NO-dependent CFTR activation (normal and CF)

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NO-dependent CFTR activation (normal and CF)

Cystic fibrosis (CF) is a multisystem disease associated with mutations in the gene encoding the CF transmembrane conductance regulatory (CFTR) protein [1]. The most common mutation associated with CF results in deletion of a single amino acid, phenylalanine, at position 508 in CFTR protein (mutant deltaF508 CFTR protein) [2], [3].

Exhaled nitric oxide (NO), elevated in most inflammatory lung diseases, is decreased in CF. According to some studies, impaired NO formation in lower airways correlates with more progressive lung disease [4].

NO is produced by a family of NO synthases (NOS) by transformation of L-arginine to L-citrulline and NO. In human, there are three isoforms of NOS: neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). nNOS and eNOS are constitutively expressed and produce small amounts of NO, whereas iNOS expression is mainly induced by inflammatory stimuli. Induced iNOS synthesizes relatively large quantities of NO. All three isoforms are expressed in human airways [4].

In the case of CF, airway epithelial cells are more susceptible to bacterial and viral infection due to impairment of the host NO defense pathway. Polymorphisms of constitutive NOS (nNOS and eNOS) and reduced iNOS expression contributes to decreased NO production along with bacterial consumption [4], [5], [6], [7], [8]. Alternatively, lower concentration of airway NO in CF could be caused by lack of substrate, L-arginine. [9]. L-arginine is a common substrate for both NOSs (e.g., iNOS) and arginase (ARG1). ARG1 activity is increased in CF patients. Increased ARG1 activity can result in L-arginine deficiency and thereby contribute to low airway NO formation and impaired pulmonary function [10], [11].

NO can also be released from S-Nitrosoglutathione, an endogenous signaling molecule that at low micromolar concentrations increases expression, maturation, and function of both wild-type and deltaF508 CFTR in epithelial cells [12], [13], [14]. S-Nitrosoglutathione mainly acts independently of the classic NO radical/cyclic GMP pathway [15]. A number of enzymes can catabolize S-Nitrosoglutathione to form free NO radicals, including Cu/Zn superoxide dismutase (SOD1) and thioredoxin reductases (TXNRD1, TXNRD2 and TXNRD3) [16], [17], [18], [19].

NO mediates many effects through production of cyclic GMP (cGMP) by NO-sensitive guanylate cyclase. cGMP activates type II isoform of cGMP dependent protein kinase G (Protein kinase G 2). The latter phosphorylates CFTR and increases its activity. NO-sensitive Guanylate cyclase alpha-2/beta-1 isoform is localized in the plasma membrane where it mediates stimulatory effect of NO on CFTR activity much more efficiently than other NO-dependent guanylate cyclase isoforms [20]. The selective membrane effects of the Guanylate cyclase alpha-2/beta-1 isoform in this signaling relay are mediated by a compartmentalized pool of cGMP that is resistant to degradation by cellular phosphodiesterases, such as phosphodiesterase 5A (PDE5A) [20], [21], [22].

NO and cGMP stimulate CFTR activity and can down-regulate amiloride-sensitive epithelial sodium absorption [4], [23], [24].

CFTR is an apical membrane Cl- channel in epithelial cells. CFTR negatively regulates the amiloride-sensitive epithelial sodium channel (ENaC). ENaC inhibition by CFTR is documented in CF patients which suffer from airway obstruction and chronic infection that results from decreased mucociliary clearance secondary to missing CFTR and high ENaC activity [25].

CFTR and ENaC are the principal rate-limiting steps for Cl- secretion and Na+ absorption by ciliated airway epithelia. Mutations in the CFTR gene lead to hyperabsorption of sodium chloride and a reduction in the periciliary salt and water content which leads to impaired mucociliary clearance [26], [27], [28].

The mechanism of CFTR inhibition of ENaC activity is not known. The proposed mechanisms range from altered cellular trafficking of ENaC to direct protein/protein interactions [29], [30], [31].

