Inhibition of Protease–Epithelial Sodium Channel Signaling Improves Mucociliary Function in Cystic Fibrosis Airways

Reihill, James; Walker, Brian; Hamilton, Robert A.; Ferguson, Timothy; Elborn, J.S.; Stutts, M. Jackson; Harvey, Bill; Saint‐Criq, Vinciane; Hendrick, Siobhan M.; Martin, S. Lorraine

doi:10.1164/rccm.201511-2216oc

Cited by 54 publications

(59 citation statements)

References 57 publications

(30 reference statements)

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“…6). Although “ENaC-targeting concept” is about to be confirmed by the recent basic report51 and the clinical study for the treatment of CF on a long-acting inhaled ENaC inhibitor, P1037 (VX371) (Phase 2 CLEAN-CF), beneficial effects of ONO-3403 on C57/BL6J-βENaC-Tg mice may be exerted by ENaC-independent unknown mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases

Shuto¹,

Kamei²,

Fujikawa³

et al. 2016

Sci Rep

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Protease-antiprotease imbalance and oxidative stress are considered to be major pathophysiological hallmarks of severe obstructive lung diseases including chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), but limited information is available on their direct roles in the regulation of pulmonary phenotypes. Here, we utilized βENaC-transgenic (Tg) mice, the previously established mouse model of severe obstructive lung diseases, to produce lower-mortality but pathophysiologically highly useful mouse model by backcrossing the original line with C57/BL6J mice. C57/BL6J-βENaC-Tg mice showed higher survival rates and key pulmonary abnormalities of COPD/CF, including mucous hypersecretion, inflammatory and emphysematous phenotypes and pulmonary dysfunction. DNA microarray analysis confirmed that protease- and oxidative stress-dependent pathways are activated in the lung tissue of C57/BL6J-βENaC-Tg mice. Treatments of C57/BL6J-βENaC-Tg mice with a serine protease inhibitor ONO-3403, a derivative of camostat methylate (CM), but not CM, and with an anti-oxidant N-acetylcystein significantly improved pulmonary emphysema and dysfunction. Moreover, depletion of a murine endogenous antioxidant vitamin C (VC), by genetic disruption of VC-synthesizing enzyme SMP30 in C57/BL6J-βENaC-Tg mice, exaggerated pulmonary phenotypes. Thus, these assessments clarified that protease-antiprotease imbalance and oxidative stress are critical pathways that exacerbate the pulmonary phenotypes of C57/BL6J-βENaC-Tg mice, consistent with the characteristics of human COPD/CF.

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Section: Discussionmentioning

confidence: 99%

Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases

Shuto¹,

Kamei²,

Fujikawa³

et al. 2016

Sci Rep

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“…QUB-TL1 is a potent CAP inhibitor, which has been shown to diminish ENaC-mediation sodium absorption [74]. reclinical studies of QUB-TL1 in airway epithelial cell culture demonstrated that QUB-TL1 inhibits prostasin, matriptase, and furin.…”

Section: Enac Inhibitors In Developmentmentioning

confidence: 99%

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis

Shei

Peabody

Kaza

et al. 2018

Current Opinion in Pharmacology

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Cystic fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR dysfunction is characterized by abnormal mucociliary transport due to a dehydrated airway surface liquid (ASL) and hyperviscous mucus, among other pathologies of host defense. ASL depletion is caused by the absence of CFTR medicated chloride secretion along with continued activity of the epithelial sodium channel (ENaC) activity, which can also be affected by CFTR mediated anion conductance. Therefore, ENaC has been proposed as a therapeutic target to ameliorate ASL dehydration and improve mucus transport. Inhibition of ENaC has been shown to restore ASL hydration and enhance mucociliary transport in induced models of CF lung disease. To date, no therapy inhibiting ENaC has successfully translated to clinical efficacy, in part due to concerns regarding off-target effects, systemic exposure, durability of effect, and adverse effects. Recent efforts have been made to develop novel, rationally designed therapeutics to produce specific, long-lasting inhibition of ENaC activity in the airways while simultaneously minimizing off target fluid transport effects, systemic exposure and side effects. Such approaches comprise next-generation small molecule direct inhibitors, indirect channel-activating protease inhibitors, synthetic peptide analogs, and oligonucleotide-based therapies. These novel therapeutics represent an exciting step forward in the development of ENaC-directed therapies for CF.

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“…The cystic fibrosis transmembrane conductance regulator (CFTR) is a multi-domain, cell surface membrane glycoprotein that acts as a chloride channel [Tazi et al, 2016]. CFTR can regulate the epithelial sodium channel [Reihill et al, 2016], plasma membrane recycling [Bomberger et al, 2014], and plays a significant role in the regulation of ER stress responses [Bartoszewski et al, 2008]. Pratic o AD have previously reported that mutations of the CFTR genotype: F508/ 12TG-5T and 470MV correlate with liver disease of cystic fibrosis patients, suggesting that CFTR might be involved in liver damage [Pratico et al, 2015].…”

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confidence: 99%

Folate Protects Hepatocytes of Hyperhomocysteinemia Mice From Apoptosis via Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Activated Endoplasmic Reticulum Stress

Sun

Mao

et al. 2017

J. Cell. Biochem.

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Inhibition of Protease–Epithelial Sodium Channel Signaling Improves Mucociliary Function in Cystic Fibrosis Airways

Abstract: QUB-TL1 corrects aberrant CAP activities, providing a mechanism to delay or prevent the development of CF lung disease in a manner independent of CF transmembrane conductance regulator mutation.

Cited by 54 publications

References 57 publications

Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases

Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis

Folate Protects Hepatocytes of Hyperhomocysteinemia Mice From Apoptosis via Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Activated Endoplasmic Reticulum Stress

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