Skip to main content
Top
Published in: Respiratory Research 1/2013

Open Access 01-12-2013 | Research

Serum heat shock protein 47 levels in patients with drug-induced lung disease

Authors: Tomoyuki Kakugawa, Shin-ichi Yokota, Yuji Ishimatsu, Tomayoshi Hayashi, Shota Nakashima, Shintaro Hara, Noriho Sakamoto, Yasuhiro Matsuoka, Hiroshi Kubota, Mariko Mine, Hiroshi Mukae, Kazuhiro Nagata, Shigeru Kohno

Published in: Respiratory Research | Issue 1/2013

Login to get access

Abstract

Background

Heat shock protein (HSP) 47 is a collagen-specific molecular chaperone that is required for molecular maturation of various types of collagens. We recently reported that HSP47 serum levels were markedly higher in patients with acute exacerbations of idiopathic pulmonary fibrosis (IPF) when compared with patients with stable IPF, suggesting that serum HSP47 levels correlate with interstitial pneumonia activity. The aim of this study was to evaluate serum HSP47 levels in patients with drug-induced lung disease (DILD).

Methods

Findings from high-resolution computed tomographic chest scans of 47 patients with DILD were classified into one of four predominant patterns: organizing pneumonia (OP) (n = 4), nonspecific interstitial pneumonia (NSIP) (n = 24), hypersensitivity pneumonitis (HP) (n = 11), and diffuse alveolar damage (DAD) (n = 8). Serum levels of HSP47, Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-A, and SP-D were measured in these patients.

Results

The PaO2/fraction of inspired oxygen (FiO2) (P/F) ratios were significantly lower and the alveolar-arterial difference of oxygen (A-a DO2) was significantly higher in the DAD group than in the other groups. Patients with DAD had the worst outcomes among the different subgroups. Patients in the DAD group had significantly higher serum HSP47 levels than those in other groups. Receiver operating characteristic curves revealed that HSP47 was superior to KL-6, SP-A, and SP-D for discriminating between the DAD group and the other groups. The cut-off level for HSP47 that resulted in the highest diagnostic accuracy was 1711.5 pg/mL. The sensitivity, specificity, and diagnostic accuracy were 87.5%, 97.4%, and 95.7%, respectively. Serum levels of HSP47 in the group of patients requiring glucocorticoids were significantly higher than those in patients who experienced clinical improvement without glucocorticoid administration. Serum HSP47 levels also significantly correlated with various respiratory parameters.

