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Should we monitor exhaled NO to assess the restoration of CFTR function in CF patients?
Journal of Cystic Fibrosis 14 (2015) 683 – 684 www.elsevier.com/locate/jcf
Should we monitor exhaled NO to assess the restoration of CFTR function in CF patients? Anh Tuan Dinh-Xuan ⁎, Thông Hua-Huy Paris Descartes University, Department of Physiology, Sorbonne Paris Cité, Cochin Hospital, 27 rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France ⁎ Corresponding author at: Cochin Hospital, Department of Physiology, 27 rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France. Received 21 September 2015; accepted 15 October 2015
Nitric oxide (NO) is a ubiquitous intra- and intercellular messenger with many physiological functions which make it unique among various gases produced by the human body [1]. As NO is over produced by a large variety of cells during inflammatory processes, measuring its production would be a logical means to monitor inflammation in human disease [1]. This is the case for NO detected in the exhaled air, and assessed by its fractional concentration measured at a constant expiratory flow rate of 50 mL.s−1 (FENO). FENO measurement has provided investigators worldwide with many useful information related to airways inflammation from patients with various respiratory disorders, especially atopic asthma [2]. Surprisingly FENO is paradoxically low in patients suffering from the two other major respiratory diseases associated with chronic airways inflammation, namely tobacco-related chronic bronchitis and cystic fibrosis (CF) [3]. When the underlying mechanisms explaining low FENO are well understood for tobacco-induced chronic obstructive pulmonary disease, biological pathways leading to reduced NO production in CF are still debated, with the putative implications of not only one but many intricate mechanisms [4]. In the airways numerous cell types, including the epithelium, are capable to synthesize NO from L-arginine and oxygen. NO production is catalysed by a family of enzymes, the NO synthases (NOS), which are either constitutively expressed or driven by inflammatory processes taking place in the whole lung, from large conducting airways to alveolar spaces [1]. Impaired NO production usually results from either reduced NOS gene expression and/or enzyme activity, or perturbed L-arginine metabolism [5]. Alternatively, physiological effects of NO are readily negated when NO combines with oxygen reactive species. This mechanism is of particular importance in a variety of inflammatory disorders, including CF, where oxidative stress is known to play a prominent role [5]. Owing to its biological effects, the absence, or reduced amount, of NO leads to the impairment of many physiological lung function. For example, as NO has
antimicrobial, bronchodilatory and vasodilatory effects, lack of NO paves the way to lung infection by various microorganisms, including P. aeruginosa, bronchial obstruction, and pulmonary vascular endothelial dysfunction [4–7]. Furthermore, many of the downstream products of the NO signalling pathway, e.g. the second messenger cyclic guanosine monophosphate (cGMP), and its related cGMP-dependent protein kinase (PKG), critically control the normal function of the epithelial sodium channel (ENaC), a key player in transepithelial ion transport homeostasis. As a result impaired NO production lowers intracellular cGMP and reduces PKG activity. As cGMP inhibits ENaC and PKG stimulates CFTR [4], the ensuing increased sodium influx and reduced chloride efflux disturb the normal ions and water transport at the luminal epithelial membrane of CF airways. The inverse relationship between FENO and baseline transepithelial nasal potential difference further supports the idea that lack of NO perturbs ENaC and CFTR functions in such a way to favour abnormal ions and fluid transport across the respiratory epithelium [8]. Conversely, amounting evidence now suggests that increasing NO in the airways of CF patients improves CFTR function. Treatment of CF cells with NO donors promotes ΔF508-CFTR maturation and function, and results in increased chloride efflux. Conversely, the question as to whether CFTR-targeting compounds can increase NO production in CF patients has not been properly addressed, until the two investigations reported in this issue of the Journal [9,10]. Grasemann et al. [9] and Kotha et al. [10] independently looked at the effects of 4 weeks treatment with the CFTR-targeting drug, Ivacaftor, on pulmonary function and FENO in two small groups of CF patients (15 and 5, respectively). Both studies consistently showed increased FENO in most CF patients after one month of Ivacaftor treatment [9,10], an effect which was more pronounced in paediatric as compared with adult CF patients [9]. As both studies also showed improved lung function with Ivacaftor, one might wonder as to whether increased FENO was directly related to restoration of CFTR function or was
684
Should we monitor exhaled NO to assess the restoration of CFTR function in CF patients?
