Angiotensin II Type 1 Receptor Antagonist Attenuates Lung Fibrosis in Hyperoxia-Exposed Newborn Rats

Chou, Hsiu Chu; Lang, Yaw-Dong; Wang, Leng-Fang; Wu, Tzu Ying; Hsieh, Yu Fang; Chen, Chung-Ming

doi:10.1124/jpet.111.186288

Cited by 13 publications

(15 citation statements)

References 26 publications

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“…Furthermore, activation and production of AngII is associated with lung fibrosis which can be attenuated by AT 1 blocker or ACE inhibitor [37], [38], [39]. In the present study, we observed that AngII level in plasma and lung tissue was up-regulated by silicosis, and similarly that ACE and AT 1 in the lung were also elevated.…”

Section: Discussionsupporting

confidence: 63%

A New Antifibrotic Target of Ac-SDKP: Inhibition of Myofibroblast Differentiation in Rat Lung with Silicosis

Fang

Sun

et al. 2012

PLoS ONE

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BackgroundMyofibroblast differentiation, characterized by α-smooth muscle actin (α-SMA) expression, is a key process in organ fibrosis, and is induced by TGF-β. Here we examined whether an anti-fibrotic agent, N-acetyl-seryl-aspartyl-lysylproline (Ac-SDKP), can regulate induction of TGF-β signaling and myofibroblast differentiation as a potential key component of its anti-fibrotic mechanism in vivo and in vitro.Methodology/Principal FindingsRat pulmonary fibroblasts were cultured in vitro and divided to 4 groups 1) control; 2) TGF-β1; 3) TGF-β1+ LY364947; 4) TGF-β1+Ac-SDKP. For in vivo studies, six groups of animals were utilized 1) control 4w; 2) silicotic 4w; 3) control 8w; 4) silicotic 8w; 5) Ac-SDKP post-treatment; 6)Ac-SDKP pre-treatment. SiO2 powders were douched in the trachea of rat to make the silicotic model. Myofibroblast differentiation was measured by examining expression of α-SMA, as well as expression of serum response factor (SRF), a key regulator of myofibroblast differentiation. The expressions of collagen, TGF-β1 and RAS signaling were also assessed. The results revealed that TGF-β1 strongly induced myofibroblast differentiation and collagen synthesis in vitro, and that pre-treatment with Ac-SDKP markedly attenuated myofibroblast activation, as well as induction of TGF-β1 and its receptor. Similar results were observed in vivo in the pathologically relevant rat model of silicosis. Ac-SDKP treatment in vivo strongly attenuated 1) silicosis-induced increased expressions of TGF-β1 and RAS signaling, 2) myofibroblast differentiation as indicated by a robust decrease of SRF and α-SMA-positive myofibroblast localization in siliconic nodules in the lung, 3) collagen deposition.Conclusion/SignificanceThe results of the present study suggest a novel mechanism of action for Ac-SDKP’s beneficial effect in silicosis, which involves attenuation of TGF-β1 and its receptors, SRF and Ang II type 1 receptor (AT1) expression, collagen deposition and myofibroblast differentiation. The results further suggest that therapies targeting myofibroblast differentiation may have therapeutic efficacy in treatment of silicosis of the lung.

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Section: Discussionsupporting

confidence: 63%

A New Antifibrotic Target of Ac-SDKP: Inhibition of Myofibroblast Differentiation in Rat Lung with Silicosis

Fang

Sun

et al. 2012

PLoS ONE

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“…With in-depth studies of the RAS, it has been found that AngII might stimulate the proliferation of fibroblasts, chemotactically drives inflammatory cells, and promotes the apoptosis of AT-II cells, indicating its role in the fibrotic pathogenesis of multiple organs (18,19). Studies have confirmed that the AngII receptor is widely expressed in the alveolar epithelium (20) and its expression is significantly increased during hyperoxic injury (21). Other studies have shown that, through inhibiting AngII and its receptor, hyperoxia-induced collagen deposition in the lung tissue could be reduced, thus reversing the occurrence of pulmonary fibrosis (21,22).…”