Conclusion

This study demonstrated that serum HSP47 levels were elevated in patients with DILD with a DAD pattern who had the worst outcomes among the different subgroups, and that this was correlated with P/F ratio and A-a DO2.
Appendix
Available only for authorised users
Literature
1.
go back to reference Silva CI, Muller NL: Drug-induced lung diseases: most common reaction patterns and corresponding high-resolution CT manifestations. Semin Ultrasound CT MR. 2006, 27 (2): 111-116. 10.1053/j.sult.2006.01.001.PubMedCrossRef Silva CI, Muller NL: Drug-induced lung diseases: most common reaction patterns and corresponding high-resolution CT manifestations. Semin Ultrasound CT MR. 2006, 27 (2): 111-116. 10.1053/j.sult.2006.01.001.PubMedCrossRef
2.
go back to reference Endo M, Johkoh T, Kimura K, Yamamoto N: Imaging of gefitinib-related interstitial lung disease: multi-institutional analysis by the West Japan Thoracic Oncology Group. Lung Cancer. 2006, 52 (2): 135-140. 10.1016/j.lungcan.2006.02.002.PubMedCrossRef Endo M, Johkoh T, Kimura K, Yamamoto N: Imaging of gefitinib-related interstitial lung disease: multi-institutional analysis by the West Japan Thoracic Oncology Group. Lung Cancer. 2006, 52 (2): 135-140. 10.1016/j.lungcan.2006.02.002.PubMedCrossRef
3.
go back to reference Ichikado K, Suga M, Muller NL, Taniguchi H, Kondoh Y, Akira M, Johkoh T, Mihara N, Nakamura H, Takahashi M, et al: Acute interstitial pneumonia: comparison of high-resolution computed tomography findings between survivors and nonsurvivors. Am J Respir Crit Care Med. 2002, 165 (11): 1551-1556. 10.1164/rccm.2106157.PubMedCrossRef Ichikado K, Suga M, Muller NL, Taniguchi H, Kondoh Y, Akira M, Johkoh T, Mihara N, Nakamura H, Takahashi M, et al: Acute interstitial pneumonia: comparison of high-resolution computed tomography findings between survivors and nonsurvivors. Am J Respir Crit Care Med. 2002, 165 (11): 1551-1556. 10.1164/rccm.2106157.PubMedCrossRef
4.
go back to reference Ohnishi H, Yokoyama A, Kondo K, Hamada H, Abe M, Nishimura K, Hiwada K, Kohno N: Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. Am J Respir Crit Care Med. 2002, 165 (3): 378-381. 10.1164/ajrccm.165.3.2107134.PubMedCrossRef Ohnishi H, Yokoyama A, Kondo K, Hamada H, Abe M, Nishimura K, Hiwada K, Kohno N: Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. Am J Respir Crit Care Med. 2002, 165 (3): 378-381. 10.1164/ajrccm.165.3.2107134.PubMedCrossRef
5.
go back to reference Kinder BW, Brown KK, McCormack FX, Ix JH, Kervitsky A, Schwarz MI, King TE: Serum surfactant protein-A is a strong predictor of early mortality in idiopathic pulmonary fibrosis. Chest. 2009, 135 (6): 1557-1563. 10.1378/chest.08-2209.PubMedPubMedCentralCrossRef Kinder BW, Brown KK, McCormack FX, Ix JH, Kervitsky A, Schwarz MI, King TE: Serum surfactant protein-A is a strong predictor of early mortality in idiopathic pulmonary fibrosis. Chest. 2009, 135 (6): 1557-1563. 10.1378/chest.08-2209.PubMedPubMedCentralCrossRef
6.
go back to reference Kawase S, Hattori N, Ishikawa N, Horimasu Y, Fujitaka K, Furonaka O, Isobe T, Miyoshi S, Hamada H, Yamane T, et al: Change in serum KL-6 level from baseline is useful for predicting life-threatening EGFR-TKIs induced interstitial lung disease. Respir Res. 2011, 12: 97-10.1186/1465-9921-12-97.PubMedPubMedCentralCrossRef Kawase S, Hattori N, Ishikawa N, Horimasu Y, Fujitaka K, Furonaka O, Isobe T, Miyoshi S, Hamada H, Yamane T, et al: Change in serum KL-6 level from baseline is useful for predicting life-threatening EGFR-TKIs induced interstitial lung disease. Respir Res. 2011, 12: 97-10.1186/1465-9921-12-97.PubMedPubMedCentralCrossRef
7.