There is also a unique relationship in the CF airway between prokaryotic and eukaryotic cells. The airway colonization with denitrifying bacteria, such as Pseudomonas aeruginosa and Burkholderia species, alters nitrogen balance in the CF airway. CF lung infection is associated with decreased concentrations of oxidized forms of nitrogen (such as NO) and increased concentrations of reduced forms of nitrogen (such as nitrous oxide (N(2)O) and ammonium (NH(3))) in the CF airways [32].

The reduction of NO to N(2)O can be catalyzed by enzymes like Nitric oxide reductase (NOR (P. aeruginosa)) in the P. aeruginosa denitrification pathway [32], [33], [34]. NOR (P. aeruginosa) can also catalyze the reduction of N(2)O to molecular nitrogen (N2) [35], [36]. One of the most prevalent species of the Burkholderia cepacia complex found in CF patients, Burkholderia vietnamiensis, can produce a Nitrogenase complex that catalyzes the reduction of N(2) to NH(3) [37].

In epithelial cells, NH(3) inhibits chloride transport (via CFTR channel), and NO inhibits amiloride-sensitive sodium transport (via ENaC channel) and augments chloride transport [32], [38], [39]. Thereby, a shift from oxidized to reduced forms of nitrogen can increase epithelial salt transport abnormalities in CF airways and adversely affect CF disease.

Mucoid, mucA mutant P. aeruginosa bacteria cause chronic lung infections in CF patients and are refractory to phagocytosis and antibiotics. As chronic CF lung disease progresses, mucoid, alginate-overproducing strains emerge and become the predominant form [40].

P. aeruginosa is capable of anaerobic growth by respiration using nitrite (NO(2)(-)) as terminal electron acceptor. The reduction of (NO(2)(-)) to NO is catalyzed by P. aeruginosa enzyme Nitric reductase (NirS (P. aeruginosa)) [40].

Mucoid, mucA mutant P. aeruginosa has the inherently low NirS and NOR activity and, thereby, has limited capacity for NO(2)(-) and NO removal. Treatment of mucoid, mucA mutant bacteria with NO(2)(-) (15 mM) at pH 6.5 under anaerobic conditions, similar to conditions within mucopurulent secretions in the airways of CF patients, leads to the death of these bacteria. Thereby, the treatment (e.g. aerosolization) of CF patients with NO(2)(-) and NO can exert antimicrobial effect on mucoid P. aeruginosa [40].

References:

