation) [1].Clinical manifestations of cGVHD include inflammation and fibrosis [2].We previously reported that cGVHD is frequently related to dry eye, with 50% of patients developing or experiencing worsened pre-existing dry eye after HSCT [3], and that the lacrimal glands of cGVHD patients show marked fibrosis and inflammatory cell infiltration around medium-sized ducts in the interlobular areas [4]
Chronic graft-versus-host disease, a multisystem chronic allo-immune and auto-immune disorder, is a serious and potentially life-threatening long-term complication of allogeneic HSCT [1].Clinical manifestations of cGVHD include inflammation and fibrosis [2].We previously reported that cGVHD is frequently related to dry eye, with 50% of patients developing or experiencing worsened pre-existing dry eye after HSCT [3], and that the lacrimal glands of cGVHD patients show marked fibrosis and inflammatory cell infiltration around medium-sized ducts in the interlobular areas [4]
Fibroblasts Express Angiotensin II, angiotensin II type 1 receptor (AT1R), and angiotensin II type 2 receptor (AT2R), and the mRNA of Angiotensinogen is Increased in the Lacrimal Glands of cGVHD Model Mice We examined the localization of angiotensin II, AT1R, and AT2R by immunohistochemistry using specific antibodies
Summary
Chronic graft-versus-host disease (cGVHD), a multisystem chronic allo-immune and auto-immune disorder, is a serious and potentially life-threatening long-term complication of allogeneic HSCT (hematopoietic stem cell transplantation) [1].Clinical manifestations of cGVHD include inflammation and fibrosis [2].We previously reported that cGVHD is frequently related to dry eye, with 50% of patients developing or experiencing worsened pre-existing dry eye after HSCT [3], and that the lacrimal glands of cGVHD patients show marked fibrosis and inflammatory cell infiltration around medium-sized ducts in the interlobular areas [4]. Chronic graft-versus-host disease (cGVHD), a multisystem chronic allo-immune and auto-immune disorder, is a serious and potentially life-threatening long-term complication of allogeneic HSCT (hematopoietic stem cell transplantation) [1]. Clinical manifestations of cGVHD include inflammation and fibrosis [2]. Chronic pulmonary dysfunction occurs in 20% to 50% of cGVHD patients, depending on the donor source and the time interval after HSCT. The chronic lung injury is subdivided into two types: obstructive lung disease (OLD) and restrictive lung disease (RLD). Collagen deposition and fibrosis development are observed either in the peribronchiolar space (OLD) or interstitial space (RLD) [5]. Evidence of cholestasis is present in approximately 80% of patients with cGVHD. In the histopathology of liver cGVHD, ductopenia, portal fibrosis, and chronic cholestasis reflect chronicity [6]. The pathophysiology of cGVHD is not completely understood, and an effective therapy for it has not been established
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