Mineralocorticoid receptor antagonists attenuate pulmonary inflammation and bleomycin-evoked fibrosis in rodent models

Lieber, Gissela; Fernandez, Xiomara; Mingo, Garfield G.; Jia, Yanlin; Caniga, Michael; Gil, Malgorzata A; Keshwani, Shanil; Woodhouse, Janice D; Cicmil, Milenko; Moy, Lily Y.; Kelly, Nancy; Jimenez, Johanna; Crawley, Yvette; Anthes, John C.; Klappenbach, Joel A.; Ma, Yulu; McLeod, Robbie L.

doi:10.1016/j.ejphar.2013.08.019

Cited by 32 publications

(41 citation statements)

References 44 publications

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“…In addition, the therapeutic efficacy of drug intervention targeting this system has been reported in bleomycin-induced lung injury models [26][27][28][29][30][31]. Zhao and coworker first demonstrated the therapeutical potential of spironolactone in ameliorating bleomycin-induced lung fibrosis [32], which is also supported by a recent study [33]. A growing body of evidence suggests that manipulation of the mononuclear phagocyte phenotype switching could be a feasible approach to alter the severity and persistence of pulmonary injury and fibrosis in experimental models [34][35][36].…”

Section: Discussionmentioning

confidence: 90%

Spironolactone Attenuates Bleomycin-Induced Pulmonary Injury Partially via Modulating Mononuclear Phagocyte Phenotype Switching in Circulating and Alveolar Compartments

Zhou

et al. 2013

PLoS ONE

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BackgroundRecent experimental studies provide evidence indicating that manipulation of the mononuclear phagocyte phenotype could be a feasible approach to alter the severity and persistence of pulmonary injury and fibrosis. Mineralocorticoid receptor (MR) has been reported as a target to regulate macrophage polarization. The present work was designed to investigate the therapeutic potential of MR antagonism in bleomycin-induced acute lung injury and fibrosis.Methodology/Principal FindingsWe first demonstrated the expression of MR in magnetic bead-purified Ly6G-/CD11b+ circulating monocytes and in alveolar macrophages harvested in bronchoalveolar lavage fluid (BALF) from C57BL/6 mice. Then, a pharmacological intervention study using spironolactone (20mg/kg/day by oral gavage) revealed that MR antagonism led to decreased inflammatory cell infiltration, cytokine production (downregulated monocyte chemoattractant protein-1, transforming growth factor β1, and interleukin-1β at mRNA and protein levels) and collagen deposition (decreased lung total hydroxyproline content and collagen positive area by Masson’ trichrome staining) in bleomycin treated (2.5mg/kg, via oropharyngeal instillation) male C57BL/6 mice. Moreover, serial flow cytometry analysis in blood, BALF and enzymatically digested lung tissue, revealed that spironolactone could partially inhibit bleomycin-induced circulating Ly6Chi monocyte expansion, and reduce alternative activation (F4/80+CD11c+CD206+) of mononuclear phagocyte in alveoli, whereas the phenotype of interstitial macrophage (F4/80+CD11c-) remained unaffected by spironolactone during investigation.Conclusions/SignificanceThe present work provides the experimental evidence that spironolactone could attenuate bleomycin-induced acute pulmonary injury and fibrosis, partially via inhibition of MR-mediated circulating monocyte and alveolar macrophage phenotype switching.

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Section: Discussionmentioning

confidence: 90%

Spironolactone Attenuates Bleomycin-Induced Pulmonary Injury Partially via Modulating Mononuclear Phagocyte Phenotype Switching in Circulating and Alveolar Compartments

Zhou

et al. 2013

PLoS ONE

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“…Elevated levels of aldosterone, which is a physiological activator of MR, are known to induce hypertension, alter inflammation and fibrosis and exacerbate cardiovascular diseases [17,18]. MR antagonists have successfully been used as clinical interventions for the treatment of hypertension, heart failure and post-myocardial infarction remodelling [17,19]. Prophylactic MR antagonism with spironolactone (Sp) in rats has been shown to completely prevent the ischemic injuries of kidney, heart and brain [15,[19][20][21][22].…”

mentioning

confidence: 99%

“…MR antagonists have successfully been used as clinical interventions for the treatment of hypertension, heart failure and post-myocardial infarction remodelling [17,19]. Prophylactic MR antagonism with spironolactone (Sp) in rats has been shown to completely prevent the ischemic injuries of kidney, heart and brain [15,[19][20][21][22]. Several studies have tried t o e l u c i d a t e t h e u n d e r l y i n g m e c h a n i s m o f M R antagonist-induced cardioprotection [23].…”

mentioning

confidence: 99%

Reduction of Acute Lung Injury by Administration of Spironolactone After Intestinal Ischemia and Reperfusion in Rats