  1. Rowe SM, Miller S, Sorscher EJ
    Cystic fibrosis. The New England journal of medicine 2005 May 12;352(19):1992-2001
  2. Gibson RL, Burns JL, Ramsey BW
    Pathophysiology and management of pulmonary infections in cystic fibrosis. American journal of respiratory and critical care medicine 2003 Oct 15;168(8):918-51
  3. Dubin PJ, McAllister F, Kolls JK
    Is cystic fibrosis a TH17 disease? Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2007 Jun;56(6):221-7
  4. de Winter-de Groot KM, van der Ent CK
    Nitric oxide in cystic fibrosis. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 2005 Aug;4 Suppl 2:25-9
  5. Kelley TJ, Drumm ML
    Inducible nitric oxide synthase expression is reduced in cystic fibrosis murine and human airway epithelial cells. The Journal of clinical investigation 1998 Sep 15;102(6):1200-7
  6. Grasemann H, Storm van's Gravesande K, Buscher R, Knauer N, Silverman ES, Palmer LJ, Drazen JM, Ratjen F
    Endothelial nitric oxide synthase variants in cystic fibrosis lung disease. American journal of respiratory and critical care medicine 2003 Feb 1;167(3):390-4
  7. Zheng S, Xu W, Bose S, Banerjee AK, Haque SJ, Erzurum SC
    Impaired nitric oxide synthase-2 signaling pathway in cystic fibrosis airway epithelium. American journal of physiology. Lung cellular and molecular physiology 2004 Aug;287(2):L374-81
  8. Moeller A, Horak F Jr, Lane C, Knight D, Kicic A, Brennan S, Franklin P, Terpolilli J, Wildhaber JH, Stick SM
    Inducible NO synthase expression is low in airway epithelium from young children with cystic fibrosis. Thorax 2006 Jun;61(6):514-20
  9. Grasemann H, Kurtz F, Ratjen F
    Inhaled L-arginine improves exhaled nitric oxide and pulmonary function in patients with cystic fibrosis. American journal of respiratory and critical care medicine 2006 Jul 15;174(2):208-12
  10. Grasemann H, Schwiertz R, Matthiesen S, Racke K, Ratjen F
    Increased arginase activity in cystic fibrosis airways. American journal of respiratory and critical care medicine 2005 Dec 15;172(12):1523-8
  11. Grasemann H, Schwiertz R, Grasemann C, Vester U, Racke K, Ratjen F
    Decreased systemic bioavailability of L-arginine in patients with cystic fibrosis. Respiratory research 2006 Jun 9;7:87
  12. Zaman K, McPherson M, Vaughan J, Hunt J, Mendes F, Gaston B, Palmer LA
    S-nitrosoglutathione increases cystic fibrosis transmembrane regulator maturation. Biochemical and biophysical research communications 2001 Jun 1;284(1):65-70
  13. Zaman K, Palmer LA, Doctor A, Hunt JF, Gaston B
    Concentration-dependent effects of endogenous S-nitrosoglutathione on gene regulation by specificity proteins Sp3 and Sp1. The Biochemical journal 2004 May 15;380(Pt 1):67-74
  14. Chen L, Patel RP, Teng X, Bosworth CA, Lancaster JR Jr, Matalon S
    Mechanisms of cystic fibrosis transmembrane conductance regulator activation by S-nitrosoglutathione. The Journal of biological chemistry 2006 Apr 7;281(14):9190-9
  15. Zaman K, Carraro S, Doherty J, Henderson EM, Lendermon E, Liu L, Verghese G, Zigler M, Ross M, Park E, Palmer LA, Doctor A, Stamler JS, Gaston B
    S-nitrosylating agents: a novel class of compounds that increase cystic fibrosis transmembrane conductance regulator expression and maturation in epithelial cells. Molecular pharmacology 2006 Oct;70(4):1435-42
  16. Nikitovic D, Holmgren A
    S-nitrosoglutathione is cleaved by the thioredoxin system with liberation of glutathione and redox regulating nitric oxide. The Journal of biological chemistry 1996 Aug 9;271(32):19180-5
  17. Romeo AA, Capobianco JA, English AM
    Superoxide dismutase targets NO from GSNO to Cysbeta93 of oxyhemoglobin in concentrated but not dilute solutions of the protein. Journal of the American Chemical Society 2003 Nov 26;125(47):14370-8
  18. Gaston BM, Carver J, Doctor A, Palmer LA
    S-nitrosylation signaling in cell biology. Molecular interventions 2003 Aug;3(5):253-63
  19. Zeitlin PL
    Is it go or NO go for S-nitrosylation modification-based therapies of cystic fibrosis transmembrane regulator trafficking? Molecular pharmacology 2006 Oct;70(4):1155-8
  20. Bellingham M, Evans TJ
    The alpha2beta1 isoform of guanylyl cyclase mediates plasma membrane localized nitric oxide signalling. Cellular signalling 2007 Oct;19(10):2183-93
  21. Poschet JF, Timmins GS, Taylor-Cousar JL, Ornatowski W, Fazio J, Perkett E, Wilson KR, Yu HD, de Jonge HR, Deretic V
    Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis. American journal of physiology. Lung cellular and molecular physiology 2007 Sep;293(3):L712-9
