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Open Access 01-12-2018 | Research article

Elevated α-defensin levels in plasma and bronchoalveolar lavage fluid from patients with myositis-associated interstitial lung disease

Authors: Noriho Sakamoto, Hiroshi Ishimoto, Tomoyuki Kakugawa, Minoru Satoh, Tomoko Hasegawa, Shin Tanaka, Atsuko Hara, Shota Nakashima, Hirokazu Yura, Takuto Miyamura, Hanako Koyama, Towako Morita, Seiko Nakamichi, Yasushi Obase, Yuji Ishimatsu, Hiroshi Mukae

Published in: BMC Pulmonary Medicine | Issue 1/2018

Abstract

Background

Interstitial lung disease (ILD) is a prognostic indicator of poor outcome in myositis. Although the pathogenesis of myositis-associated ILD is not well understood, neutrophils are thought to play a pivotal role. Neutrophils store azurophil granules that contain defensins, which are antimicrobial peptides that regulate the inflammatory response. Here, we evaluated levels of the human neutrophil peptides (HNPs) α-defensin 1 through 3 in patients with myositis-associated ILD to determine whether HNPs represent disease markers and play a role in the pathogenesis of myositis-associated ILD.

Methods

HNP levels were measured in the plasma and bronchoalveolar lavage fluid (BALF) of 56 patients with myositis-associated ILD and 24 healthy controls by enzyme-linked immunosorbent assay.

Results

Analysis revealed significantly higher HNP levels in plasma and BALF samples from patients with myositis-associated ILD as compared to those of healthy controls; however, plasma HNPs were significantly correlated with total cell counts in BALF. Additionally, BALF HNP levels were positively correlated with serum surfactant protein-A and the percentage of neutrophils in BALF, and BALF HNP levels correlated with the percentage of reticular opacities in high-resolution computed tomography results for patients with anti-aminoacyl-tRNA synthetase (ARS) antibody positive myositis-associated ILD. Survival did not differ between patients with higher and lower levels of plasma and BALF HNPs.

Conclusions

Plasma and BALF HNPs might reflect the disease activities of myositis-associated ILD, especially in patients with anti-ARS antibody positive myositis-associated ILD. However further studies are necessary to clarify whether HNPs represent disease markers and play roles in disease pathogenesis.

Lundberg IE, Miller FW, Tjarnlund A, Bottai M. Diagnosis and classification of idiopathic inflammatory myopathies. J Intern Med. 2016;280:39–51.CrossRefPubMedPubMedCentral

Marie I, Hachulla E, Cherin P, Dominique S, Hatron PY, Hellot MF, Devulder B, Herson S, Levesque H, Courtois H. Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum. 2002;47:614–22.CrossRefPubMed

Mukae H, Ishimoto H, Sakamoto N, Hara S, Kakugawa T, Nakayama S, Ishimatsu Y, Kawakami A, Eguchi K, Kohno S. Clinical differences between interstitial lung disease associated with clinically amyopathic dermatomyositis and classic dermatomyositis. Chest. 2009;136:1341–7.CrossRefPubMed

Chinoy H, Adimulam S, Marriage F, New P, Vincze M, Zilahi E, Kapitany A, Gyetvai A, Ekholm L, Novota P, et al. Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study. Ann Rheum Dis. 2012;71:961–5.CrossRefPubMed

Hamaguchi Y, Fujimoto M, Matsushita T, Kaji K, Komura K, Hasegawa M, Kodera M, Muroi E, Fujikawa K, Seishima M, et al. Common and distinct clinical features in adult patients with anti-aminoacyl-tRNA synthetase antibodies: heterogeneity within the syndrome. PLoS One. 2013;8:e60442.CrossRefPubMedPubMedCentral

Lega JC, Reynaud Q, Belot A, Fabien N, Durieu I, Cottin V. Idiopathic inflammatory myopathies and the lung. Eur Respir Rev. 2015;24:216–38.CrossRefPubMed

Schnabel A, Reuter M, Biederer J, Richter C, Gross WL. Interstitial lung disease in polymyositis and dermatomyositis: clinical course and response to treatment. Semin Arthritis Rheum. 2003;32:273–84.CrossRefPubMed

Fujisawa T, Hozumi H, Kono M, Enomoto N, Hashimoto D, Nakamura Y, Inui N, Yokomura K, Koshimizu N, Toyoshima M, et al. Prognostic factors for myositis-associated interstitial lung disease. PLoS One. 2014;9:e98824.CrossRefPubMedPubMedCentral

Sakamoto N, Mukae H, Fujii T, Ishii H, Yoshioka S, Kakugawa T, Sugiyama K, Mizuta Y, Kadota J, Nakazato M, et al. Differential effects of alpha- and beta-defensin on cytokine production by cultured human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2005;288:L508–13.CrossRefPubMed

10.

