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. 1998 Sep 15;102(6):1200–1207. doi: 10.1172/JCI2357

Inducible nitric oxide synthase expression is reduced in cystic fibrosis murine and human airway epithelial cells.

T J Kelley 1, M L Drumm 1
PMCID: PMC509103  PMID: 9739054

Abstract

It has been reported that exhaled nitric oxide levels are reduced in cystic fibrosis (CF) patients. We have examined the inducible isoform of nitric oxide synthase (iNOS) in the airways by immunostaining and found that iNOS is constitutively expressed in the airway epithelia of non-CF mouse and human tissues but essentially absent in the epithelium of CF airways. We explored potential consequences of lost iNOS expression and found that iNOS inhibition significantly increases mouse nasal trans-epithelial potential difference, and hindered the ability of excised mouse lungs to prevent growth of Pseudomonas aeruginosa. The absence of continuous nitric oxide production in epithelial cells of CF airways may play a role in two CF-associated characteristics: hyperabsorption of sodium and susceptibility to bacterial infections.

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Selected References

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  1. Ahn K. Y., Mohaupt M. G., Madsen K. M., Kone B. C. In situ hybridization localization of mRNA encoding inducible nitric oxide synthase in rat kidney. Am J Physiol. 1994 Nov;267(5 Pt 2):F748–F757. doi: 10.1152/ajprenal.1994.267.5.F748. [DOI] [PubMed] [Google Scholar]
  2. Balfour-Lynn I. M., Laverty A., Dinwiddie R. Reduced upper airway nitric oxide in cystic fibrosis. Arch Dis Child. 1996 Oct;75(4):319–322. doi: 10.1136/adc.75.4.319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barnes P. J. Nitric oxide and airways. Eur Respir J. 1993 Feb;6(2):163–165. [PubMed] [Google Scholar]
  4. Costanzo L. S., Windhager E. E. Effects of PTH, ADH, and cyclic AMP on distal tubular Ca and Na reabsorption. Am J Physiol. 1980 Nov;239(5):F478–F485. doi: 10.1152/ajprenal.1980.239.5.F478. [DOI] [PubMed] [Google Scholar]
  5. Crawford I., Maloney P. C., Zeitlin P. L., Guggino W. B., Hyde S. C., Turley H., Gatter K. C., Harris A., Higgins C. F. Immunocytochemical localization of the cystic fibrosis gene product CFTR. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9262–9266. doi: 10.1073/pnas.88.20.9262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dötsch J., Demirakça S., Terbrack H. G., Hüls G., Rascher W., Kühl P. G. Airway nitric oxide in asthmatic children and patients with cystic fibrosis. Eur Respir J. 1996 Dec;9(12):2537–2540. doi: 10.1183/09031936.96.09122537. [DOI] [PubMed] [Google Scholar]
  7. Eckman E. A., Cotton C. U., Kube D. M., Davis P. B. Dietary changes improve survival of CFTR S489X homozygous mutant mouse. Am J Physiol. 1995 Nov;269(5 Pt 1):L625–L630. doi: 10.1152/ajplung.1995.269.5.L625. [DOI] [PubMed] [Google Scholar]
  8. Felley-Bosco E., Ambs S., Lowenstein C. J., Keefer L. K., Harris C. C. Constitutive expression of inducible nitric oxide synthase in human bronchial epithelial cells induces c-fos and stimulates the cGMP pathway. Am J Respir Cell Mol Biol. 1994 Aug;11(2):159–164. doi: 10.1165/ajrcmb.11.2.7519434. [DOI] [PubMed] [Google Scholar]
  9. Geary C. A., Goy M. F., Boucher R. C. Synthesis and vectorial export of cGMP in airway epithelium: expression of soluble and CNP-specific guanylate cyclases. Am J Physiol. 1993 Dec;265(6 Pt 1):L598–L605. doi: 10.1152/ajplung.1993.265.6.L598. [DOI] [PubMed] [Google Scholar]
  10. Goldman M. J., Anderson G. M., Stolzenberg E. D., Kari U. P., Zasloff M., Wilson J. M. Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell. 1997 Feb 21;88(4):553–560. doi: 10.1016/s0092-8674(00)81895-4. [DOI] [PubMed] [Google Scholar]