  22. Clarke LL
    Phosphodiesterase 5 inhibitors and cystic fibrosis: correcting chloride channel dysfunction. American journal of respiratory and critical care medicine 2008 Mar 1;177(5):469-70
  23. Elmer HL, Brady KG, Drumm ML, Kelley TJ
    Nitric oxide-mediated regulation of transepithelial sodium and chloride transport in murine nasal epithelium. The American journal of physiology 1999 Mar;276(3 Pt 1):L466-73
  24. Lazrak A, Samanta A, Matalon S
    Biophysical properties and molecular characterization of amiloride-sensitive sodium channels in A549 cells. American journal of physiology. Lung cellular and molecular physiology 2000 Apr;278(4):L848-57
  25. Smith JJ, Karp PH, Welsh MJ
    Defective fluid transport by cystic fibrosis airway epithelia. The Journal of clinical investigation 1994 Mar;93(3):1307-11
  26. Mall M, Grubb BR, Harkema JR, O'Neal WK, Boucher RC
    Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nature medicine 2004 May;10(5):487-93
  27. Terheggen-Lagro SW, Rijkers GT, van der Ent CK
    The role of airway epithelium and blood neutrophils in the inflammatory response in cystic fibrosis. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 2005 Aug;4 Suppl 2:15-23
  28. Huang P, Gilmore E, Kultgen P, Barnes P, Milgram S, Stutts MJ
    Local regulation of cystic fibrosis transmembrane regulator and epithelial sodium channel in airway epithelium. Proceedings of the American Thoracic Society 2004;1(1):33-7
  29. Kunzelmann K, Schreiber R, Nitschke R, Mall M
    Control of epithelial Na+ conductance by the cystic fibrosis transmembrane conductance regulator. Pflugers Archiv : European journal of physiology 2000 Jun;440(2):193-201
  30. Berdiev BK, Cormet-Boyaka E, Tousson A, Qadri YJ, Oosterveld-Hut HM, Hong JS, Gonzales PA, Fuller CM, Sorscher EJ, Lukacs GL, Benos DJ
    Molecular proximity of cystic fibrosis transmembrane conductance regulator and epithelial sodium channel assessed by fluorescence resonance energy transfer. The Journal of biological chemistry 2007 Dec 14;282(50):36481-8
  31. Donaldson SH, Boucher RC
    Sodium channels and cystic fibrosis. Chest 2007 Nov;132(5):1631-6
  32. Gaston B, Ratjen F, Vaughan JW, Malhotra NR, Canady RG, Snyder AH, Hunt JF, Gaertig S, Goldberg JB
    Nitrogen redox balance in the cystic fibrosis airway: effects of antipseudomonal therapy. American journal of respiratory and critical care medicine 2002 Feb 1;165(3):387-90
  33. Arai H, Igarashi Y, Kodama T
    The structural genes for nitric oxide reductase from Pseudomonas aeruginosa. Biochimica et biophysica acta 1995 Apr 4;1261(2):279-84
  34. Kumita H, Matsuura K, Hino T, Takahashi S, Hori H, Fukumori Y, Morishima I, Shiro Y
    NO reduction by nitric-oxide reductase from denitrifying bacterium Pseudomonas aeruginosa: characterization of reaction intermediates that appear in the single turnover cycle. The Journal of biological chemistry 2004 Dec 31;279(53):55247-54
  35. Vosswinkel R, Neidt I, Bothe H
    The production and utilization of nitric oxide by a new, denitrifying strain of Pseudomonas aeruginosa. Archives of microbiology 1991;156(1):62-9
  36. SooHoo CK, Hollocher TC
    Purification and characterization of nitrous oxide reductase from Pseudomonas aeruginosa strain P2. The Journal of biological chemistry 1991 Feb 5;266(4):2203-9
  37. Menard A, Monnez C, Estrada de Los Santos P, Segonds C, Caballero-Mellado J, Lipuma JJ, Chabanon G, Cournoyer B
    Selection of nitrogen-fixing deficient Burkholderia vietnamiensis strains by cystic fibrosis patients: involvement of nif gene deletions and auxotrophic mutations. Environmental microbiology 2007 May;9(5):1176-85
  38. Prasad M, Smith JA, Resnick A, Awtrey CS, Hrnjez BJ, Matthews JB
    Ammonia inhibits cAMP-regulated intestinal Cl- transport. Asymmetric effects of apical and basolateral exposure and implications for epithelial barrier function. The Journal of clinical investigation 1995 Nov;96(5):2142-51
  39. Jain L, Chen XJ, Brown LA, Eaton DC
    Nitric oxide inhibits lung sodium transport through a cGMP-mediated inhibition of epithelial cation channels. The American journal of physiology 1998 Apr;274(4 Pt 1):L475-84
  40. Yoon SS, Coakley R, Lau GW, Lymar SV, Gaston B, Karabulut AC, Hennigan RF, Hwang SH, Buettner G, Schurr MJ, Mortensen JE, Burns JL, Speert D, Boucher RC, Hassett DJ
    Anaerobic killing of mucoid Pseudomonas aeruginosa by acidified nitrite derivatives under cystic fibrosis airway conditions. The Journal of clinical investigation 2006 Feb;116(2):436-46