Section: Discussionmentioning

confidence: 99%

“…Studies have confirmed that the AngII receptor is widely expressed in the alveolar epithelium (20) and its expression is significantly increased during hyperoxic injury (21). Other studies have shown that, through inhibiting AngII and its receptor, hyperoxia-induced collagen deposition in the lung tissue could be reduced, thus reversing the occurrence of pulmonary fibrosis (21,22). However, the specific molecular mechanism is not yet fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…Its effects on the lung development of newborn rats might involve the upregulation of AT 1 R expression inside the lung cells. The AT 1 R is one of the major receptors through which AngII promotes cellular mitosis and proliferation inside the lung, binds AngII in a dose-dependent manner, and promotes the proliferation and activation of human lung fibroblasts, inducing collagen deposition in the lung tissue (21,22). These data suggest that this pathway is one of the major pathways involved in the development of hyperoxia-induced lung injury and secondary pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of the angiotensin II-p22phox-reactive oxygen species signaling pathway, apoptosis and 8-oxoguanine-DNA glycosylase 1 retrieval in hyperoxia-induced lung injury and fibrosis in rats

Wang

Yu-xi

Zhu

et al. 2017

Experimental and Therapeutic Medicine

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The present study was designed to explore the impact of hyperoxia on lung injury and fibrosis via the angiotensin II (AngII)-p22phox-reactive oxygen species (ROS) signaling pathway, apoptosis and 8-oxoguanine-DNA glycosylase 1 (OGG1) repair enzyme. Newborn Sprague-Dawley rats were randomly divided in the newborn air group, newborn hyperoxia group and newborn intervention group, the latter of which was administered the chymotrypsin inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1, 6-dihydropyrimidine-1-yl)-N-[4-dioxo-1-phenyl-7-(2-pyridyloxy)] 2-heptyl-acetamide (NK3201). A group of adult rats also received hyperoxic treatment. Histomorphological changes in lung tissues were dynamically observed. AngII, ROS, angiotensin type 1 receptor (AT1R) and p22phox messenger RNA (mRNA) levels, and OGG1 and peroxisome proliferator-activated receptor-γ (PPARγ) protein levels in the lung tissues were detected at various times after hyperoxia. Hyperoxia led to traumatic changes in the lungs of newborn rats that resulted in decreased viability, increased mortality, morphological changes and the apoptosis of alveolar type II epithelial cells (AT-II), as well as increased expression levels of AngII, AT1R and p22phox, which would ultimately lead to secondary diseases. NK3201 significantly inhibited the hyperoxia-induced increased expression of AngII, AT1R and p22phox and further promoted OGG1 and PPARγ protein expression, thus reducing the intrapulmonary ROS level, the apoptotic index and caspase-3 levels. However, the adult hyperoxia group only exhibited tachypnea and reduced viability. This study suggested that the AngII-p22phox-ROS signaling pathway, PPARγ and OGG1 together contributed to the hyperoxia-induced lung injury and that NK3201 was able to reverse the effects of hyperoxia.

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“…Angiotensin II is implicated in fibrotic pathogenesis in the lung and liver [17], [19]. Recent studies have shown that treatment with blockers of angiotensin II action, especially AT1R antagonists, can decrease inflammation and fibrosis of the kidney, lung, and liver in animal models of fibrotic disease [20]–[22].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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.

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Angiotensin II Type 1 Receptor Antagonist Attenuates Lung Fibrosis in Hyperoxia-Exposed Newborn Rats

Cited by 13 publications

References 26 publications

A New Antifibrotic Target of Ac-SDKP: Inhibition of Myofibroblast Differentiation in Rat Lung with Silicosis

A New Antifibrotic Target of Ac-SDKP: Inhibition of Myofibroblast Differentiation in Rat Lung with Silicosis

Regulation of the angiotensin II-p22phox-reactive oxygen species signaling pathway, apoptosis and 8-oxoguanine-DNA glycosylase 1 retrieval in hyperoxia-induced lung injury and fibrosis in rats

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

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