Aarbiou J, Rabe KF, Hiemstra PS. Role of defensins in inflammatory lung disease. Ann Med. 2002;34:96–101.CrossRefPubMed

11.

Mendez-Samperio P. Recent advances in the field of antimicrobial peptides in inflammatory diseases. Adv Biomed Res. 2013;2:50.CrossRefPubMedPubMedCentral

12.

Mukae H, Matsumoto N, Ashitani J, Mashimoto H, Kadota J, Nakazato M, Kohno S, Matsukura S. Neutrophil-related cytokines and neutrophil products in bronchoalveolar lavage fluid of a patient with ANCA negative Wegener's granulomatosis. Eur Respir J. 1996;9:1950–4.CrossRefPubMed

13.

Mukae H, Ishimoto H, Yanagi S, Ishii H, Nakayama S, Ashitani J, Nakazato M, Kohno S. Elevated BALF concentrations of alpha- and beta-defensins in patients with pulmonary alveolar proteinosis. Respir Med. 2007;101:715–21.CrossRefPubMed

14.

Sakamoto N, Ishimatsu Y, Kakugawa T, Yura H, Tomonaga M, Harada T, Nakashima S, Hara S, Hara A, Ishimoto H, et al. Elevated plasma alpha-defensins in patients with acute exacerbation of fibrotic interstitial pneumonia. Respir Med. 2015;109:265–71.CrossRefPubMed

15.

Mukae H, Iiboshi H, Nakazato M, Hiratsuka T, Tokojima M, Abe K, Ashitani J, Kadota J, Matsukura S, Kohno S. Raised plasma concentrations of alpha-defensins in patients with idiopathic pulmonary fibrosis. Thorax. 2002;57:623–8.CrossRefPubMedPubMedCentral

16.

Ashitani J, Mukae H, Nakazato M, Ihi T, Mashimoto H, Kadota J, Kohno S, Matsukura S. Elevated concentrations of defensins in bronchoalveolar lavage fluid in diffuse panbronchiolitis. Eur Respir J. 1998;11:104–11.CrossRefPubMed

17.

Ashitani J, Mukae H, Hiratsuka T, Nakazato M, Kumamoto K, Matsukura S. Elevated levels of alpha-defensins in plasma and BAL fluid of patients with active pulmonary tuberculosis. Chest. 2002;121:519–26.CrossRefPubMed

18.

Ashitani J, Mukae H, Hiratsuka T, Nakazato M, Kumamoto K, Matsukura S. Plasma and BAL fluid concentrations of antimicrobial peptides in patients with Mycobacterium avium-intracellulare infection. Chest. 2001;119:1131–7.CrossRefPubMed

19.

Sakamoto N, Kakugawa T, Hara A, Nakashima S, Yura H, Harada T, Ishimoto H, Yatera K, Kuwatsuka Y, Hara T, et al. Association of elevated alpha-defensin levels with interstitial pneumonia in patients with systemic sclerosis. Respir Res. 2015;16:148.CrossRefPubMedPubMedCentral

20.

Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975;292:403–7.CrossRefPubMed

21.

Sontheimer RD. Would a new name hasten the acceptance of amyopathic dermatomyositis (dermatomyositis sine myositis) as a distinctive subset within the idiopathic inflammatory dermatomyopathies spectrum of clinical illness? J Am Acad Dermatol. 2002;46:626–36.CrossRefPubMed

22.

Johkoh T, Muller NL, Colby TV, Ichikado K, Taniguchi H, Kondoh Y, Fujimoto K, Kinoshita M, Arakawa H, Yamada H, et al. Nonspecific interstitial pneumonia: correlation between thin-section CT findings and pathologic subgroups in 55 patients. Radiology. 2002;225:199–204.CrossRefPubMed

23.

Sumikawa H, Johkoh T, Ichikado K, Taniguchi H, Kondoh Y, Fujimoto K, Tateishi U, Hiramatsu T, Inoue A, Natsag J, et al. Usual interstitial pneumonia and chronic idiopathic interstitial pneumonia: analysis of CT appearance in 92 patients. Radiology. 2006;241:258–66.CrossRefPubMed

24.

Sakamoto N, Mukae H, Fujii T, Kakugawa T, Kaida H, Kadota J, Kohno S. Soluble form of Fas and Fas ligand in serum and bronchoalveolar lavage fluid of individuals infected with human T-lymphotropic virus type 1. Respir Med. 2004;98:213–9.CrossRefPubMed

25.