it simply due to better lung function achieved after 4 weeks of Ivacaftor treatment. Grasemann et al. have shown that the latter is unlikely as FENO remained low whilst lung function significantly improved in patients treated with either Dornase alpha or hypertonic saline [9]. As in both studies FENO was only measured twice, i.e. at study entry and after 4 weeks of treatment with Ivacaftor, one might also question the validity of the observed FENO improvement, especially in such small groups of patients. To address this crucial issue, Koha et al. have shown that repeated measurement of FENO yielded stable results over time in a parallel group of 29 untreated CF children [10], reinforcing the idea that FENO improvement in treated patients is likely attributable to Ivacaftor rather than daily intraindividual variation of FENO. Looking at the results from both papers, and keeping in mind that these have been obtained in two observational studies with very small groups of patients [9,10], investigators intrigued by the peculiar and still incompletely understood links between NO production and CFTR function must however admit that this topic is probably now entering a new phase of conceptual development. Indeed the idea of measuring FENO as a biomarker of restored CFTR function might seem both an exciting and very promising one. Still, we should not be overly enthusiastic as additional confirmatory results are required. These will be obtained with future prospective and controlled studies in larger cohorts of CF patients. Only then, one can be certain that FENO, a surrogate marker of airways inflammation known for decades [3], can also be used to monitor restored CFTR function. The good news however is if the conclusions of both clinical studies [9,10] reported in this issue of the Journal hold true, basic science research will then be needed to solve another question we tend to overlook. Indeed, as stated previously if we know the various mechanisms explaining how low NO production and/or activity can impair lung function, mucociliary clearance, and favour lung infection with P. aeruginosa in CF, the field of research aiming to unravel the links between restored CFTR function and increased NO production is mostly unsuspected and largely unexplored to date. Let us bet that the fundamental question these two studies have implicitly led to, i.e. what are the underlying mechanisms of the control exerted by CFTR over NO production, will be soon addressed, and hopefully answered.
References [1] Ricciardolo FL, Sterk PJ, Gaston B, Folkerts G. Nitric oxide in health and disease of the respiratory system. Physiol Rev 2004;84:731–65. [2] Dinh-Xuan AT, Annesi-Maesano I, Berger P, Chambellan A, Chanez P, Chinet T, et al. Contribution of exhaled nitric oxide measurement in airway inflammation assessment in asthma. A position paper from the French Speaking Respiratory Society. Rev Mal Respir 2015;32:193–215. [3] Thébaud B, Arnal JF, Mercier JC, Dinh-Xuan AT. Inhaled and exhaled nitric oxide. Cell Mol Life Sci 1999;55:1103–12. [4] de Winter-de Groot KM, van der Ent CK. Nitric oxide in cystic fibrosis. J Cyst Fibros 2005;4(Suppl. 2):25–9. [5] Grasemann H, Ratjen F. Nitric oxide and L-arginine deficiency in cystic fibrosis. Curr Pharm Des 2012;18:726–36. [6] Keen C, Olin AC, Edentoft A, Gronowitz E, Strandvik B. Airway nitric oxide in patients with cystic fibrosis is associated with pancreatic function, Pseudomonas infection, and polyunsaturated fatty acids. Chest 2007;131: 1857–64. [7] Dinh-Xuan AT, Higenbottam TW, Pepke-Zaba J, Clelland C, Wallwork J. Reduced endothelium-dependent relaxation of cystic fibrosis pulmonary arteries. Eur J Pharmacol 1989;163:401–3. [8] Texereau J, Fajac I, Hubert D, Coste J, Dusser DJ, Bienvenu T, et al. Reduced exhaled NO is related to impaired nasal potential difference in patients with cystic fibrosis. Vascul Pharmacol 2005;43:385–9. [9] Grasemann H, Gonska T, Avolio J, Klingel M, Tullis E, Ratjen F. Effect of ivacaftor therapy on exhaled nitric oxide in patients with cystic fibrosis. J Cyst Fibros 2015;14:728–33. [10] Kotha K, Szczesniak RD, Naren AP, Fenchel MC, Duan LL, McPhail GL, et al. Concentration of fractional excretion of nitric oxide (FENO): A potential airway biomarker of restored CFTR function. J Cyst Fibros 2015;14:734–41.
Anh Tuan Dinh-Xuan Paris Descartes University, Department of Physiology, Sorbonne Paris Cité, Cochin Hospital, 27 rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France Corresponding author at: Cochin Hospital, Department of Physiology, 27 rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France. E-mail address: [email protected].
