Immunomodulatory activity of vardenafil on induced lung inflammation in cystic fibrosis mice

Lubamba, Bob; Huaux, François; Lebacq, Jean; Marbaix, Étienne; Dhooghe, Barbara; Panin, Nadtha; Wallemacq, Pierre; Leal, Teresinha

doi:10.1016/j.jcf.2012.03.003

Cited by 26 publications

(28 citation statements)

References 32 publications

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“…Our data showed that LCA induced the activation of NF-κB and markedly increased the release of inflammatory cytokines, and these effects were greatly reduced by vardenafil treatment. These findings are consistent with previous investigations that showed the ability of vardenafil to suppress NF-κB activation and subsequently the release of inflammatory cytokines in autoimmune hepatitis [17] and lung inflammation [42].…”

Section: Discussionsupporting

confidence: 93%

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

El‐Agamy

Almaramhy

Ahmed

et al. 2018

Cell Physiol Biochem

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Background/Aims: Phosphodiesterase-5 inhibitors have beneficial effects in multiple liver diseases possibly through the reduction of oxidative stress and inflammatory response. However, these effects have not yet been examined in cholestatic liver dysfunction. Hence, this study aimed to explore the ability of vardenafil, a known phosphodiesterase-5 inhibitor, to repress lithocholic acid (LCA)-induced cholestatic liver injury and investigate the possible molecular pathways. Methods: Male Swiss albino mice were treated with LCA (0.125 mg/g) twice daily for 7 days to induce cholestatic liver damage. Vardenafil was administered 3 days before and throughout the administration of LCA. Serum markers of hepatotoxicity and hepatic nitro-oxidative stress along with antioxidant parameters were measured, and the histopathology of liver tissues was assessed. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes was examined using PCR. The activation of nuclear factor kappa-B (NF-κB) and the levels of inflammatory cytokines were determined. NLRP3 inflammasome and its components were studied by PCR and western blot. Results: LCA induced marked cholestatic liver damage as demonstrated by increased serum transaminases, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin, and bile acids. Examination of liver specimens confirmed the biochemical results. Nitro-oxidative stress parameters were significantly elevated along with reduced antioxidant capacity in hepatic tissue following LCA administration. LCA suppressed Nrf2 and its target genes and decreased the mRNA expression and binding capacity of Nrf2 as well as the mRNA expression of GCLm, GCLc, Nqo1, and HO-1. Additionally, LCA enhanced the activation of NF-κB, which was accompanied by elevations of inflammatory cytokines. Importantly, LCA induced the activation of NLRP3 inflammasome. LCA increased the expression of NLRP3, ASC, caspase-1, and IL-1β genes and proteins in hepatic tissue. The activities of IL-1β and caspase-1 were increased in the LCA group. Interestingly, vardenafil ameliorated LCA-induced hepatic injury and alleviated all biochemical, histopathological, and inflammatory parameters. Conclusions: These data elucidated the effects of Nrf2 inhibition and NLRP3 inflammasome activation in LCA-induced liver injury. The hepatoprotective activity of vardenafil in LCA-induced cholestatic damage may result from the drug’s ability to activate Nrf2 signaling and prevent the activation of NLRP3, which could suppress the inflammatory responses in hepatic tissue. Thus, vardenafil can be considered a novel anti-inflammatory remedy for cholestatic liver damage.

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Section: Discussionsupporting

confidence: 93%

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

El‐Agamy

Almaramhy

Ahmed

et al. 2018

Cell Physiol Biochem

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“…More recently, we have found that vardenafil, selected as a representative PDE5 inhibitor for its longer-lasting CFTR activating effect, modulates the vicious circle of lung inflammation and attenuates the expression of pro-inflammatory cytokines and chemokines and cell infiltrates in the bronchoalveolar lavage (BAL) of CF and wild-type mice (Lubamba et al, 2012b). Intraperitoneal administration of a single pharmacological dose (0.14 mg/kg body weight) of vardenafil is followed by a reducing response in cell infiltrate and in the biosynthesis of several biomarkers of the inflammatory response.…”

Section: Pde5 Inhibitors For the Treatment Of Cystic Fibrosismentioning

confidence: 99%

“…injection, of a single therapeutic dose of vardenafil (vard) to wild-type (A) and F508del-CF (B) mice on the inflammatory response induced by lipopolyssaccharide from P. aeruginosa (LPS) . Biosynthesis of CCL-2 is significantly reduced in the bronchoalveolar lavage of vardenafil-treated CF and non-CF animals (Lubamba et al, 2012b). …”

Section: Pde5 Inhibitors For the Treatment Of Cystic Fibrosismentioning

confidence: 99%

PDE5 Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis

Noël

Dhooghe²,

Leal

2012

Front. Pharmacol.

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Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF), there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5) inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil, or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects, and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF.

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“…PDEi are postulated to have anti-inflammatory effects resulting from their correction of chloride transport through the CFTR, or through the downstream effects of increased cyclic guanosine monophosphate on defective protein glycosylation and bacterial adherence; however, the exact mechanism of the anti-inflammatory activity of PDE is unknown. 11,14,16 …”

Section: Introductionmentioning

confidence: 99%

“…Recent in vitro and in vivo studies have shown that PDEi can potentiate CFTR-mediated chloride transport activity in respiratory and digestive tissues. 14,17–20 Additionally, investigators have shown that this class of drugs corrects mislocalization of the mutant protein by displacing it from the intracellular compartment towards the apical cell compartment studied. 20,21 Thus, both the cellular localization and activity of F508del CFTR in the airway can be restored by PDEi.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and tolerability of oral sildenafil in adults with cystic fibrosis lung disease

Taylor‐Cousar

Wiley

Felton

et al. 2015

Journal of Cystic Fibrosis

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Rationale Airway inflammation is central to cystic fibrosis (CF) pathophysiology. Pre-clinical models have shown that phosphodiesterase inhibitors (PDEi) like sildenafil have anti-inflammatory activity. PDEi have not been studied in CF subjects. Objectives We evaluated the pharmacokinetics, tolerability, and safety of sildenafil in subjects with CF. Sputum biomarkers were used to explore efficacy. Methods An open-label pilot study of oral sildenafil administration was conducted in adults with mild to moderate CF lung disease. Subjects received oral sildenafil 20 or 40 mg p.o. t.i.d. for 6 weeks. Measurements and Main Results Twenty subjects completed the study. Estimated elimination rate constants were statistically different in subjects with CF compared to previously published non-CF subjects. Side effects were generally mild. There were no drug-related serious adverse events. Sputum neutrophil elastase activity decreased. Conclusions Subjects with CF may eliminate sildenafil at a faster rate than non-CF subjects. Sildenafil administration was safe in subjects with CF, and decreased sputum elastase activity. Sildenafil warrants further study as an anti-inflammatory in CF.

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Immunomodulatory activity of vardenafil on induced lung inflammation in cystic fibrosis mice

Abstract: Vardenafil reduces lung inflammation with a more pronounced effect in F508del-CF mice, particularly on macrophage cell markers.

Cited by 26 publications

References 32 publications

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

PDE5 Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis

Pharmacokinetics and tolerability of oral sildenafil in adults with cystic fibrosis lung disease

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