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Published in: Clinical and Molecular Allergy 1/2012

Open Access 01-12-2012 | Research

Clara cell protein in nasal lavage fluid and nasal nitric oxide - biomarkers with anti-inflammatory properties in allergic rhinitis

Authors: Kristina Irander, Jörgen P Palm, Magnus P Borres, Bijar Ghafouri

Published in: Clinical and Molecular Allergy | Issue 1/2012

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Abstract

Background

Clara cell protein (CC16) is ascribed a protective and anti-inflammatory role in airway inflammation. Lower levels have been observed in asthmatic subjects as well as in subjects with intermittent allergic rhinitis than in healthy controls. Nasal nitric oxide (nNO) is present in high concentrations in the upper airways, and considered a biomarker with beneficial effects, due to inhibition of bacteria and viruses along with stimulation of ciliary motility. The aim of this study was to evaluate the presumed anti-inflammatory effects of nasal CC16 and nNO in subjects with allergic rhinitis.

Methods

The levels of CC16 in nasal lavage fluids, achieved from subjects with persistent allergic rhinitis (n = 13), intermittent allergic rhinitis in an allergen free interval (n = 5) and healthy controls (n = 7), were analyzed by Western blot. The levels of nNO were measured by the subtraction method using NIOX®. The occurrences of effector cells in allergic inflammation, i.e. metachromatic cells (MC, mast cells and basophiles) and eosinophils (Eos) were analyzed by light microscopy in samples achieved by nasal brushing.

Results

The levels of CC16 correlated with nNO levels (r2 = 0.37; p = 0.02) in allergic subjects.
The levels of both biomarkers showed inverse relationships with MC occurrence, as higher levels of CC16 (p = 0.03) and nNO (p = 0.05) were found in allergic subjects with no demonstrable MC compared to the levels in subjects with demonstrable MC. Similar relationships, but not reaching significance, were observed between the CC16 and nNO levels and Eos occurrence. The levels of CC16 and nNO did not differ between the allergic and the control groups.