go back to reference Ohnishi H, Yokoyama A, Yasuhara Y, Watanabe A, Naka T, Hamada H, Abe M, Nishimura K, Higaki J, Ikezoe J, et al: Circulating KL-6 levels in patients with drug induced pneumonitis. Thorax. 2003, 58 (10): 872-875. 10.1136/thorax.58.10.872.PubMedPubMedCentralCrossRef Ohnishi H, Yokoyama A, Yasuhara Y, Watanabe A, Naka T, Hamada H, Abe M, Nishimura K, Higaki J, Ikezoe J, et al: Circulating KL-6 levels in patients with drug induced pneumonitis. Thorax. 2003, 58 (10): 872-875. 10.1136/thorax.58.10.872.PubMedPubMedCentralCrossRef
8.
go back to reference Ishida Y, Kubota H, Yamamoto A, Kitamura A, Bachinger HP, Nagata K: Type I collagen in Hsp47-null cells is aggregated in endoplasmic reticulum and deficient in N-propeptide processing and fibrillogenesis. Mol Biol Cell. 2006, 17 (5): 2346-2355. 10.1091/mbc.E05-11-1065.PubMedPubMedCentralCrossRef Ishida Y, Kubota H, Yamamoto A, Kitamura A, Bachinger HP, Nagata K: Type I collagen in Hsp47-null cells is aggregated in endoplasmic reticulum and deficient in N-propeptide processing and fibrillogenesis. Mol Biol Cell. 2006, 17 (5): 2346-2355. 10.1091/mbc.E05-11-1065.PubMedPubMedCentralCrossRef
9.
go back to reference Nagata K, Saga S, Yamada KM: A major collagen-binding protein of chick embryo fibroblasts is a novel heat shock protein. J Cell Biol. 1986, 103 (1): 223-229. 10.1083/jcb.103.1.223.PubMedCrossRef Nagata K, Saga S, Yamada KM: A major collagen-binding protein of chick embryo fibroblasts is a novel heat shock protein. J Cell Biol. 1986, 103 (1): 223-229. 10.1083/jcb.103.1.223.PubMedCrossRef
10.
go back to reference Nagai N, Hosokawa M, Itohara S, Adachi E, Matsushita T, Hosokawa N, Nagata K: Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis. J Cell Biol. 2000, 150 (6): 1499-1506. 10.1083/jcb.150.6.1499.PubMedPubMedCentralCrossRef Nagai N, Hosokawa M, Itohara S, Adachi E, Matsushita T, Hosokawa N, Nagata K: Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis. J Cell Biol. 2000, 150 (6): 1499-1506. 10.1083/jcb.150.6.1499.PubMedPubMedCentralCrossRef
11.
go back to reference Sauk JJ, Smith T, Norris K, Ferreira L: Hsp47 and the translation-translocation machinery cooperate in the production of alpha 1(I) chains of type I procollagen. J Biol Chem. 1994, 269 (6): 3941-3946.PubMed Sauk JJ, Smith T, Norris K, Ferreira L: Hsp47 and the translation-translocation machinery cooperate in the production of alpha 1(I) chains of type I procollagen. J Biol Chem. 1994, 269 (6): 3941-3946.PubMed
12.
go back to reference Taguchi T, Razzaque MS: The collagen-specific molecular chaperone HSP47: is there a role in fibrosis?. Trends Mol Med. 2007, 13 (2): 45-53. 10.1016/j.molmed.2006.12.001.PubMedCrossRef Taguchi T, Razzaque MS: The collagen-specific molecular chaperone HSP47: is there a role in fibrosis?. Trends Mol Med. 2007, 13 (2): 45-53. 10.1016/j.molmed.2006.12.001.PubMedCrossRef
13.
go back to reference Ishii H, Mukae H, Kakugawa T, Iwashita T, Kaida H, Fujii T, Hayashi T, Kadota J, Kohno S: Increased expression of collagen-binding heat shock protein 47 in murine bleomycin-induced pneumopathy. Am J Physiol Lung Cell Mol Physiol. 2003, 285 (4): L957-L963.PubMedCrossRef Ishii H, Mukae H, Kakugawa T, Iwashita T, Kaida H, Fujii T, Hayashi T, Kadota J, Kohno S: Increased expression of collagen-binding heat shock protein 47 in murine bleomycin-induced pneumopathy. Am J Physiol Lung Cell Mol Physiol. 2003, 285 (4): L957-L963.PubMedCrossRef
14.
go back to reference Kakugawa T, Mukae H, Hayashi T, Ishii H, Abe K, Fujii T, Oku H, Miyazaki M, Kadota J, Kohno S: Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis. Eur Respir J. 2004, 24 (1): 57-65. 10.1183/09031936.04.00120803.PubMedCrossRef Kakugawa T, Mukae H, Hayashi T, Ishii H, Abe K, Fujii T, Oku H, Miyazaki M, Kadota J, Kohno S: Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis. Eur Respir J. 2004, 24 (1): 57-65. 10.1183/09031936.04.00120803.PubMedCrossRef
15.
