Pharmacological In Vivo Inhibition of <i>S</i>-Nitrosoglutathione Reductase Attenuates Bleomycin-Induced Inflammation and Fibrosis

Luzina, Irina G.; Lockatell, Virginia; Todd, Nevins W.; Kopach, Pavel; Pentikis, Helen S.; Atamas, Sergei P.

doi:10.1124/jpet.115.224675

Cited by 16 publications

(13 citation statements)

References 72 publications

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“…Additionally, we observed statistically significant increases in collagen content in the lung, accompanied by increased lung weight and lung index in treated animals compared to untreated mice. Analysis of biomarkers in BALf showed significant increases in TGF-β1, IL-6, VEGF, TIMP1, and CRP levels, all of which are consistent with previous reports [12][13][14][15][16][17].…”

Section: Discussionsupporting

confidence: 92%

Bleomycin mouse model with active-phase pulmonary fibrosis and no acute mortality

Kadam¹,

Faix²,

Schnitzer³

2020

Preprint

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Background The bleomycin mouse model is the most prevalent animal model used to study idiopathic pulmonary fibrosis (IPF), ranging from basic pathophysiological mechanisms to therapeutic modalities. High mortality rates, inconsistencies in disease induction, and great severity of the disease phenotype have limited its utility and clinical relevance. In this study, we identify conditions in the mouse bleomycin model that maintain the desired IPF phenotype found in patients while avoiding the usual, associated rapid mouse mortality. Methods In two independent studies, we analyzed the effects of incremental intratracheal (IT) high (1-3 U/kg) and low (0.05-0.5 U/kg) bleomycin doses on pulmonary fibrosis in mice. We observed dose effects on weight loss, morbidity and mortality, inflammation, lung collagen content, presence of various biomarkers in bronchoalveolar lavage fluid (BALf), and histology 14 days post-treatment, when the animals were in the active phase of fibrosis. Results We characterize the fibrotic effects of various bleomycin doses in mice on pulmonary inflammation, myofibroblast activation, vascular leakiness, angiogenesis, and extracellular tissue remodeling. Higher bleomycin doses induced acute disease with severe and saturated responses, extreme and progressive weight loss, and high morbidity and mortality rates. In contrast, lower doses of bleomycin induced a milder and chronic response, featuring robust, active-phase fibrosis with mild weight loss and no mortality. Conclusion Here we demonstrate that the bleomycin mouse model can be used to reproduce symptoms of IPF patients in an animal by using low doses of bleomycin. Low concentrations of bleomycin induce chronic and progressive fibrosis with no mortality.

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Section: Discussionsupporting

confidence: 92%

Bleomycin mouse model with active-phase pulmonary fibrosis and no acute mortality

Kadam¹,

Faix²,

Schnitzer³

2020

Preprint

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“…Daily maintenance of mice was performed at the Baltimore VA Medical Center Research Animal Facility/University of Maryland Animal Facility, which is approved by the Association for Assessment and Accreditation of Laboratory Animal Care. To model pulmonary inflammation and fibrosis, a single dose of 0.075 U of bleomycin (Sigma-Aldrich, St. Louis, MO), diluted in 50 ml of sterile PBS, was delivered to mouse lungs on day 0, as previously reported (37,38,46). Briefly, a minor anterior midline neck incision was made to make the trachea visible, a MicroSprayer (Penn-Century, Wyndmoor, Philadelphia, PA) was inserted intratracheally, and the bleomycin solution was instilled.…”

Section: Methodsmentioning

confidence: 99%

Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts

Wyman

Noor

Fishelevich

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary fibrosis is a severe condition with no cure and limited therapeutic options. A better understanding of its pathophysiology is needed. Recent studies have suggested that pulmonary fibrosis may be driven by accelerated aging-related mechanisms. Sirtuins (SIRTs), particularly SIRT1, SIRT3, and SIRT6, are well-known mediators of aging; however, limited data exist on the contribution of sirtuins to lung fibrosis. We assessed the mRNA and protein levels of all seven known sirtuins in primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in comparison with lung fibroblasts from healthy controls. These unbiased tests revealed a tendency for all sirtuins to be expressed at lower levels in fibroblasts from patients compared with controls, but the greatest decrease was observed with SIRT7. Similarly, SIRT7 was decreased in lung tissues of bleomycin-challenged mice. Inhibition of SIRT7 with siRNA in cultured lung fibroblasts resulted in an increase in collagen and α-smooth muscle actin (α-SMA). Reciprocally, overexpression of SIRT7 resulted in lower basal and TGF-β-induced levels of COL1A1, COL1A2, COL3A1, and α-SMA mRNAs, as well as collagen and α-SMA proteins. Induced changes in SIRT7 had no effect on endogenous TGF-β mRNA levels or latent TGF-β activation, but overexpression of SIRT7 reduced the levels of Smad3 mRNA and protein. In conclusion, the decline in SIRT7 in lung fibroblasts has a profibrotic effect, which is mediated by changes in Smad3 levels.

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“…Using an allergic asthma mouse model, intranasally administered SPL-334 decreased CD4+ Th2 cytokines, eosinophils, and mitigated the lung inflammatory response (Ferrini et al, 2013). Likewise, in a mouse model of ILD SPL-334 functions as both a prophylactic agent and a therapeutic to attenuate profibrotic cytokines and collagen accumulation in the lungs (Luzina et al, 2015). Unlike N6022 and N91115, SPL-334 is not in human clinical trials.…”

Section: Therapeutic Inhibition Of Gsnormentioning

confidence: 99%

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy

Barnett

Buxton

2017

Critical Reviews in Biochemistry and Molecular Biology

119

101

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S-nitrosoglutathione reductase (GSNOR), or ADH5, is an enzyme in the alcohol dehydrogenase (ADH) family. It is unique when compared to other ADH enzymes in that primary short-chain alcohols are not its principle substrate. GSNOR metabolizes S-nitrosoglutathione (GSNO), S-hydroxymethylglutathione (the spontaneous adduct of formaldehyde and glutathione), and some alcohols. GSNOR modulates reactive nitric oxide (•NO) availability in the cell by catalyzing the breakdown of GSNO, and indirectly regulates S-nitrosothiols (RSNOs) through GSNO-mediated protein S-nitrosation. The dysregulation of GSNOR can significantly alter cellular homeostasis, leading to disease. GSNOR plays an important regulatory role in smooth muscle relaxation, immune function, inflammation, neuronal development, and cancer progression, among many other processes. In recent years, the therapeutic inhibition of GSNOR has been investigated to treat asthma, cystic fibrosis and interstitial lung disease (ILD). The direct action of •NO on cellular pathways, as well as the important regulatory role of protein S-nitrosation, are closely tied to GSNOR regulation and define this enzyme as an important therapeutic target.

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Pharmacological In Vivo Inhibition of S-Nitrosoglutathione Reductase Attenuates Bleomycin-Induced Inflammation and Fibrosis

Cited by 16 publications

References 72 publications

Bleomycin mouse model with active-phase pulmonary fibrosis and no acute mortality

Bleomycin mouse model with active-phase pulmonary fibrosis and no acute mortality

Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy

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