BACKGROUND: Th-2 cytokine milieu including interleukin 4 (IL-4) was detected in fibrotic lung diseases. Chronic extrinsic allergic alveolitis (EAA) may be also accompanied by marked fibrogenesis. The aim of this study was to determine if IL-4 and its receptor (IL-4R-alpha) play any role in the clinical presentation and pathogenesis of chronic EAA. METHODS: Twenty patients originally investigated for interstitial lung disease and finally diagnosed affected with chronic EAA and sarcoidosis were prospectively enrolled into the study. Concentrations of IL-4, IL-4R-aplha and total protein were assessed in the bronchoalveolar lavage fluid (BALF) of all enrolled subjects as well as high resolution computed tomography (HRCT) scores and pulmonary function tests. RESULTS: BALF IL-4R-alpha and total protein concentrations were significantly higher in chronic EAA patients (p < 0.05). Concentrations of BALF IL-4R-alpha were significantly higher in men than in women (p < 0.05) in EAA group. Total protein BALF levels were significantly elevated in ex-smokers with EAA compared to nonsmokers (p < 0.05). A positive correlation (p < 0.01) between IL-4R-alpha BALF concentrations and HRCT interstitial scores were observed in chronic EAA group; the IL-4R-alpha/total protein ratio showed the same significant positive correlation. A negative correlation between lung function results and IL-4R-alpha, and IL-4R-alpha/total protein as well, was also found (p < 0.05). CONCLUSIONS: We suggest a clinical relevance for the IL-4/IL-4R axis in the etiopathogenesis of chronic EAA. IL-4R-alpha could serve as a potential biomarker of lung fibrogenesis.

Department of Respiratory Diseases ThomayerHospital Videnska 800 Prague 4 140 00 Czech Republic

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Dall’Aglio PP, Pesci A, Bertorelli G, Brianti E, Scarpa S. Study of immune complexes in bronchoalveolar lavage fluids. Respiration. 1988;54(Suppl 1):36–41. PubMed

Schuyler M, Gott K, Mapel V, Cherne A, Nikula KJ. Experimental hypersensitivity pneumonitis: influence of Th2 bias. Int J Exp Pathol. 1999;80:335–348. PubMed PMC

Mitaka K, Miyazaki Y, Yasui M, Furuie M, Miyake S, Inase N, Yoshizawa Y. Th2-biased immune responses are important in a murine model of chronic hypersensitivity pneumonitis. Int Arch Allergy Immunol. 2011;154:264–274. doi: 10.1159/000321114. PubMed DOI

Wills-Karp M, Finkelman FD. Untangling the complex web of IL-4- and IL-13-mediated signaling pathways. Sci Signal. 2008;1:pe55. doi: 10.1126/scisignal.1.51.pe55. PubMed DOI PMC

Yamaji-Kegan K, Su Q, Angelini DJ, Johns RA. IL-4 is proangiogenic in the lung under hypoxic conditions. J Immunol. 2009;182:5469–5476. doi: 10.4049/jimmunol.0713347. PubMed DOI PMC

Costabel U, Hunninghake GW. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur Respir J. 1999;14:735–737. doi: 10.1034/j.1399-3003.1999.14d02.x. PubMed DOI

Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J. ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J. 2005;26:153–161. doi: 10.1183/09031936.05.00034505. PubMed DOI

Quanier PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Report Working Party Standardization of Lung Function Tests, European Community For Steel and Coal. Official statement of the European respiratory society. Eur Respir J Suppl. 1993;16:1–100. PubMed

Gay SE, Kazerooni EA, Toews GB, Lynch JP 3rd, Gross BH, Cascade PN, Spizarny DL, Flint A, Schork MA, Whyte RI, Popovich J, Hyzy R, Martinez FJ. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med. 1998;157:1063–1072. doi: 10.1164/ajrccm.157.4.9703022. PubMed DOI

Hauber HP, Gholami D, Meyer A, Pforte A. Increased interleukin-13 expression in patients with sarcoidosis. Thorax. 2003;58:519–524. doi: 10.1136/thorax.58.6.519. PubMed DOI PMC

Bohnert A, Schürmann M, Hartung A, Hackstein H, Müller-Quernheim J, Bein G. No linkage of the interleukin-4 receptor locus on chromosome 16p11.2-12.1 with sarcoidosis in German multiplex families. Eur J Immunogenet. 2002;29:269–272. doi: 10.1046/j.1365-2370.2002.00291.x. PubMed DOI

Rybicki BA, Iannuzzi MC. Epidemiology of sarcoidosis: recent advances and future prospects. Semin Respir Crit Care Med. 2007;28:22–35. doi: 10.1055/s-2007-970331. PubMed DOI

Wallace WA, Howie SE. Immunoreactive interleukin 4 and interferon-gamma expression by type II alveolar epithelial cells in interstitial lung disease. J Pathol. 1999;187:475–480. doi: 10.1002/(SICI)1096-9896(199903)187:4<475::AID-PATH268>3.0.CO;2-N. PubMed DOI

Ghadirian E, Denis M. Murine hypersensitivity pneumonitis: interleukin-4 administration partially abrogates the disease process. Microb Pathog. 1992;12:377–382. doi: 10.1016/0882-4010(92)90100-3. PubMed DOI