  1. Rowe SM, Miller S, Sorscher EJ
    Cystic fibrosis. The New England journal of medicine 2005 May 12;352(19):1992-2001
  2. Gibson RL, Burns JL, Ramsey BW
    Pathophysiology and management of pulmonary infections in cystic fibrosis. American journal of respiratory and critical care medicine 2003 Oct 15;168(8):918-51
  3. Dubin PJ, McAllister F, Kolls JK
    Is cystic fibrosis a TH17 disease? Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2007 Jun;56(6):221-7
  4. de Winter-de Groot KM, van der Ent CK
    Nitric oxide in cystic fibrosis. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 2005 Aug;4 Suppl 2:25-9
  5. Kelley TJ, Drumm ML
    Inducible nitric oxide synthase expression is reduced in cystic fibrosis murine and human airway epithelial cells. The Journal of clinical investigation 1998 Sep 15;102(6):1200-7
  6. Grasemann H, Storm van's Gravesande K, Buscher R, Knauer N, Silverman ES, Palmer LJ, Drazen JM, Ratjen F
    Endothelial nitric oxide synthase variants in cystic fibrosis lung disease. American journal of respiratory and critical care medicine 2003 Feb 1;167(3):390-4
  7. Zheng S, Xu W, Bose S, Banerjee AK, Haque SJ, Erzurum SC
    Impaired nitric oxide synthase-2 signaling pathway in cystic fibrosis airway epithelium. American journal of physiology. Lung cellular and molecular physiology 2004 Aug;287(2):L374-81
  8. Moeller A, Horak F Jr, Lane C, Knight D, Kicic A, Brennan S, Franklin P, Terpolilli J, Wildhaber JH, Stick SM
    Inducible NO synthase expression is low in airway epithelium from young children with cystic fibrosis. Thorax 2006 Jun;61(6):514-20
  9. Grasemann H, Kurtz F, Ratjen F
    Inhaled L-arginine improves exhaled nitric oxide and pulmonary function in patients with cystic fibrosis. American journal of respiratory and critical care medicine 2006 Jul 15;174(2):208-12
  10. Grasemann H, Schwiertz R, Matthiesen S, Racke K, Ratjen F
    Increased arginase activity in cystic fibrosis airways. American journal of respiratory and critical care medicine 2005 Dec 15;172(12):1523-8
  11. Grasemann H, Schwiertz R, Grasemann C, Vester U, Racke K, Ratjen F
    Decreased systemic bioavailability of L-arginine in patients with cystic fibrosis. Respiratory research 2006 Jun 9;7:87
  12. Zaman K, McPherson M, Vaughan J, Hunt J, Mendes F, Gaston B, Palmer LA
    S-nitrosoglutathione increases cystic fibrosis transmembrane regulator maturation. Biochemical and biophysical research communications 2001 Jun 1;284(1):65-70
  13. Zaman K, Palmer LA, Doctor A, Hunt JF, Gaston B
    Concentration-dependent effects of endogenous S-nitrosoglutathione on gene regulation by specificity proteins Sp3 and Sp1. The Biochemical journal 2004 May 15;380(Pt 1):67-74
  14. Chen L, Patel RP, Teng X, Bosworth CA, Lancaster JR Jr, Matalon S
    Mechanisms of cystic fibrosis transmembrane conductance regulator activation by S-nitrosoglutathione. The Journal of biological chemistry 2006 Apr 7;281(14):9190-9
  15. Zaman K, Carraro S, Doherty J, Henderson EM, Lendermon E, Liu L, Verghese G, Zigler M, Ross M, Park E, Palmer LA, Doctor A, Stamler JS, Gaston B