go back to reference Kakugawa T, Mukae H, Hishikawa Y, Ishii H, Sakamoto N, Ishimatsu Y, Fujii T, Koji T, Kohno S: Localization of HSP47 mRNA in murine bleomycin-induced pulmonary fibrosis. Virchows Arch. 2010, 456 (3): 309-315. 10.1007/s00428-009-0876-x.PubMedCrossRef Kakugawa T, Mukae H, Hishikawa Y, Ishii H, Sakamoto N, Ishimatsu Y, Fujii T, Koji T, Kohno S: Localization of HSP47 mRNA in murine bleomycin-induced pulmonary fibrosis. Virchows Arch. 2010, 456 (3): 309-315. 10.1007/s00428-009-0876-x.PubMedCrossRef
16.
go back to reference Hagiwara S, Iwasaka H, Matsumoto S, Noguchi T: Antisense oligonucleotide inhibition of heat shock protein (HSP) 47 improves bleomycin-induced pulmonary fibrosis in rats. Respir Res. 2007, 8: 37-10.1186/1465-9921-8-37.PubMedPubMedCentralCrossRef Hagiwara S, Iwasaka H, Matsumoto S, Noguchi T: Antisense oligonucleotide inhibition of heat shock protein (HSP) 47 improves bleomycin-induced pulmonary fibrosis in rats. Respir Res. 2007, 8: 37-10.1186/1465-9921-8-37.PubMedPubMedCentralCrossRef
17.
go back to reference Kakugawa T, Mukae H, Hayashi T, Ishii H, Nakayama S, Sakamoto N, Yoshioka S, Sugiyama K, Mine M, Mizuta Y, et al: Expression of HSP47 in usual interstitial pneumonia and nonspecific interstitial pneumonia. Respir Res. 2005, 6: 57-10.1186/1465-9921-6-57.PubMedPubMedCentralCrossRef Kakugawa T, Mukae H, Hayashi T, Ishii H, Nakayama S, Sakamoto N, Yoshioka S, Sugiyama K, Mine M, Mizuta Y, et al: Expression of HSP47 in usual interstitial pneumonia and nonspecific interstitial pneumonia. Respir Res. 2005, 6: 57-10.1186/1465-9921-6-57.PubMedPubMedCentralCrossRef
18.
go back to reference Amenomori M, Mukae H, Sakamoto N, Kakugawa T, Hayashi T, Hara A, Hara S, Fujita H, Ishimoto H, Ishimatsu Y, et al: HSP47 in lung fibroblasts is a predictor of survival in fibrotic nonspecific interstitial pneumonia. Respir Med. 2010, 104 (6): 895-901. 10.1016/j.rmed.2010.01.011.PubMedCrossRef Amenomori M, Mukae H, Sakamoto N, Kakugawa T, Hayashi T, Hara A, Hara S, Fujita H, Ishimoto H, Ishimatsu Y, et al: HSP47 in lung fibroblasts is a predictor of survival in fibrotic nonspecific interstitial pneumonia. Respir Med. 2010, 104 (6): 895-901. 10.1016/j.rmed.2010.01.011.PubMedCrossRef
19.
go back to reference Kakugawa T, Yokota S, Ishimatsu Y, Hayashi T, Nakashima S, Hara S, Sakamoto N, Kubota H, Mine M, Matsuoka Y, et al: Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis. Cell Stress Chaperones. 2013, 18 (5): 581-590. 10.1007/s12192-013-0411-5.PubMedPubMedCentralCrossRef Kakugawa T, Yokota S, Ishimatsu Y, Hayashi T, Nakashima S, Hara S, Sakamoto N, Kubota H, Mine M, Matsuoka Y, et al: Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis. Cell Stress Chaperones. 2013, 18 (5): 581-590. 10.1007/s12192-013-0411-5.PubMedPubMedCentralCrossRef
20.
go back to reference Myers JL, Limper AH, Swensen SJ: Drug-induced lung disease: a pragmatic classification incorporating HRCT appearances. Semin Respir Crit Care Med. 2003, 24 (4): 445-454.PubMedCrossRef Myers JL, Limper AH, Swensen SJ: Drug-induced lung disease: a pragmatic classification incorporating HRCT appearances. Semin Respir Crit Care Med. 2003, 24 (4): 445-454.PubMedCrossRef
21.
go back to reference 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 (3): 213-219. 10.1016/j.rmed.2003.09.015.PubMedCrossRef 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 (3): 213-219. 10.1016/j.rmed.2003.09.015.PubMedCrossRef
22.
go back to reference Yokota S, Kubota H, Matsuoka Y, Naitoh M, Hirata D, Minota S, Takahashi H, Fujii N, Nagata K: Prevalence of HSP47 antigen and autoantibodies to HSP47 in the sera of patients with mixed connective tissue disease. Biochem Biophys Res Commun. 2003, 303 (2): 413-418. 10.1016/S0006-291X(03)00352-8.PubMedCrossRef Yokota S, Kubota H, Matsuoka Y, Naitoh M, Hirata D, Minota S, Takahashi H, Fujii N, Nagata K: Prevalence of HSP47 antigen and autoantibodies to HSP47 in the sera of patients with mixed connective tissue disease. Biochem Biophys Res Commun. 2003, 303 (2): 413-418. 10.1016/S0006-291X(03)00352-8.PubMedCrossRef
23.