  11. Gosselin D., DeSanctis J., Boulé M., Skamene E., Matouk C., Radzioch D. Role of tumor necrosis factor alpha in innate resistance to mouse pulmonary infection with Pseudomonas aeruginosa. Infect Immun. 1995 Sep;63(9):3272–3278. doi: 10.1128/iai.63.9.3272-3278.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Grasemann H., Michler E., Wallot M., Ratjen F. Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis. Pediatr Pulmonol. 1997 Sep;24(3):173–177. doi: 10.1002/(sici)1099-0496(199709)24:3<173::aid-ppul2>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  13. Grubb B. R., Vick R. N., Boucher R. C. Hyperabsorption of Na+ and raised Ca(2+)-mediated Cl- secretion in nasal epithelia of CF mice. Am J Physiol. 1994 May;266(5 Pt 1):C1478–C1483. doi: 10.1152/ajpcell.1994.266.5.C1478. [DOI] [PubMed] [Google Scholar]
  14. Guo F. H., De Raeve H. R., Rice T. W., Stuehr D. J., Thunnissen F. B., Erzurum S. C. Continuous nitric oxide synthesis by inducible nitric oxide synthase in normal human airway epithelium in vivo. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7809–7813. doi: 10.1073/pnas.92.17.7809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hamid Q., Springall D. R., Riveros-Moreno V., Chanez P., Howarth P., Redington A., Bousquet J., Godard P., Holgate S., Polak J. M. Induction of nitric oxide synthase in asthma. Lancet. 1993 Dec 18;342(8886-8887):1510–1513. doi: 10.1016/s0140-6736(05)80083-2. [DOI] [PubMed] [Google Scholar]
  16. Hibbs J. B., Jr, Taintor R. R., Vavrin Z., Rachlin E. M. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun. 1988 Nov 30;157(1):87–94. doi: 10.1016/s0006-291x(88)80015-9. [DOI] [PubMed] [Google Scholar]
  17. Hoffman R. A., Zhang G., Nüssler N. C., Gleixner S. L., Ford H. R., Simmons R. L., Watkins S. C. Constitutive expression of inducible nitric oxide synthase in the mouse ileal mucosa. Am J Physiol. 1997 Feb;272(2 Pt 1):G383–G392. doi: 10.1152/ajpgi.1997.272.2.G383. [DOI] [PubMed] [Google Scholar]
  18. Ismailov I. I., Awayda M. S., Jovov B., Berdiev B. K., Fuller C. M., Dedman J. R., Kaetzel M., Benos D. J. Regulation of epithelial sodium channels by the cystic fibrosis transmembrane conductance regulator. J Biol Chem. 1996 Mar 1;271(9):4725–4732. doi: 10.1074/jbc.271.9.4725. [DOI] [PubMed] [Google Scholar]
  19. Kelley T. J., Al-Nakkash L., Drumm M. L. C-type natriuretic peptide increases chloride permeability in normal and cystic fibrosis airway cells. Am J Respir Cell Mol Biol. 1997 Apr;16(4):464–470. doi: 10.1165/ajrcmb.16.4.9115758. [DOI] [PubMed] [Google Scholar]
  20. Kelley T. J., Thomas K., Milgram L. J., Drumm M. L. In vivo activation of the cystic fibrosis transmembrane conductance regulator mutant deltaF508 in murine nasal epithelium. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2604–2608. doi: 10.1073/pnas.94.6.2604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kharitonov S. A., Yates D., Robbins R. A., Logan-Sinclair R., Shinebourne E. A., Barnes P. J. Increased nitric oxide in exhaled air of asthmatic patients. Lancet. 1994 Jan 15;343(8890):133–135. doi: 10.1016/s0140-6736(94)90931-8. [DOI] [PubMed] [Google Scholar]
  22. Koller B. H., Kim H. S., Latour A. M., Brigman K., Boucher R. C., Jr, Scambler P., Wainwright B., Smithies O. Toward an animal model of cystic fibrosis: targeted interruption of exon 10 of the cystic fibrosis transmembrane regulator gene in embryonic stem cells. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10730–10734. doi: 10.1073/pnas.88.23.10730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Light D. B., Schwiebert E. M., Karlson K. H., Stanton B. A. Atrial natriuretic peptide inhibits a cation channel in renal inner medullary collecting duct cells. Science. 1989 Jan 20;243(4889):383–385. doi: 10.1126/science.2463673. [DOI] [PubMed] [Google Scholar]
  24. Lundberg J. O., Nordvall S. L., Weitzberg E., Kollberg H., Alving K. Exhaled nitric oxide in paediatric asthma and cystic fibrosis. Arch Dis Child. 1996 Oct;75(4):323–326. doi: 10.1136/adc.75.4.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. MacMicking J. D., Nathan C., Hom G., Chartrain N., Fletcher D. S., Trumbauer M., Stevens K., Xie Q. W., Sokol K., Hutchinson N. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell. 1995 May 19;81(4):641–650. doi: 10.1016/0092-8674(95)90085-3. [DOI] [PubMed] [Google Scholar]