21 September 2015
Should we monitor exhaled NO to assess the restoration of CFTR function in CF patients? Anh Tuan Dinh-Xuan ⁎, Thông Hua-Huy Paris Descartes University, Department of Physiology, Sorbonne Paris Cité, Cochin Hospital, 27 rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France ⁎ Corresponding author at: Cochin Hospital, Department of Physiology, 27 rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France. Received 21 September 2015; accepted 15 October 2015
Nitric oxide (NO) is a ubiquitous intra- and intercellular messenger with many physiological functions which make it unique among various gases produced by the human body [1]. As NO is over produced by a large variety of cells during inflammatory processes, measuring its production would be a logical means to monitor inflammation in human disease [1]. This is the case for NO detected in the exhaled air, and assessed by its fractional concentration measured at a constant expiratory flow rate of 50 mL.s−1 (FENO). FENO measurement has provided investigators worldwide with many useful information related to airways inflammation from patients with various respiratory disorders, especially atopic asthma [2]. Surprisingly FENO is paradoxically low in patients suffering from the two other major respiratory diseases associated with chronic airways inflammation, namely tobacco-related chronic bronchitis and cystic fibrosis (CF) [3]. When the underlying mechanisms explaining low FENO are well understood for tobacco-induced chronic obstructive pulmonary disease, biological pathways leading to reduced NO production in CF are still debated, with the putative implications of not only one but many intricate mechanisms [4]. In the airways numerous cell types, including the epithelium, are capable to synthesize NO from L-arginine and oxygen. NO production is catalysed by a family of enzymes, the NO synthases (NOS), which are either constitutively expressed or driven by inflammatory processes taking place in the whole lung, from large conducting airways to alveolar spaces [1]. Impaired NO production usually results from either reduced NOS gene expression and/or enzyme activity, or perturbed L-arginine metabolism [5]. Alternatively, physiological effects of NO are readily negated when NO combines with oxygen reactive species. This mechanism is of particular importance in a variety of inflammatory disorders, including CF, where oxidative stress is known to play a prominent role [5]. Owing to its biological effects, the absence, or reduced amount, of NO leads to the impairment of many physiological lung function. For example, as NO has
antimicrobial, bronchodilatory and vasodilatory effects, lack of NO paves the way to lung infection by various microorganisms, including P. aeruginosa, bronchial obstruction, and pulmonary vascular endothelial dysfunction [4–7]. Furthermore, many of the downstream products of the NO signalling pathway, e.g. the second messenger cyclic guanosine monophosphate (cGMP), and its related cGMP-dependent protein kinase (PKG), critically control the normal function of the epithelial sodium channel (ENaC), a key player in transepithelial ion transport homeostasis. As a result impaired NO production lowers intracellular cGMP and reduces PKG activity. As cGMP inhibits ENaC and PKG stimulates CFTR [4], the ensuing increased sodium influx and reduced chloride efflux disturb the normal ions and water transport at the luminal epithelial membrane of CF airways. The inverse relationship between FENO and baseline transepithelial nasal potential difference further supports the idea that lack of NO perturbs ENaC and CFTR functions in such a way to favour abnormal ions and fluid transport across the respiratory epithelium [8]. Conversely, amounting evidence now suggests that increasing NO in the airways of CF patients improves CFTR function. Treatment of CF cells with NO donors promotes ΔF508-CFTR maturation and function, and results in increased chloride efflux. Conversely, the question as to whether CFTR-targeting compounds can increase NO production in CF patients has not been properly addressed, until the two investigations reported in this issue of the Journal [9,10]. Grasemann et al. [9] and Kotha et al. [10] independently looked at the effects of 4 weeks treatment with the CFTR-targeting drug, Ivacaftor, on pulmonary function and FENO in two small groups of CF patients (15 and 5, respectively). Both studies consistently showed increased FENO in most CF patients after one month of Ivacaftor treatment [9,10], an effect which was more pronounced in paediatric as compared with adult CF patients [9]. As both studies also showed improved lung function with Ivacaftor, one might wonder as to whether increased FENO was directly related to restoration of CFTR function or was
684
Should we monitor exhaled NO to assess the restoration of CFTR function in CF patients?