go back to reference Obuchowski NA, Zepp RC: Simple steps for improving multiple-reader studies in radiology. AJR Am J Roentgenol. 1996, 166 (3): 517-521. 10.2214/ajr.166.3.8623619.PubMedCrossRef Obuchowski NA, Zepp RC: Simple steps for improving multiple-reader studies in radiology. AJR Am J Roentgenol. 1996, 166 (3): 517-521. 10.2214/ajr.166.3.8623619.PubMedCrossRef
24.
go back to reference Iwashita T, Kadota J, Naito S, Kaida H, Ishimatsu Y, Miyazaki M, Ozono Y, Kohno S: Involvement of collagen-binding heat shock protein 47 and procollagen type I synthesis in idiopathic pulmonary fibrosis: contribution of type II pneumocytes to fibrosis. Hum Pathol. 2000, 31 (12): 1498-1505. 10.1053/hupa.2000.20378.PubMedCrossRef Iwashita T, Kadota J, Naito S, Kaida H, Ishimatsu Y, Miyazaki M, Ozono Y, Kohno S: Involvement of collagen-binding heat shock protein 47 and procollagen type I synthesis in idiopathic pulmonary fibrosis: contribution of type II pneumocytes to fibrosis. Hum Pathol. 2000, 31 (12): 1498-1505. 10.1053/hupa.2000.20378.PubMedCrossRef
25.
go back to reference Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med. 2000, 342 (18): 1334-1349. 10.1056/NEJM200005043421806.PubMedCrossRef Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med. 2000, 342 (18): 1334-1349. 10.1056/NEJM200005043421806.PubMedCrossRef
26.
go back to reference Vahid B, Marik PE: Pulmonary complications of novel antineoplastic agents for solid tumors. Chest. 2008, 133 (2): 528-538. 10.1378/chest.07-0851.PubMedCrossRef Vahid B, Marik PE: Pulmonary complications of novel antineoplastic agents for solid tumors. Chest. 2008, 133 (2): 528-538. 10.1378/chest.07-0851.PubMedCrossRef
27.
go back to reference Sunamoto M, Kuze K, Tsuji H, Ohishi N, Yagi K, Nagata K, Kita T, Doi T: Antisense oligonucleotides against collagen-binding stress protein HSP47 suppress collagen accumulation in experimental glomerulonephritis. Lab Invest. 1998, 78 (8): 967-972.PubMed Sunamoto M, Kuze K, Tsuji H, Ohishi N, Yagi K, Nagata K, Kita T, Doi T: Antisense oligonucleotides against collagen-binding stress protein HSP47 suppress collagen accumulation in experimental glomerulonephritis. Lab Invest. 1998, 78 (8): 967-972.PubMed
28.
go back to reference Nishino T, Miyazaki M, Abe K, Furusu A, Mishima Y, Harada T, Ozono Y, Koji T, Kohno S: Antisense oligonucleotides against collagen-binding stress protein HSP47 suppress peritoneal fibrosis in rats. Kidney Int. 2003, 64 (3): 887-896. 10.1046/j.1523-1755.2003.00169.x.PubMedCrossRef Nishino T, Miyazaki M, Abe K, Furusu A, Mishima Y, Harada T, Ozono Y, Koji T, Kohno S: Antisense oligonucleotides against collagen-binding stress protein HSP47 suppress peritoneal fibrosis in rats. Kidney Int. 2003, 64 (3): 887-896. 10.1046/j.1523-1755.2003.00169.x.PubMedCrossRef
29.
go back to reference Obata Y, Nishino T, Kushibiki T, Tomoshige R, Xia Z, Miyazaki M, Abe K, Koji T, Tabata Y, Kohno S: HSP47 siRNA conjugated with cationized gelatin microspheres suppresses peritoneal fibrosis in mice. Acta Biomater. 2012, 8 (7): 2688-2696. 10.1016/j.actbio.2012.03.050.PubMedCrossRef Obata Y, Nishino T, Kushibiki T, Tomoshige R, Xia Z, Miyazaki M, Abe K, Koji T, Tabata Y, Kohno S: HSP47 siRNA conjugated with cationized gelatin microspheres suppresses peritoneal fibrosis in mice. Acta Biomater. 2012, 8 (7): 2688-2696. 10.1016/j.actbio.2012.03.050.PubMedCrossRef
Metadata
Title
Serum heat shock protein 47 levels in patients with drug-induced lung disease
Authors
Tomoyuki Kakugawa
Shin-ichi Yokota
Yuji Ishimatsu
Tomayoshi Hayashi
Shota Nakashima
Shintaro Hara
Noriho Sakamoto
Yasuhiro Matsuoka
Hiroshi Kubota
Mariko Mine
Hiroshi Mukae
Kazuhiro Nagata
Shigeru Kohno
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2013
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-14-133

Other articles of this Issue 1/2013

Respiratory Research 1/2013 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.