Background: Repeated aspiration pneumonia is a serious problem in the elderly. In aspiration pneumonia, neutrophils play an important role in acute lung injury, while CD18-independent neutrophil transmigration pathways have also been reported in acid-aspiration pneumonia animal models. However, the involvement of IL-17A and β1 integrin still remains unclear. The β1 integrin subfamily integrin α9β1 has been shown to be expressed on human neutrophils and to mediate adhesion to extracellular matrix proteins including the vascular cell adhesion molecule-1. Objectives: To elucidate the possible involvement of β1 integrin subfamily and IL-17A in aspiration pneumonia. Methods: We analyzed the expression levels of CD11b, CD18 and integrin α9β1 in circulating neutrophils and serum concentration of IL-17A, IL-22 and IL-23 in elderly aspiration pneumonia patients (n = 32, 14 males and 18 females, 78.8 ± 3.9 years old) at 2 time points (on the day of admission before starting antibiotics and the day after finishing antibiotics) and compared the results with those of a control group (n = 30, 13 males and 17 females, 76.1 ± 3.4 years old). Results: Recombinant IL-17A stimulated integrin α9β1 and CD11b expression levels in healthy human neutrophils in vitro. The expression levels of integrin α9β1 and CD11b in circulating neutrophils were significantly higher in pneumonia patients compared with the controls. In addition, serum IL-17A concentration was significantly increased in pneumonia patients. Integrin α9β1 levels positively correlated with serum IL-17A and CD18 expression levels. Conclusions: These findings suggest a potential role of integrin α9β1 expressed in neutrophils and elevated serum IL-17A in extravasation of neutrophils in cases of aspiration pneumonia.

1.
Marik PE, Kaplan D: Aspiration pneumonia and dysphasia in the elderly. Chest 2003;124: 328-336.
2.
Kikuchi R, Watabe N, Konno T, Mishina N, Sekizawa K, Sasaki H: High incidence of silent aspiration in elderly patients with community-acquired pneumonia. Am J Respir Crit Care Med 1994;150:251-253.
3.
Taooka Y, Maeda A, Hiyama K, Ishioka S, Yamakido M: Effects of neutrophil elastase inhibitor on bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 1997;156:260-265.
4.
Tamagawa K, Taooka Y, Maeda A, Hiyama K, Ishioka S, Yamakido M: Inhibitory effects of a lecithinized superoxide dismutase on bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 2000;161:1279-1284.
5.
Cowburn AS, Condliffe AM, Farahi N, Summers C, Chilvers ER: Advances in neutrophil biology: clinical implications. Chest 2008;134:606-612.
6.
Doerschuk CM, Mizgerd JP, Kubo H, Qin L, Kumasaka T: Adhesion molecules and cellular biomechanical changes in acute lung injury: Giles F. Filley lecture. Chest 1999;116:37S-43S.
7.
Doerschuk CM: Leukocyte trafficking in alveoli and airway passages. Respir Res 2000;1:136-140.
8.
Motosugi H, Quinlan WM, Bree M, Doerschuk CM: Role of CD11b in focal acid-induced pneumonia and contralateral lung injury in rats. Am J Respir Crit Care Med 1998;157:192-198.
9.
Bowden RA, Ding ZM, Donnachie EM, Petersen TK, Michael LH, Ballantyne CM, Burns AR: Role of α4 integrin and VCAM-1 in CD18-independent neutrophil migration across mouse cardiac endothelium. Circ Res 2002;90:562-569.
10.
Shang T, Yednock T, Issekutz AC: α9β1 Integrin is expressed on human neutrophils and contributes to neutrophil migration through human lung and synovial fibroblast barriers. J Leukoc Biol 1999;66:809-816.
11.
Tasaka S, Richer SE, Mizgerd JP, Doerschuk CM: Very late antigen-4 in CD18-independent neutrophil emigration during acute bacterial pneumonia in mice. Am J Respir Crit Care Med 2002;166:53-60.
12.
Palmer EL, Rüegg C, Ferrando R, Pytela R, Sheppard D: Sequence and tissue distribution of the integrin α9 subunit, a novel partner of β1 that is widely distributed in epithelia and muscle. J Cell Biol 1993;123:1289-1297.
13.
Taooka Y, Chen J, Yednock T, Sheppard D: The integrin α9β1 mediates adhesion to activated endothelial cells and transendothelial neutrophil migration through interaction with vascular cell adhesion molecule-1. J Cell Biol 1999;145:413-420.
14.
Glynn P, Coakley R, Kilgallen I, O'Neill S: Neutrophil CD11b and soluble ICAM-1 and E-selectin in community acquired pneumonia. Eur Respir J 1999;13:1380-1385.
15.