Schuyler M, Gott K, Edwards B. Th1 cells that adoptively transfer experimental hypersensitivity pneumonitis are activated memory cells. Lung. 1999;177:377–389. doi: 10.1007/PL00007655. PubMed DOI

Jakubzick C, Kunkel SL, Puri RK, Hogaboam CM. Therapeutic targeting of IL-4- and IL-13-responsive cells in pulmonary fibrosis. Immunol Res. 2004;30:339–349. doi: 10.1385/IR:30:3:339. PubMed DOI

Vasakova M, Striz I, Slavcev A, Jandova S, Dutka J, Terl M, Kolesar L, Sulc J. Correlation of IL-1alpha and IL-4 gene polymorphisms and clinical parameters in idiopathic pulmonary fibrosis. Scand J Immunol. 2007;65:265–270. doi: 10.1111/j.1365-3083.2007.01896.x. PubMed DOI

Pechkovsky DV, Prasse A, Kollert F, Engel KM, Dentler J, Luttmann W, Friedrich K, Müller-Quernheim J, Zissel G. Alternatively activated alveolar macrophages in pulmonary fibrosis-mediator production and intracellular signal transduction. Clin Immunol. 2010;137:89–101. doi: 10.1016/j.clim.2010.06.017. PubMed DOI

Hwang SJ, Kim S, Park WS, Chung DH. IL-4-secreting NKT cells prevent hypersensitivity pneumonitis by suppressing IFN-gamma-producing neutrophils. J Immunol. 2006;177:5258–5268. PubMed

Best AC, Meng J, Lynch AM, Bozic CM, Miller D, Grunwald GK, Lynch DA. Idiopathic pulmonary fibrosis: physiologic tests, quantitative CT indexes, and CT visual scores as predictors of mortality. Radiology. 2008;246:935–940. doi: 10.1148/radiol.2463062200. PubMed DOI

Sato T, Saito Y, Chikuma M, Saito Y, Nagai S. Fluorimetric determination of trace amounts of albumin in bronchoalveolar lavage fluid with eriochrome cyanine R. Biol Pharm Bull. 2007;30:1187–1190. doi: 10.1248/bpb.30.1187. PubMed DOI

Meuronen A, Majuri ML, Alenius H, Mäntylä T, Wolff H, Piirilä P, Laitinen A. Decreased cytokine and chemokine mRNA expression in bronchoalveolar lavage in asymptomatic smoking subjects. Respiration. 2008;75:450–458. doi: 10.1159/000114855. PubMed DOI

Burke WM, Roberts CM, Bryant DH, Cairns D, Yeates M, Morgan GW, Martin BJ, Blake H, Penny R, Zaunders JJ. Smoking-induced changes in epithelial lining fluid volume, cell density and protein. Eur Respir J. 1992;5:780–784. PubMed

Ward C, Thien F, Secombe J, Gollant S, Walters EH. Bronchoalveolar lavage fluid urea as a measure of pulmonary permeability in healthy smokers. Eur Respir J. 2000;15:285–290. doi: 10.1034/j.1399-3003.2000.15b11.x. PubMed DOI

Low B, Liang M, Fu J. p38 mitogen-activated protein kinase mediates sidestream cigarette smoke-induced endothelial permeability. J Pharmacol Sci. 2007;104:225–231. doi: 10.1254/jphs.FP0070385. PubMed DOI

Blanchet M-R, Israël-Assayag E, Cormier Y. Inhibitory effect of nicotine on experimental hypersensitivity pneumonitis in vivo and in vitro. Am J Respir Crit Care Med. 2004;169:903–909. doi: 10.1164/rccm.200210-1154OC. PubMed DOI

Furuiye M, Miyake S, Miyazaki Y, Ohtani Y, Inase N, Umino T, Yoshizawa Y. Effect of cigarette smoking on the development of murine chronic pigeon breeder’s lung. The difference between a short-term and a long-term exposure. J Med Dent Sci. 2007;54:87–95. PubMed

Pinzan CF, Ruas LP, Casabona-Fortunato AS, Carvalho FC, Roque-Barreira MC. Immunological basis for the gender differences in murine Paracoccidioidesbrasiliensis infection. PLoS One. 2010;5:e10757. doi: 10.1371/journal.pone.0010757. PubMed DOI PMC

Okuyama K, Hamanaka Y, Kawano T, Ohkawara Y, Takayanagi M, Kikuchi T, Ohno I. T cell subsets related with a sex difference in IL-5 production. Int Arch Allergy Immunol. 2011;155(Suppl 1):21–26. PubMed

Liva SM, Voskuhl RR. Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. J Immunol. 2001;167:2060–2067. PubMed

Aebischer T, Laforsch S, Hurwitz R, Brombacher F, Meyer TF. Immunity against Helicobacter pylori: significance of interleukin-4 receptor alpha chain status and gender of infected mice. Infect Immun. 2001;69:556–558. doi: 10.1128/IAI.69.1.556-558.2001. PubMed DOI PMC

Interstitial Score and Concentrations of IL-4Rα, PAR-2, and MMP-7 in Bronchoalveolar Lavage Fluid Could Be Useful Markers for Distinguishing Idiopathic Interstitial Pneumonias