it simply due to better lung function achieved after 4 weeks of Ivacaftor treatment. Grasemann et al. have shown that the latter is unlikely as FENO remained low whilst lung function significantly improved in patients treated with either Dornase alpha or hypertonic saline [9]. As in both studies FENO was only measured twice, i.e. at study entry and after 4 weeks of treatment with Ivacaftor, one might also question the validity of the observed FENO improvement, especially in such small groups of patients. To address this crucial issue, Koha et al. have shown that repeated measurement of FENO yielded stable results over time in a parallel group of 29 untreated CF children [10], reinforcing the idea that FENO improvement in treated patients is likely attributable to Ivacaftor rather than daily intraindividual variation of FENO. Looking at the results from both papers, and keeping in mind that these have been obtained in two observational studies with very small groups of patients [9,10], investigators intrigued by the peculiar and still incompletely understood links between NO production and CFTR function must however admit that this topic is probably now entering a new phase of conceptual development. Indeed the idea of measuring FENO as a biomarker of restored CFTR function might seem both an exciting and very promising one. Still, we should not be overly enthusiastic as additional confirmatory results are required. These will be obtained with future prospective and controlled studies in larger cohorts of CF patients. Only then, one can be certain that FENO, a surrogate marker of airways inflammation known for decades [3], can also be used to monitor restored CFTR function. The good news however is if the conclusions of both clinical studies [9,10] reported in this issue of the Journal hold true, basic science research will then be needed to solve another question we tend to overlook. Indeed, as stated previously if we know the various mechanisms explaining how low NO production and/or activity can impair lung function, mucociliary clearance, and favour lung infection with P. aeruginosa in CF, the field of research aiming to unravel the links between restored CFTR function and increased NO production is mostly unsuspected and largely unexplored to date. Let us bet that the fundamental question these two studies have implicitly led to, i.e. what are the underlying mechanisms of the control exerted by CFTR over NO production, will be soon addressed, and hopefully answered.
References [1] Ricciardolo FL, Sterk PJ, Gaston B, Folkerts G. Nitric oxide in health and disease of the respiratory system. Physiol Rev 2004;84:731–65. [2] Dinh-Xuan AT, Annesi-Maesano I, Berger P, Chambellan A, Chanez P, Chinet T, et al. Contribution of exhaled nitric oxide measurement in airway inflammation assessment in asthma. A position paper from the French Speaking Respiratory Society. Rev Mal Respir 2015;32:193–215. [3] Thébaud B, Arnal JF, Mercier JC, Dinh-Xuan AT. Inhaled and exhaled nitric oxide. Cell Mol Life Sci 1999;55:1103–12. [4] de Winter-de Groot KM, van der Ent CK. Nitric oxide in cystic fibrosis. J Cyst Fibros 2005;4(Suppl. 2):25–9. [5] Grasemann H, Ratjen F. Nitric oxide and L-arginine deficiency in cystic fibrosis. Curr Pharm Des 2012;18:726–36. [6] Keen C, Olin AC, Edentoft A, Gronowitz E, Strandvik B. Airway nitric oxide in patients with cystic fibrosis is associated with pancreatic function, Pseudomonas infection, and polyunsaturated fatty acids. Chest 2007;131: 1857–64. [7] Dinh-Xuan AT, Higenbottam TW, Pepke-Zaba J, Clelland C, Wallwork J. Reduced endothelium-dependent relaxation of cystic fibrosis pulmonary arteries. Eur J Pharmacol 1989;163:401–3. [8] Texereau J, Fajac I, Hubert D, Coste J, Dusser DJ, Bienvenu T, et al. Reduced exhaled NO is related to impaired nasal potential difference in patients with cystic fibrosis. Vascul Pharmacol 2005;43:385–9. [9] Grasemann H, Gonska T, Avolio J, Klingel M, Tullis E, Ratjen F. Effect of ivacaftor therapy on exhaled nitric oxide in patients with cystic fibrosis. J Cyst Fibros 2015;14:728–33. [10] Kotha K, Szczesniak RD, Naren AP, Fenchel MC, Duan LL, McPhail GL, et al. Concentration of fractional excretion of nitric oxide (FENO): A potential airway biomarker of restored CFTR function. J Cyst Fibros 2015;14:734–41.
Anh Tuan Dinh-Xuan Paris Descartes University, Department of Physiology, Sorbonne Paris Cité, Cochin Hospital, 27 rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France Corresponding author at: Cochin Hospital, Department of Physiology, 27 rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France. E-mail address: [email protected].
21 September 2015