Abstract
Background: The loss of cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride conductance does not fully explain the diverse pathologies evident in patients with cystic fibrosis (CF). Bicarbonate (HCO3-) secretion is also impaired in CFTR expressing tissues and CFTR is thought to regulate HCO3- secretion at the apical membrane of epithelial cells. We hypothesised that the epithelial lining fluid (ELF) of patients with CF would be acidified and that this may be worsened during an infective exacerbation due to the increased inflammatory burden.
Methods: pH and nitrite levels in exhaled breath condensate (EBC) from 12 healthy non-smoking controls and 30 patients with CF (11 of whom were in an infective exacerbation) were measured. A further nine patients were studied before and after intravenous antibiotic treatment for an exacerbation of CF.
Results: The pH of EBC was significantly lower in patients with stable CF than in controls (5.88 (0.32) v 6.15 (0.16), p=0.017), and was further reduced in CF patients with an exacerbation (5.32 (0.38), p=0.001) compared with stable CF patients. EBC pH increased significantly following antibiotic treatment from 5.27 (0.42) to 5.71 (0.42), p=0.049). Nitrite levels in EBC were increased in CF patients with an exacerbation compared with control subjects (4.4 (4.0) µm v 1.6 (1.6) µm p=0.047). No correlation was found between EBC pH and nitrite levels.
Conclusions: These findings support the hypothesis that airway acidification occurs in CF. This acidity is in part a function of inflammation as the pH of the EBC of patients increased significantly with treatment of an exacerbation, although not to control levels. Acidic pH of the ELF may play a role in the pathophysiology of CF lung disease and requires further investigation.
Full Text
The Full Text of this article is available as a PDF (114.8 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bhaskar K. R., Gong D. H., Bansil R., Pajevic S., Hamilton J. A., Turner B. S., LaMont J. T. Profound increase in viscosity and aggregation of pig gastric mucin at low pH. Am J Physiol. 1991 Nov;261(5 Pt 1):G827–G832. doi: 10.1152/ajpgi.1991.261.5.G827. [DOI] [PubMed] [Google Scholar]
- Blaisdell C. J., Edmonds R. D., Wang X. T., Guggino S., Zeitlin P. L. pH-regulated chloride secretion in fetal lung epithelia. Am J Physiol Lung Cell Mol Physiol. 2000 Jun;278(6):L1248–L1255. doi: 10.1152/ajplung.2000.278.6.L1248. [DOI] [PubMed] [Google Scholar]
- Bodem C. R., Lampton L. M., Miller D. P., Tarka E. F., Everett E. D. Endobronchial pH. Relevance of aminoglycoside activity in gram-negative bacillary pneumonia. Am Rev Respir Dis. 1983 Jan;127(1):39–41. doi: 10.1164/arrd.1983.127.1.39. [DOI] [PubMed] [Google Scholar]
- Choi J. Y., Muallem D., Kiselyov K., Lee M. G., Thomas P. J., Muallem S. Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis. Nature. 2001 Mar 1;410(6824):94–97. doi: 10.1038/35065099. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clary-Meinesz C., Mouroux J., Cosson J., Huitorel P., Blaive B. Influence of external pH on ciliary beat frequency in human bronchi and bronchioles. Eur Respir J. 1998 Feb;11(2):330–333. doi: 10.1183/09031936.98.11020330. [DOI] [PubMed] [Google Scholar]
- Devor D. C., Singh A. K., Lambert L. C., DeLuca A., Frizzell R. A., Bridges R. J. Bicarbonate and chloride secretion in Calu-3 human airway epithelial cells. J Gen Physiol. 1999 May;113(5):743–760. doi: 10.1085/jgp.113.5.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guerrin F., Robin H., Lambert P., Kine A. pH métrie bronchique in situ. Effets de l'hypoxie-hypercapnie. J Physiol (Paris) 1969;61 (Suppl 2):305–306. [PubMed] [Google Scholar]
- Ho L. P., Innes J. A., Greening A. P. Nitrite levels in breath condensate of patients with cystic fibrosis is elevated in contrast to exhaled nitric oxide. Thorax. 1998 Aug;53(8):680–684. doi: 10.1136/thx.53.8.680. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hunt J. F., Fang K., Malik R., Snyder A., Malhotra N., Platts-Mills T. A., Gaston B. Endogenous airway acidification. Implications for asthma pathophysiology. Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):694–699. doi: 10.1164/ajrccm.161.3.9911005. [DOI] [PubMed] [Google Scholar]