Crowe CR, Chen K, Pociask DA, Alcorn JF, Krivich C, Enelow RI, Ross TM, Witztum JL, Kolls JK: Critical Role of IL-17RA in immunopathology of influenza infection. J Immunol 2009;183:5301-5310.
16.
Di Stefano A, Caramori G, Gnemmi I, Contoli M, Vicari C, Capelli A, Magno F, D'Anna SE, Zanini A, Brun P, Casolari P, Chung KF, Barnes PJ, Papi A, Adcock I, Balbi B: T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients. Clin Exp Immunol 2009;157:316-324.
17.
Miyashita N, Kawai Y, Akaike H, Ouchi K, Hayashi T, Kurihara T, Okimoto N: Clinical features and the role of atypical pathogens in nursing and healthcare-associated pneumonia (NHCAP): differences between a teaching university hospital and a community hospital. Intern Med 2012;51:585-594.
18.
Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, Lewis SA, Macfarlane JT: Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003;58:377-382.
19.
Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, Coley CM, Marrie TJ, Kapoor WN: A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336:243-250.
20.
Smith Hammond CA, Goldstein LB: Cough and aspiration of food and liquids due to oral-pharyngeal dysphasia: ACCP evidence-based clinical practice guidelines. Chest 2006;129:154S-168S.
21.
Teramoto S, Matsuse T, Fukuchi Y, Ouchi Y: Simple two-step swallowing provocation test for elderly patients with aspiration pneumonia. Lancet 1999;353:1243.
22.
Marcinkiewicz C, Taooka Y, Yokosaki Y, Calvete JJ, Marcinkiewicz MM, Lobb RR, Niewiarowski S, Sheppard D: Inhibitory effects of MLDG-containing heterodimetric disintegrin reveal distinct structural requirements for interaction of integrin α9β1 with VCAM-1, tenascin-C and osteopontin. J Biol Chem 2000;275:31930-31937.
23.
Werr J, Eriksson EE, Hedqvist P, Lindbom L: Engagement of β2 integrins induces surface expression of β1 integrin receptors in human neutrophils. J Leukoc Biol 2000;68:553-560.
24.
Saldanha-Gama RF, Moraes JA, Mariano-Oliveira A, Coelho AL, Walsh EM, Marcinkiewicz C, Barja-Fidalgo C: α9β1 integrin engagement inhibits neutrophil spontaneous apoptosis: involvement of Bcl-2 family members. Biochim Biophys Acta 2010;1803:848-857.
25.
Ross EA, Douglas MR, Wong SH, Ross EJ, Curnow SJ, Nash GB, Rainger E, Scheel-Toellner D, Lord JM, Salmon M, Buckley CD: Interaction between integrin α9β1 and vascular cell adhesion molecule-1 (VCAM-1) inhibits neutrophil apoptosis. Blood 2006;107:1178-1183.
26.
Nemzek JA, Fry C, Abatan O: Low-dose carbon monoxide treatment attenuates early pulmonary neutrophil recruitment after acid aspiration. Am J Physiol Lung Cell Mol Physiol 2008;294:L644-L653.
27.
Lin RY, Astiz ME, Saxon JC, Rackow EC: Altered leukocyte immunophenotypes in septic shock: studies of HLA-DR, CD11b, CD14 and IL-2R expression. Chest 1993;104:847-853.
28.
Gupta SK, Vlahakis NE: Integrin α9β1: unique signaling pathways reveal diverse biological roles. Cell Adh Migr 2010;4:194-198.
29.
Walker MG, Yao LJ, Patterson EK, Joseph MG, Cepinskas G, Veldhuizen RAW, Lewis JF, Yamashita CM: The effect of tidal volume on systemic inflammation in acid-induced lung injury. Respiration 2011;81:333-342.
30.
Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Scwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J, Shellito JE, Bagby GJ, Nelson S, Charrier K, Peschon JJ, Kolls JK: Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 2001;194:519-527.
31.
Weaver CT, Hatton RD, Mangan PR, Harrington LE: IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev lmmunol 2007;25:821-852.
32.
Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL: Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 2003;278:1910-1914.
33.
Kudva A, Scheller EV, Robinson KM, Crowe CR, Choi SM, Slight SR, Khader SA, Dubin PJ, Enelow RI, Kolls JK, Alcorn JF: Influenza A inhibits Th17-mediated host defense against bacterial pneumonia in mice. J Immunol 2011;186:1666-1674.
34.
Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, Reinhart TA, McAllister F, Edeal J, Gaus K, Husain S, Kreindler JL, Dubin PJ, Pilewski JM, Myerburg MM, Mason CA, Iwakura Y, Kolls JK: IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med 2008;14:275-281.
35.
Liu JZ, Pezeshki M, Raffatellu M: Th17 cytokines and host-pathogen interactions at the mucosa: dichotomies of help and harm. Cytokine 2009;48:156-160.
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