Background: CC chemokines play important roles in the pathogenesis of interstitial lung diseases. Elevated CC chemokine levels have been observed in bronchoalveolar lavage (BAL) fluid of patients with idiopathic pulmonary fibrosis (IPF). Objectives: We aimed to examine whether the levels of four CC chemokines, i.e. monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1α (MIP-1α/CCL3), thymus- and activation-regulated chemokine (TARC/CCL17), and macrophage-derived chemokine (MDC/CCL22), in BAL fluid are predictive of the prognosis of IPF patients. Methods: We compared the chemokine levels of patients alive 5 years after diagnosis and those who had died. Lung function data, CT scores, and serum markers were also compared. Results: Among 39 patients (29 males, median age, 60 years), 19 patients (48%) died within 5 years after the diagnosis. Whereas percent vital capacity was not different, percent lung diffusion capacity for carbon monoxide was significantly higher in the surviving patients than in the nonsurviving patients (p < 0.01). Median CCL2 levels of surviving and nonsurviving patients were 154.3 (interquartile range, IQR: 67.3–381.8) and 427.2 (IQR: 329.2–1184.1) pg/ml, respectively (p < 0.02). CCL3 levels in BAL fluid did not differ between the surviving and nonsurviving patients. CCL17 was detected in BAL fluid of 7 patients, 6 of whom died within 5 years. CCL22 was detectable in BAL fluid of 10 patients, only 1 of whom survived. Serum levels of KL-6 and lactate dehydrogenase did not differ between the surviving and nonsurviving patients. Conclusion: Elevated levels of CCL2, CCL17 and CCL22 in BAL fluid might be predictive of a poor outcome in patients with IPF.

Keywords:
Bronchoalveolar lavage fluid, Chemokine, Idiopathic pulmonary fibrosis, Prognostic markers
1.
Katzenstein AL, Myers JL: Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998;157:1301–1315.
2.
American Thoracic Society/European Respiratory Society: American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2002;165:277–304.
3.
Misumi S, Lynch DA: Idiopathic pulmonary fibrosis/usual interstitial pneumonia: imaging diagnosis, spectrum of abnormalities, and temporal progression. Proc Am Thorac Soc 2006;3:307–314.
4.
Carrington CB, Gaensler EA, Coutu RE, Fitzgerald MX, Gupta RG: Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 1978;298:801–809.
5.
Panos RJ, Mortenson RL, Niccoli SA, King TE Jr: Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment. Am J Med 1990;88:396–404.
6.
Schwartz DA, Helmers RA, Galvin JR, Van Fossen DS, Frees KL, Dayton CS, Burmeister LF, Hunninghake GW: Determinants of survival in idiopathic pulmonary fibrosis. Am J Respir Crit CareMed 1994;149:450–454.
7.
Hallstrand TS, Boitano LJ, Johnson WC, Spada CA, Hayes JG, Raghu G: The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis. Eur Respir J 2005;25:96–103.
8.
Hamada K, Nagai S, Tanaka S, Handa T, Shigematsu M, Nagao T, Mishima M, Kitaichi M, Izumi T: Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis. Chest 2007;131:650–656.
9.
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.
10.
Agostini C, Gurrieri C: Chemokine/cytokine cocktail in idiopathic pulmonary fibrosis. Proc Am Thorac Soc 2006;3:357–363.
11.
Car BD, Meloni F, Luisetti M, Semenzato G, Gialdroni-Grassi G, Walz A: Elevated IL-8 and MCP-1 in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Am J Respir Crit Care Med 1994;149:655–659.
12.
Suga M, Iyonaga K, Ichiyasu H, Saita N, Yamasaki H, Ando M: Clinical significance of MCP-1 levels in BAL fluid and serum in patients with interstitial lung diseases. Eur Respir J 1999;14:376–382.
13.
Standiford TJ, Rolfe MW, Kunkel SL, Lynch JP 3rd, Burdick MD, Gilbert AR, Orringer MB, Whyte RI, Strieter RM: Macrophage inflammatory protein-1α expression in interstitial lung disease. J Immunol 1993;151:2852–2863.
14.
Belperio JA, Dy M, Murray L, Burdick MD, Xue YY, Strieter RM, Keane MP: The role of the Th2 CC chemokine ligand CCL17 in pulmonary fibrosis. J Immunol 2004;173:4692–4698.