Conclusions

The correlation between nasal CC16 and nNO levels in patients with allergic rhinitis, along with an inverse relationship between their levels and the occurrences of MC in allergic inflammation, may indicate that both biomarkers have anti-inflammatory effects by suppression of cell recruitment. The mechanisms behind these observations warrant further analyses.
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Literature
1.
go back to reference Bernard A, Lauwerys R: Low-molecular-weight proteins as markers of organ toxicity with special reference to Clara cell protein. Toxicol Lett. 1995, 77: 145-151. 10.1016/0378-4274(95)03284-3CrossRefPubMed Bernard A, Lauwerys R: Low-molecular-weight proteins as markers of organ toxicity with special reference to Clara cell protein. Toxicol Lett. 1995, 77: 145-151. 10.1016/0378-4274(95)03284-3CrossRefPubMed
2.
go back to reference Broeckaert F, Bernard A: Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy. 2000, 30: 469-475. 10.1046/j.1365-2222.2000.00760.xCrossRefPubMed Broeckaert F, Bernard A: Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy. 2000, 30: 469-475. 10.1046/j.1365-2222.2000.00760.xCrossRefPubMed
3.
go back to reference Lakind JS, Holgate ST, Ownby DR, Mansur AH, Helms PJ, Pyatt D, Hays SM: A critical review of the use of Clara cell secretory protein (CC16) as a biomaker of acute or chronic pulmonary effects. Biomarkers. 2007, 12: 445-467. 10.1080/13547500701359327CrossRefPubMed Lakind JS, Holgate ST, Ownby DR, Mansur AH, Helms PJ, Pyatt D, Hays SM: A critical review of the use of Clara cell secretory protein (CC16) as a biomaker of acute or chronic pulmonary effects. Biomarkers. 2007, 12: 445-467. 10.1080/13547500701359327CrossRefPubMed
4.
go back to reference Lindahl M, Svartz J, Tagesson C: Demonstration of different forms of the anti-inflammatory proteins lipocortin-1 and Clara cell protein-16 in human nasal and bronchoalveolar lavage fluids. Electrophoresis. 1999, 20: 881-890. 10.1002/(SICI)1522-2683(19990101)20:4/5<881::AID-ELPS881>3.0.CO;2-6CrossRefPubMed Lindahl M, Svartz J, Tagesson C: Demonstration of different forms of the anti-inflammatory proteins lipocortin-1 and Clara cell protein-16 in human nasal and bronchoalveolar lavage fluids. Electrophoresis. 1999, 20: 881-890. 10.1002/(SICI)1522-2683(19990101)20:4/5<881::AID-ELPS881>3.0.CO;2-6CrossRefPubMed
5.
go back to reference Lindahl M, Irander K, Tagesson C, Ståhlbom B: Nasal lavage fluid and proteomics as means to identify the effects of the irritating epoxy chemical dimethylbenzylamine. Biomarkers. 2004, 9: 56-70. 10.1080/13547500410001662005CrossRefPubMed Lindahl M, Irander K, Tagesson C, Ståhlbom B: Nasal lavage fluid and proteomics as means to identify the effects of the irritating epoxy chemical dimethylbenzylamine. Biomarkers. 2004, 9: 56-70. 10.1080/13547500410001662005CrossRefPubMed
6.
go back to reference Gomes EC, Stone V, Florida-James G: Impact of heat and pollution on oxidative stress and CC16 secretion after 8 km run. Eur J Appl Physiol. 2011, 111: 2089-2097. 10.1007/s00421-011-1839-xCrossRefPubMed Gomes EC, Stone V, Florida-James G: Impact of heat and pollution on oxidative stress and CC16 secretion after 8 km run. Eur J Appl Physiol. 2011, 111: 2089-2097. 10.1007/s00421-011-1839-xCrossRefPubMed
7.
go back to reference Johansson S, Keen C, Ståhl A, Wennergren G, Benson M: Low levels of CC16 in nasal fluid of children with birch pollen-induced rhinitis. Allergy. 2005, 60: 638-642. 10.1111/j.1398-9995.2005.00775.xCrossRefPubMed Johansson S, Keen C, Ståhl A, Wennergren G, Benson M: Low levels of CC16 in nasal fluid of children with birch pollen-induced rhinitis. Allergy. 2005, 60: 638-642. 10.1111/j.1398-9995.2005.00775.xCrossRefPubMed
8.
go back to reference Benson M, Jansson L, Adner M, Luts A, Uddman R, Cardell LO: Gene profiling reveals decreased expression of uteroglobin and other anti-inflammatory genes in nasal fluid cells from patients with intermittent allergic rhinitis. Clin Exp Allergy. 2005, 35: 473-478. 10.1111/j.1365-2222.2005.02206.xCrossRefPubMed Benson M, Jansson L, Adner M, Luts A, Uddman R, Cardell LO: Gene profiling reveals decreased expression of uteroglobin and other anti-inflammatory genes in nasal fluid cells from patients with intermittent allergic rhinitis. Clin Exp Allergy. 2005, 35: 473-478. 10.1111/j.1365-2222.2005.02206.xCrossRefPubMed
9.
go back to reference Benson M, Fransson M, Martinsson T, Naluai ÅT, Uddman R, Cardell LO: Inverse relation between nasal fluid Clara Cell Protein 16 levels and symptoms and signs of rhinitis in allergen-challenged patients with intermittent allergic rhinitis. Allergy. 2007, 62: 178-183.CrossRefPubMed Benson M, Fransson M, Martinsson T, Naluai ÅT, Uddman R, Cardell LO: Inverse relation between nasal fluid Clara Cell Protein 16 levels and symptoms and signs of rhinitis in allergen-challenged patients with intermittent allergic rhinitis. Allergy. 2007, 62: 178-183.CrossRefPubMed