  26. Meng Q. H., Springall D. R., Bishop A. E., Morgan K., Evans T. J., Habib S., Gruenert D. C., Gyi K. M., Hodson M. E., Yacoub M. H. Lack of inducible nitric oxide synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis. J Pathol. 1998 Mar;184(3):323–331. doi: 10.1002/(SICI)1096-9896(199803)184:3<323::AID-PATH2>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  27. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  28. Ottaviani E., Paeman L. R., Cadet P., Stefano G. B. Evidence for nitric oxide production and utilization as a bacteriocidal agent by invertebrate immunocytes. Eur J Pharmacol. 1993 Dec 1;248(4):319–324. doi: 10.1016/0926-6917(93)90006-c. [DOI] [PubMed] [Google Scholar]
  29. Persson M. G., Zetterström O., Agrenius V., Ihre E., Gustafsson L. E. Single-breath nitric oxide measurements in asthmatic patients and smokers. Lancet. 1994 Jan 15;343(8890):146–147. doi: 10.1016/s0140-6736(94)90935-0. [DOI] [PubMed] [Google Scholar]
  30. Pheng L. H., Francoeur C., Denis M. The involvement of nitric oxide in a mouse model of adult respiratory distress syndrome. Inflammation. 1995 Oct;19(5):599–610. doi: 10.1007/BF01539139. [DOI] [PubMed] [Google Scholar]
  31. Riordan J. R., Rommens J. M., Kerem B., Alon N., Rozmahel R., Grzelczak Z., Zielenski J., Lok S., Plavsic N., Chou J. L. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989 Sep 8;245(4922):1066–1073. doi: 10.1126/science.2475911. [DOI] [PubMed] [Google Scholar]
  32. Roczniak A., Burns K. D. Nitric oxide stimulates guanylate cyclase and regulates sodium transport in rabbit proximal tubule. Am J Physiol. 1996 Jan;270(1 Pt 2):F106–F115. doi: 10.1152/ajprenal.1996.270.1.F106. [DOI] [PubMed] [Google Scholar]
  33. Rommens J. M., Iannuzzi M. C., Kerem B., Drumm M. L., Melmer G., Dean M., Rozmahel R., Cole J. L., Kennedy D., Hidaka N. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989 Sep 8;245(4922):1059–1065. doi: 10.1126/science.2772657. [DOI] [PubMed] [Google Scholar]
  34. Rosbe K. W., Mims J. W., Prazma J., Petrusz P., Rose A., Drake A. F. Immunohistochemical localization of nitric oxide synthase activity in upper respiratory epithelium. Laryngoscope. 1996 Sep;106(9 Pt 1):1075–1079. doi: 10.1097/00005537-199609000-00006. [DOI] [PubMed] [Google Scholar]
  35. Saito S., Onozuka K., Shinomiya H., Nakano M. Sensitivity of bacteria to NaNO2 and to L-arginine-dependent system in murine macrophages. Microbiol Immunol. 1991;35(4):325–329. doi: 10.1111/j.1348-0421.1991.tb01561.x. [DOI] [PubMed] [Google Scholar]
  36. Sato T., Kamata Y., Irifune M., Nishikawa T. Inhibition of purified (Na+,K+)-ATPase activity from porcine cerebral cortex by NO generating drugs. Brain Res. 1995 Dec 15;704(1):117–120. doi: 10.1016/0006-8993(95)01165-x. [DOI] [PubMed] [Google Scholar]
  37. Schmidt H. H., Walter U. NO at work. Cell. 1994 Sep 23;78(6):919–925. doi: 10.1016/0092-8674(94)90267-4. [DOI] [PubMed] [Google Scholar]
  38. Smith J. J., Travis S. M., Greenberg E. P., Welsh M. J. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell. 1996 Apr 19;85(2):229–236. doi: 10.1016/s0092-8674(00)81099-5. [DOI] [PubMed] [Google Scholar]
  39. Snouwaert J. N., Brigman K. K., Latour A. M., Malouf N. N., Boucher R. C., Smithies O., Koller B. H. An animal model for cystic fibrosis made by gene targeting. Science. 1992 Aug 21;257(5073):1083–1088. doi: 10.1126/science.257.5073.1083. [DOI] [PubMed] [Google Scholar]
  40. Stutts M. J., Canessa C. M., Olsen J. C., Hamrick M., Cohn J. A., Rossier B. C., Boucher R. C. CFTR as a cAMP-dependent regulator of sodium channels. Science. 1995 Aug 11;269(5225):847–850. doi: 10.1126/science.7543698. [DOI] [PubMed] [Google Scholar]
  41. Zeiher B. G., Eichwald E., Zabner J., Smith J. J., Puga A. P., McCray P. B., Jr, Capecchi M. R., Welsh M. J., Thomas K. R. A mouse model for the delta F508 allele of cystic fibrosis. J Clin Invest. 1995 Oct;96(4):2051–2064. doi: 10.1172/JCI118253. [DOI] [PMC free article] [PubMed] [Google Scholar]

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