15.
Inoue T, Fujishima S, Ikeda E, Yoshie O, Tsukamoto N, Aiso S, Aikawa N, Kubo A, Matsushima K, Yamaguchi K: CCL22 and CCL17 in rat radiation pneumonitis and in human idiopathic pulmonary fibrosis. Eur Respir J 2004;24:49–56.
16.
Smith RE, Strieter RM, Phan SH, Lukacs NW, Huffnagle GB, Wilke CA, Burdick MD, Lincoln P, Evanoff H, Kunkel SL: Production and function of murine macrophage inflammatory protein-1α in bleomycin-induced lung injury. J Immunol 1994;153:4704–4712.
17.
Romagnani S: Cytokines and chemoattractants in allergic inflammation. Mol Immunol 2002;38:881–885.
18.
American Thoracic Society/European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med 2000;161:646–664.
19.
Kazerooni EA, Martinez FJ, Flint A, Jamadar DA, Gross BH, Spizarny DL, Cascade PN, Whyte RI, Lynch JP 3rd, Toews G: Thin-section CT obtained at 10 mm increments versus three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring. Am J Roentgenol 1997;169:977–983.
20.
Rosseau S, Selhorst J, Wiechmann K, Leissner K, Maus U, Mayer K, Grimminger F, Seeger W, Lohmeyer J: Monocyte migration through the alveolar epithelial barrier: adhesion molecule mechanisms and impact of chemokines. J Immunol 2000;164:427–435.
21.
Baran CP, Opalek JM, McMaken S, Newland CA, O’Brien JM Jr, Hunter MG, Bringardner BD, Monick MM, Brigstock DR, Stromberg PC, Hunninghake GW, Marsh CB: Important roles for macrophage colony-stimulating factor, CC chemokine ligand 2, and mononuclear phagocytes in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 2007;176:78–89.
22.
Moore BB, Paine R 3rd, Christensen PJ, Moore TA, Sitterding S, Ngan R, Wilke CA, Kuziel WA, Toews GB: Protection from pulmonary fibrosis in the absence of CCR2 signaling. J Immunol 2001;167:4368–4377.
23.
Okuma T, Terasaki Y, Kaikita K, Kobayashi H, Kuziel WA, Kawasuji M, Takeya M: C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases. J Pathol 2004;204:594–604.
24.
Gharaee-Kermani M, Denholm EM, Phan SH: Costimulation of fibroblast collagen and transforming growth factor beta1 gene expression by monocyte chemoattractant protein-1 via specific receptors. J Biol Chem 1996;271:17779–17784.
25.
Collard HR, Moore BB, Flaherty KR, et al: Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007;176:636–643.
26.
Wallace WA, Ramage EA, Lamb D, Howie SE: A type 2 (Th2-like) pattern of immune response predominates in the pulmonary interstitium of patients with cryptogenic fibrosing alveolitis (CFA). Clin Exp Immunol 1995;101:436–441.
27.
Jakubzick C, Choi ES, Joshi BH, Keane MP, Kunkel SL, Puri RK, Hogaboam CM: Therapeutic attenuation of pulmonary fibrosis via targeting of IL-4- and IL-13-responsive cells. J Immunol 2003;171:2684–2693.
28.
Alakhras M, Decker PA, Nadrous HF, Collazo-Clavell M, Ryu JH: Body mass index and mortality in patients with idiopathic pulmonary fibrosis. Chest 2007;131:1448–1453.
29.
Yokoyama A, Kondo K, Nakajima M, Matsushima T, Takahashi T, Nishimura M, Bando M, Sugiyama Y, Totani Y, Ishizaki T, Ichiyasu H, Suga M, Hamada H, Kohno N: Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis. Respirology 2006;11:164–168.
30.
Tabuena RP, Nagai S, Tsutsumi T, Handa T, Minoru T, Mikuniya T, Shigematsu M, Hamada K, Izumi T, Mishima M: Cell profiles of bronchoalveolar lavage fluid as prognosticators of idiopathic pulmonary fibrosis/usual interstitial pneumonia among Japanese patients. Respiration 2005;72:490–498.
31.
Hunninghake GW, Schwarz MI: Does current knowledge explain the pathogenesis of idiopathic pulmonary fibrosis? A perspective. Proc Am Thorac Soc 2007;4:449–452.
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2009
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