10.
go back to reference Lundberg JO: Nitric oxide and the paranasal sinuses. Anat Rec. 2008, 291: 1479-1484. 10.1002/ar.20782.CrossRef Lundberg JO: Nitric oxide and the paranasal sinuses. Anat Rec. 2008, 291: 1479-1484. 10.1002/ar.20782.CrossRef
11.
go back to reference Borres MP, Irander K, Björkstén B: Nasal metachromatic cells in infants in relation to allergic disease and family history of atopy. Pediatr Allergy Immunol. 1991, 4: 184-189.CrossRef Borres MP, Irander K, Björkstén B: Nasal metachromatic cells in infants in relation to allergic disease and family history of atopy. Pediatr Allergy Immunol. 1991, 4: 184-189.CrossRef
12.
go back to reference Borres MP, Irander K, Björkstén B: Nasal metachromatic cells in infancy in relation to the appearance of atopic disease during the first 6 years of life. Allergy. 1997, 52: 770-774. 10.1111/j.1398-9995.1997.tb01237.xCrossRefPubMed Borres MP, Irander K, Björkstén B: Nasal metachromatic cells in infancy in relation to the appearance of atopic disease during the first 6 years of life. Allergy. 1997, 52: 770-774. 10.1111/j.1398-9995.1997.tb01237.xCrossRefPubMed
13.
go back to reference Irander K, Borres MP: An 18-year follow-up of allergy development related to nasal metachromatic cell findings during infancy. Allergol Int. 2010, 59: 193-200. 10.2332/allergolint.09-OA-0132CrossRefPubMed Irander K, Borres MP: An 18-year follow-up of allergy development related to nasal metachromatic cell findings during infancy. Allergol Int. 2010, 59: 193-200. 10.2332/allergolint.09-OA-0132CrossRefPubMed
14.
go back to reference Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976, 72: 248-254. 10.1016/0003-2697(76)90527-3CrossRefPubMed Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976, 72: 248-254. 10.1016/0003-2697(76)90527-3CrossRefPubMed
15.
go back to reference , : ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005, 171: 912-930.CrossRef , : ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005, 171: 912-930.CrossRef
16.
go back to reference Palm JP, Graf P, Lundberg JON, Alving K: Characterization of exhaled nitric oxide: introducing a new reproducible method for nasal nitric oxide measurements. Eur Respir J. 2000, 16: 236-241. 10.1034/j.1399-3003.2000.16b09.xCrossRefPubMed Palm JP, Graf P, Lundberg JON, Alving K: Characterization of exhaled nitric oxide: introducing a new reproducible method for nasal nitric oxide measurements. Eur Respir J. 2000, 16: 236-241. 10.1034/j.1399-3003.2000.16b09.xCrossRefPubMed
17.
go back to reference Zetterquist W, Pedroletti C, Lundberg JON, Alving K: Salivary contribution to exhaled nitric oxide. Eur Resp J. 1999, 13: 327-333. 10.1034/j.1399-3003.1999.13b18.x.CrossRef Zetterquist W, Pedroletti C, Lundberg JON, Alving K: Salivary contribution to exhaled nitric oxide. Eur Resp J. 1999, 13: 327-333. 10.1034/j.1399-3003.1999.13b18.x.CrossRef
18.
go back to reference Shijubo N, Itoh Y, Yamaguchi T, Imada A, Hirasawa M, Yamada T, Kawai T, Abe S: Clara cell protein-positive epithelial cells are reduced in small airways of asthmatics. Am J Respir Crit Care Med. 1999, 160: 930-933.CrossRefPubMed Shijubo N, Itoh Y, Yamaguchi T, Imada A, Hirasawa M, Yamada T, Kawai T, Abe S: Clara cell protein-positive epithelial cells are reduced in small airways of asthmatics. Am J Respir Crit Care Med. 1999, 160: 930-933.CrossRefPubMed
19.
go back to reference de Burbure C, Pignatti P, Corradi M, Malerba M, Clippe A, Dumont X, Moscato G, Mutti A, Bernard A: Uteroglobin-related protein 1 and Clara cell protein in induced sputum of patients with asthma and rhinitis. Chest. 2007, 131: 172-179. 10.1378/chest.06-0835CrossRefPubMed de Burbure C, Pignatti P, Corradi M, Malerba M, Clippe A, Dumont X, Moscato G, Mutti A, Bernard A: Uteroglobin-related protein 1 and Clara cell protein in induced sputum of patients with asthma and rhinitis. Chest. 2007, 131: 172-179. 10.1378/chest.06-0835CrossRefPubMed
20.
go back to reference Turner S: The role of exhaled nitric oxide in the diagnosis, management and treatment of asthma. Mini Rev Med Chem. 2007, 7: 539-542.PubMed Turner S: The role of exhaled nitric oxide in the diagnosis, management and treatment of asthma. Mini Rev Med Chem. 2007, 7: 539-542.PubMed
21.
go back to reference Barnes PJ, Dweik RA, Gelb AF, Gibson PG, George SC, Grasemann H, Pavord ID, Ratjen F, Silkoff PE, Taylor DR, Zamel N: Exhaled nitric oxide in pulmonary diseases: a comprehensive review. Chest. 2010, 138: 682-692. 10.1378/chest.09-2090CrossRefPubMed Barnes PJ, Dweik RA, Gelb AF, Gibson PG, George SC, Grasemann H, Pavord ID, Ratjen F, Silkoff PE, Taylor DR, Zamel N: Exhaled nitric oxide in pulmonary diseases: a comprehensive review. Chest. 2010, 138: 682-692. 10.1378/chest.09-2090CrossRefPubMed