    S-nitrosylating agents: a novel class of compounds that increase cystic fibrosis transmembrane conductance regulator expression and maturation in epithelial cells. Molecular pharmacology 2006 Oct;70(4):1435-42
  16. Nikitovic D, Holmgren A
    S-nitrosoglutathione is cleaved by the thioredoxin system with liberation of glutathione and redox regulating nitric oxide. The Journal of biological chemistry 1996 Aug 9;271(32):19180-5
  17. Romeo AA, Capobianco JA, English AM
    Superoxide dismutase targets NO from GSNO to Cysbeta93 of oxyhemoglobin in concentrated but not dilute solutions of the protein. Journal of the American Chemical Society 2003 Nov 26;125(47):14370-8
  18. Gaston BM, Carver J, Doctor A, Palmer LA
    S-nitrosylation signaling in cell biology. Molecular interventions 2003 Aug;3(5):253-63
  19. Zeitlin PL
    Is it go or NO go for S-nitrosylation modification-based therapies of cystic fibrosis transmembrane regulator trafficking? Molecular pharmacology 2006 Oct;70(4):1155-8
  20. Bellingham M, Evans TJ
    The alpha2beta1 isoform of guanylyl cyclase mediates plasma membrane localized nitric oxide signalling. Cellular signalling 2007 Oct;19(10):2183-93
  21. Poschet JF, Timmins GS, Taylor-Cousar JL, Ornatowski W, Fazio J, Perkett E, Wilson KR, Yu HD, de Jonge HR, Deretic V
    Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis. American journal of physiology. Lung cellular and molecular physiology 2007 Sep;293(3):L712-9
  22. Clarke LL
    Phosphodiesterase 5 inhibitors and cystic fibrosis: correcting chloride channel dysfunction. American journal of respiratory and critical care medicine 2008 Mar 1;177(5):469-70
  23. Elmer HL, Brady KG, Drumm ML, Kelley TJ
    Nitric oxide-mediated regulation of transepithelial sodium and chloride transport in murine nasal epithelium. The American journal of physiology 1999 Mar;276(3 Pt 1):L466-73
  24. Lazrak A, Samanta A, Matalon S
    Biophysical properties and molecular characterization of amiloride-sensitive sodium channels in A549 cells. American journal of physiology. Lung cellular and molecular physiology 2000 Apr;278(4):L848-57
  25. Smith JJ, Karp PH, Welsh MJ
    Defective fluid transport by cystic fibrosis airway epithelia. The Journal of clinical investigation 1994 Mar;93(3):1307-11
  26. Mall M, Grubb BR, Harkema JR, O'Neal WK, Boucher RC
    Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nature medicine 2004 May;10(5):487-93
  27. Terheggen-Lagro SW, Rijkers GT, van der Ent CK
    The role of airway epithelium and blood neutrophils in the inflammatory response in cystic fibrosis. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 2005 Aug;4 Suppl 2:15-23
  28. Huang P, Gilmore E, Kultgen P, Barnes P, Milgram S, Stutts MJ
    Local regulation of cystic fibrosis transmembrane regulator and epithelial sodium channel in airway epithelium. Proceedings of the American Thoracic Society 2004;1(1):33-7
  29. Kunzelmann K, Schreiber R, Nitschke R, Mall M