Barut¹,

Özaçmak²,

TURAN³

et al. 2016

CIM

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Purpose: Multiple organ failure, including acute lung injury, is a common complication of intestinal ischemia and reperfusion (I/R) injury and contributes to its high mortality rate. Activated polymorphonuclear neutrophils and reactive oxygen species contribute to the lung injury caused by intestinal I/R. Mineralokortikoid receptor antagonist spironolactone has a protective effect against I/R injury in animal models of retina, kidney, heart, and brain. The aim of the present study is to investigate the effect of aldosteron receptor blocker spironolactone on lung injury induced by intestinal I/R.Methods: Wistar albino rats were divided into four groups: (1) sham control; (2) intestinal I/R (30 min of ischemia by superior mesenteric artery occlusion followed by 3 h of reperfusion); (3) spironolactone pretreatment (20 mg/kg) + I/R; and, (4) spironolactone pretreatment without I/R. Spironolactone was given orally 3 days prior to intestinal I/R. A marker for lipid peroxidation (malondialdehyde; MDA), an indicator or oxidation state (reduced glutathione; GSH), an index of polymorphonuclear neutrophil sequestration (myeloperoxidase; MPO), inducible nitric oxide synthase (iNOS) immunoreactivity, and the histopathology of the lung tissue were analyzed.Results: Spironolactone pretreatment markedly reduced intestinal I/R-induced lung injury as indicated by histology and MDA and MPO levels. Moreover, the pretreatment decreased the iNOS immunoreactivity. Conclusion:The present study strongly suggests that spironolactone pretreatment decreased neutrophil infiltration, iNOS induction, oxidative stress, and histopathological injury in an experimental model of intestinal I/R induced-lung injury of rats.

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“…These data allow considering MR as a novel potential therapeutic target for IR and NAFLD. Moreover, MR blockade has been shown to ameliorate experimental organ fibrosis in the heart , lung and kidney . If that beneficial effects also occurs in the liver then MR blockade would provide action on both metabolic and fibrogenic phenomena rendering this class of drugs potentially useful agents for NASH.…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of mineralocorticoid receptor blockade in experimental non‐alcoholic steatohepatitis

Pizarro

Solı́s

Quintero

et al. 2015

Liver International

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Background Therapeutic options to treat Non-alcoholic steatohepatitis (NASH) are limited. Mineralocorticoid receptor (MR) activation could play a role in hepatic fibrogenesis and its modulation could be beneficial for NASH. Aim To investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in experimental NASH. Methods C57bl6 mice were fed a choline-deficient-amino-acid–defined (CDAA) diet for 22 weeks with or without eplerenone supplementation. Serum levels of aminotransferases and aldosterone were measured and hepatic steatosis, inflammation, and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic, oxidative stress-associated genes and of MR were also assessed. Results CDAA diet effectively induced fibrotic NASH, and increased the hepatic expression of pro-inflammatory, pro-fibrotic and oxidative stress-associated genes. Hepatic MR mRNA levels significantly correlated with the expression of pro-inflammatory and pro-fibrotic genes and were significantly increased in hepatic stellate cells obtained from CDAA-fed animals. Eplerenone administration was associated to a reduction in histological steatosis and attenuation of liver fibrosis development, which was associated to a significant decrease in the expression of collagen-α1, collagen type III, alpha 1 and Matrix metalloproteinase-2. Conclusion The expression of MR correlates with inflammation and fibrosis development in experimental NASH. Specific MR blockade with eplerenone has hepatic anti-steatotic and anti-fibrotic effects. These data identifies eplerenone as a potential novel therapy for NASH. Considering its safety and FDA-approved status, human studies are warranted

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Mineralocorticoid receptor antagonists attenuate pulmonary inflammation and bleomycin-evoked fibrosis in rodent models

Cited by 32 publications

References 44 publications

Spironolactone Attenuates Bleomycin-Induced Pulmonary Injury Partially via Modulating Mononuclear Phagocyte Phenotype Switching in Circulating and Alveolar Compartments

Spironolactone Attenuates Bleomycin-Induced Pulmonary Injury Partially via Modulating Mononuclear Phagocyte Phenotype Switching in Circulating and Alveolar Compartments

Reduction of Acute Lung Injury by Administration of Spironolactone After Intestinal Ischemia and Reperfusion in Rats

Beneficial effects of mineralocorticoid receptor blockade in experimental non‐alcoholic steatohepatitis

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