- Ishizuka S., Yamaya M., Suzuki T., Nakayama K., Kamanaka M., Ida S., Sekizawa K., Sasaki H. Acid exposure stimulates the adherence of Streptococcus pneumoniae to cultured human airway epithelial cells: effects on platelet-activating factor receptor expression. Am J Respir Cell Mol Biol. 2001 Apr;24(4):459–468. doi: 10.1165/ajrcmb.24.4.4248. [DOI] [PubMed] [Google Scholar]
- Jayaraman S., Joo N. S., Reitz B., Wine J. J., Verkman A. S. Submucosal gland secretions in airways from cystic fibrosis patients have normal [Na(+)] and pH but elevated viscosity. Proc Natl Acad Sci U S A. 2001 Jun 26;98(14):8119–8123. doi: 10.1073/pnas.131087598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jöbsis Q., Raatgeep H. C., Schellekens S. L., Kroesbergen A., Hop W. C., de Jongste J. C. Hydrogen peroxide and nitric oxide in exhaled air of children with cystic fibrosis during antibiotic treatment. Eur Respir J. 2000 Jul;16(1):95–100. doi: 10.1034/j.1399-3003.2000.16a17.x. [DOI] [PubMed] [Google Scholar]
- Kopelman H., Corey M., Gaskin K., Durie P., Weizman Z., Forstner G. Impaired chloride secretion, as well as bicarbonate secretion, underlies the fluid secretory defect in the cystic fibrosis pancreas. Gastroenterology. 1988 Aug;95(2):349–355. doi: 10.1016/0016-5085(88)90490-8. [DOI] [PubMed] [Google Scholar]
- Kopelman H., Forstner G., Durie P., Corey M. Origins of chloride and bicarbonate secretory defects in the cystic fibrosis pancreas, as suggested by pancreatic function studies on control and CF subjects with preserved pancreatic function. Clin Invest Med. 1989 Jun;12(3):207–211. [PubMed] [Google Scholar]
- Lee M. G., Choi J. Y., Luo X., Strickland E., Thomas P. J., Muallem S. Cystic fibrosis transmembrane conductance regulator regulates luminal Cl-/HCO3- exchange in mouse submandibular and pancreatic ducts. J Biol Chem. 1999 May 21;274(21):14670–14677. doi: 10.1074/jbc.274.21.14670. [DOI] [PubMed] [Google Scholar]
- Lee M. G., Wigley W. C., Zeng W., Noel L. E., Marino C. R., Thomas P. J., Muallem S. Regulation of Cl-/ HCO3- exchange by cystic fibrosis transmembrane conductance regulator expressed in NIH 3T3 and HEK 293 cells. J Biol Chem. 1999 Feb 5;274(6):3414–3421. doi: 10.1074/jbc.274.6.3414. [DOI] [PubMed] [Google Scholar]
- Montuschi P., Kharitonov S. A., Ciabattoni G., Corradi M., van Rensen L., Geddes D. M., Hodson M. E., Barnes P. J. Exhaled 8-isoprostane as a new non-invasive biomarker of oxidative stress in cystic fibrosis. Thorax. 2000 Mar;55(3):205–209. doi: 10.1136/thorax.55.3.205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pilewski J. M., Frizzell R. A. Role of CFTR in airway disease. Physiol Rev. 1999 Jan;79(1 Suppl):S215–S255. doi: 10.1152/physrev.1999.79.1.S215. [DOI] [PubMed] [Google Scholar]
- Poulsen J. H., Fischer H., Illek B., Machen T. E. Bicarbonate conductance and pH regulatory capability of cystic fibrosis transmembrane conductance regulator. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5340–5344. doi: 10.1073/pnas.91.12.5340. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Poulsen J. H., Machen T. E. HCO3-dependent pHi regulation in tracheal epithelial cells. Pflugers Arch. 1996 Jul;432(3):546–554. doi: 10.1007/s004240050168. [DOI] [PubMed] [Google Scholar]
- Smith J. J., Welsh M. J. cAMP stimulates bicarbonate secretion across normal, but not cystic fibrosis airway epithelia. J Clin Invest. 1992 Apr;89(4):1148–1153. doi: 10.1172/JCI115696. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Veerman E. C., Valentijn-Benz M., Nieuw Amerongen A. V. Viscosity of human salivary mucins: effect of pH and ionic strength and role of sialic acid. J Biol Buccale. 1989 Dec;17(4):297–306. [PubMed] [Google Scholar]
- Wanke C. A., Cronan S., Goss C., Chadee K., Guerrant R. L. Characterization of binding of Escherichia coli strains which are enteropathogens to small-bowel mucin. Infect Immun. 1990 Mar;58(3):794–800. doi: 10.1128/iai.58.3.794-800.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wheat V. J., Shumaker H., Burnham C., Shull G. E., Yankaskas J. R., Soleimani M. CFTR induces the expression of DRA along with Cl(-)/HCO(3)(-) exchange activity in tracheal epithelial cells. Am J Physiol Cell Physiol. 2000 Jul;279(1):C62–C71. doi: 10.1152/ajpcell.2000.279.1.C62. [DOI] [PubMed] [Google Scholar]