Satoh M, Ceribelli A, Hirakata M, Chan E. Immunodiagnosis of autoimmune myopathies. In: Rose N, Hamilton R, Detrick B, Reeves W, editors. Manual of molecular and clinical laboratory immunology. 8th ed. Washington, D.C.: American Society of Microbiology Press; 2016. p. 878–87.

26.

Ceribelli A, Fredi M, Taraborelli M, Cavazzana I, Tincani A, Selmi C, Chan JY, Chan EK, Satoh M, Franceschini F. Prevalence and clinical significance of anti-MDA5 antibodies in European patients with polymyositis/dermatomyositis. Clin Exp Rheumatol. 2014;32:891–7.PubMed

27.

Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol. 1995;57:289–300.

28.

Porto BN, Stein RT. Neutrophil extracellular traps in pulmonary diseases: too much of a good thing? Front Immunol. 2016;7:311.CrossRefPubMedPubMedCentral

29.

Zhang S, Shu X, Tian X, Chen F, Lu X, Wang G. Enhanced formation and impaired degradation of neutrophil extracellular traps in dermatomyositis and polymyositis: a potential contributor to interstitial lung disease complications. Clin Exp Immunol. 2014;177:134–41.CrossRefPubMedPubMedCentral

30.

Zhang S, Shen H, Shu X, Peng Q, Wang G. Abnormally increased low-density granulocytes in peripheral blood mononuclear cells are associated with interstitial lung disease in dermatomyositis. Mod Rheumatol. 2016;27:1–8.

31.

Takahashi H, Shiratori M, Kanai A, Chiba H, Kuroki Y, Abe S. Monitoring markers of disease activity for interstitial lung diseases with serum surfactant proteins a and D. Respirology. 2006;11:S51–4.CrossRefPubMed

32.

Yura H, Sakamoto N, Satoh M, Ishimoto H, Hanaka T, Ito C, Hasegawa T, Tanaka S, Miyamura T, Nakashima S, et al. Clinical characteristics of patients with anti-aminoacyl-tRNA synthetase antibody positive idiopathic interstitial pneumonia. Respir Med. 2017;132:189–94.CrossRefPubMed

33.

Waseda Y, Johkoh T, Egashira R, Sumikawa H, Saeki K, Watanabe S, Matsunuma R, Takato H, Ichikawa Y, Hamaguchi Y, et al. Antisynthetase syndrome: pulmonary computed tomography findings of adult patients with antibodies to aminoacyl-tRNA synthetases. Eur J Radiol. 2016;85:1421–6.CrossRefPubMed

34.

Takato H, Waseda Y, Watanabe S, Inuzuka K, Katayama N, Ichikawa Y, Yasui M, Fujimura M. Pulmonary manifestations of anti-ARS antibody positive interstitial pneumonia--with or without PM/DM. Respir Med. 2013;107:128–33.CrossRefPubMed

35.

Yoshioka S, Mukae H, Ishii H, Kakugawa T, Ishimoto H, Sakamoto N, Fujii T, Urata Y, Kondo T, Kubota H, et al. Alpha-defensin enhances expression of HSP47 and collagen-1 in human lung fibroblasts. Life Sci. 2007;80:1839–45.CrossRefPubMed

36.

Amenomori M, Mukae H, Ishimatsu Y, Sakamoto N, Kakugawa T, Hara A, Hara S, Fujita H, Ishimoto H, Hayashi T, et al. Differential effects of human neutrophil peptide-1 on growth factor and interleukin-8 production by human lung fibroblasts and epithelial cells. Exp Lung Res. 2010;36:411–9.CrossRefPubMed

37.

Nakazato M, Shiomi K, Date Y, Matsukura S, Kangawa K, Minamino N, Matsuo H. Isolation and sequence determination of 6- and 8-kDa precursors of human neutrophil peptides from bone marrow, plasma and peripheral blood neutrophils. Biochem Biophys Res Commun. 1995;211:1053–62.CrossRefPubMed

Title: Elevated α-defensin levels in plasma and bronchoalveolar lavage fluid from patients with myositis-associated interstitial lung disease
Authors: Noriho Sakamoto
Hiroshi Ishimoto
Tomoyuki Kakugawa
Minoru Satoh
Tomoko Hasegawa
Shin Tanaka
Atsuko Hara
Shota Nakashima
Hirokazu Yura
Takuto Miyamura
Hanako Koyama
Towako Morita
Seiko Nakamichi
Yasushi Obase
Yuji Ishimatsu
Hiroshi Mukae
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Pulmonary Medicine / Issue 1/2018
Electronic ISSN: 1471-2466
DOI: https://doi.org/10.1186/s12890-018-0609-5

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Elevated α-defensin levels in plasma and bronchoalveolar lavage fluid from patients with myositis-associated interstitial lung disease

Abstract

Background

Methods

Results

Conclusions

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