    Control of epithelial Na+ conductance by the cystic fibrosis transmembrane conductance regulator. Pflugers Archiv : European journal of physiology 2000 Jun;440(2):193-201
  30. Berdiev BK, Cormet-Boyaka E, Tousson A, Qadri YJ, Oosterveld-Hut HM, Hong JS, Gonzales PA, Fuller CM, Sorscher EJ, Lukacs GL, Benos DJ
    Molecular proximity of cystic fibrosis transmembrane conductance regulator and epithelial sodium channel assessed by fluorescence resonance energy transfer. The Journal of biological chemistry 2007 Dec 14;282(50):36481-8
  31. Donaldson SH, Boucher RC
    Sodium channels and cystic fibrosis. Chest 2007 Nov;132(5):1631-6
  32. Gaston B, Ratjen F, Vaughan JW, Malhotra NR, Canady RG, Snyder AH, Hunt JF, Gaertig S, Goldberg JB
    Nitrogen redox balance in the cystic fibrosis airway: effects of antipseudomonal therapy. American journal of respiratory and critical care medicine 2002 Feb 1;165(3):387-90
  33. Arai H, Igarashi Y, Kodama T
    The structural genes for nitric oxide reductase from Pseudomonas aeruginosa. Biochimica et biophysica acta 1995 Apr 4;1261(2):279-84
  34. Kumita H, Matsuura K, Hino T, Takahashi S, Hori H, Fukumori Y, Morishima I, Shiro Y
    NO reduction by nitric-oxide reductase from denitrifying bacterium Pseudomonas aeruginosa: characterization of reaction intermediates that appear in the single turnover cycle. The Journal of biological chemistry 2004 Dec 31;279(53):55247-54
  35. Vosswinkel R, Neidt I, Bothe H
    The production and utilization of nitric oxide by a new, denitrifying strain of Pseudomonas aeruginosa. Archives of microbiology 1991;156(1):62-9
  36. SooHoo CK, Hollocher TC
    Purification and characterization of nitrous oxide reductase from Pseudomonas aeruginosa strain P2. The Journal of biological chemistry 1991 Feb 5;266(4):2203-9
  37. Menard A, Monnez C, Estrada de Los Santos P, Segonds C, Caballero-Mellado J, Lipuma JJ, Chabanon G, Cournoyer B
    Selection of nitrogen-fixing deficient Burkholderia vietnamiensis strains by cystic fibrosis patients: involvement of nif gene deletions and auxotrophic mutations. Environmental microbiology 2007 May;9(5):1176-85
  38. Prasad M, Smith JA, Resnick A, Awtrey CS, Hrnjez BJ, Matthews JB
    Ammonia inhibits cAMP-regulated intestinal Cl- transport. Asymmetric effects of apical and basolateral exposure and implications for epithelial barrier function. The Journal of clinical investigation 1995 Nov;96(5):2142-51
  39. Jain L, Chen XJ, Brown LA, Eaton DC
    Nitric oxide inhibits lung sodium transport through a cGMP-mediated inhibition of epithelial cation channels. The American journal of physiology 1998 Apr;274(4 Pt 1):L475-84
  40. Yoon SS, Coakley R, Lau GW, Lymar SV, Gaston B, Karabulut AC, Hennigan RF, Hwang SH, Buettner G, Schurr MJ, Mortensen JE, Burns JL, Speert D, Boucher RC, Hassett DJ
    Anaerobic killing of mucoid Pseudomonas aeruginosa by acidified nitrite derivatives under cystic fibrosis airway conditions. The Journal of clinical investigation 2006 Feb;116(2):436-46

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