22.
go back to reference Porsbjerg C, Lund TK, Pedersen L, Backer V: Inflammatory subtypes in asthma are related to airway hyperresponsiveness to mannitol and exhaled NO. J Asthma. 2009, 46: 606-612. 10.1080/02770900903015654CrossRefPubMed Porsbjerg C, Lund TK, Pedersen L, Backer V: Inflammatory subtypes in asthma are related to airway hyperresponsiveness to mannitol and exhaled NO. J Asthma. 2009, 46: 606-612. 10.1080/02770900903015654CrossRefPubMed
23.
go back to reference Maniscalco M, Sofia M, Pelaia G: Nitric oxide in upper airways inflammatory diseases. Inflamm Res. 2007, 56: 58-69. 10.1007/s00011-006-6111-1CrossRefPubMed Maniscalco M, Sofia M, Pelaia G: Nitric oxide in upper airways inflammatory diseases. Inflamm Res. 2007, 56: 58-69. 10.1007/s00011-006-6111-1CrossRefPubMed
24.
go back to reference Larsson AK, Bäck M, Hjoberg J, Dahlén SE: Inhibition of nitric-oxide synthase enhances antigen-induced contractions and increases release of cysteinyl-leucotrienes in guinea pig lung parenchyma: nitric oxide as a protective factor. J Pharmacol Exp Ther. 2005, 315: 458-465. 10.1124/jpet.105.086694CrossRefPubMed Larsson AK, Bäck M, Hjoberg J, Dahlén SE: Inhibition of nitric-oxide synthase enhances antigen-induced contractions and increases release of cysteinyl-leucotrienes in guinea pig lung parenchyma: nitric oxide as a protective factor. J Pharmacol Exp Ther. 2005, 315: 458-465. 10.1124/jpet.105.086694CrossRefPubMed
25.
go back to reference Larsson AK, Bäck M, Lundberg JO, Dahlén SE: Specific mediator inhibition by the NO donors SNP and NCX 2057 in the peripheral lung: implications for allergen-induced bronchoconstriction. Respir Res. 2009, 10: 46. 10.1186/1465-9921-10-46PubMedCentralCrossRefPubMed Larsson AK, Bäck M, Lundberg JO, Dahlén SE: Specific mediator inhibition by the NO donors SNP and NCX 2057 in the peripheral lung: implications for allergen-induced bronchoconstriction. Respir Res. 2009, 10: 46. 10.1186/1465-9921-10-46PubMedCentralCrossRefPubMed
26.
go back to reference Coleman JW: Nitric oxide: a regulator of mast cell activation and mast cell-mediated inflammation. Clin Exp Immunol. 2002, 129: 4-10. 10.1046/j.1365-2249.2002.01918.xPubMedCentralCrossRefPubMed Coleman JW: Nitric oxide: a regulator of mast cell activation and mast cell-mediated inflammation. Clin Exp Immunol. 2002, 129: 4-10. 10.1046/j.1365-2249.2002.01918.xPubMedCentralCrossRefPubMed
27.
go back to reference Lundberg JO: Airborne nitric oxide: inflammatory marker and aerocrine messenger in man. Acta Physiol Scand Suppl. 1996, 633: 1-27.PubMed Lundberg JO: Airborne nitric oxide: inflammatory marker and aerocrine messenger in man. Acta Physiol Scand Suppl. 1996, 633: 1-27.PubMed
28.
go back to reference Maniscalco M, Sofia M, Carratù L, Higenbottam T: Effect of nitric oxide inhibition on nasal airway resistance after nasal allergen challenge in allergic rhinitis. Eur J Clin Invest. 2001, 31: 462-466. 10.1046/j.1365-2362.2001.00825.xCrossRefPubMed Maniscalco M, Sofia M, Carratù L, Higenbottam T: Effect of nitric oxide inhibition on nasal airway resistance after nasal allergen challenge in allergic rhinitis. Eur J Clin Invest. 2001, 31: 462-466. 10.1046/j.1365-2362.2001.00825.xCrossRefPubMed
29.
go back to reference Moody A, Fergusson W, Wells A, Bartley J, Kolbe J: Nasal levels of nitric oxide as an outcome variable in allergic upper respiratory tract disease: Influence of atopy and hayfever on nNO. Am J Rhinol. 2006, 20: 425-429. 10.2500/ajr.2006.20.2921CrossRefPubMed Moody A, Fergusson W, Wells A, Bartley J, Kolbe J: Nasal levels of nitric oxide as an outcome variable in allergic upper respiratory tract disease: Influence of atopy and hayfever on nNO. Am J Rhinol. 2006, 20: 425-429. 10.2500/ajr.2006.20.2921CrossRefPubMed
30.
go back to reference Palm JP, Alving K, Lundberg JO: Characterization of airway nitric oxide in allergic rhinitis: the effect of intranasal administration of L-NAME. Allergy. 2003, 58: 885-892. 10.1034/j.1398-9995.2003.00098.xCrossRefPubMed Palm JP, Alving K, Lundberg JO: Characterization of airway nitric oxide in allergic rhinitis: the effect of intranasal administration of L-NAME. Allergy. 2003, 58: 885-892. 10.1034/j.1398-9995.2003.00098.xCrossRefPubMed
Metadata
Title
Clara cell protein in nasal lavage fluid and nasal nitric oxide - biomarkers with anti-inflammatory properties in allergic rhinitis
Authors
Kristina Irander
Jörgen P Palm
Magnus P Borres
Bijar Ghafouri
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Clinical and Molecular Allergy / Issue 1/2012
Electronic ISSN: 1476-7961
DOI
https://doi.org/10.1186/1476-7961-10-4

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