[雙語(yǔ)翻譯]醫(yī)學(xué)外文翻譯--生物標(biāo)志物預(yù)測(cè)異氰酸酯誘發(fā)哮喘（英文）

1、21 © Copyright The Korean Academy of Asthma, Allergy and Clinical Immunology ? The Korean Academy of Pediatric Allergy and Respiratory Disease http://e-aair.orgINTRODUCTIONThree diisocyanates cause occupational asth

2、ma (OA): toluene diisocyanate (TDI), 4,4-diphenylmethane diisocyanate (MDI), and 1,6-hexamethylene diisocyanate (HDI).1-3 TDI is the most common cause of OA in developing countries, with a prevalence of 2.9-13% in expose

3、d workers.4 The pathogenic mechanisms of isocyanate-induced asthma remain incompletely understood5 and no reliable method of serological testing has been estab-lished.Because permanent impairment of lung function was not

4、ed in long-term follow-up studies of isocyanate-induced asthma, the development of biomarkers to identify susceptible subjects among exposed workers is essential. Previously, we reported on biomarkers of TDI-induced asth

5、ma, but no others have been re-ported. In this review, we summarize potential biomarkers for isocyanate-induced asthma, based on different mechanisms, including immunologic, genetic, neurogenic, and protein markers.Bioma

6、rkers Predicting Isocyanate-Induced AsthmaNami Shrestha Palikhe, Joo-Hee Kim, Hae-Sim Park* Department of Allergy the prevalence varied between 0 and 50% of workers,10,11 depending on the conditions used to prepare the

7、ReviewAllergy Asthma Immunol Res. 2011 January;3(1):21-26. doi: 10.4168/aair.2011.3.1.21 pISSN 2092-7355 ? eISSN 2092-7363Three diisocyanates can cause occupational asthma (OA): toluene diisocyanate (TDI), 4,4 diphenylme

8、thane diisocyanate (MDI), and 1,6-hexameth-ylene diisocyanate (HDI). We analyzed potential biomarkers of isocyanate-induced OA, based on investigated immunologic, genetic, neurogenic, and protein markers, because there i

9、s no serological testing method. The prevalence of serum IgG to cytokeratin (CK)18 and CK19 in TDI-OA was signifi-cantly higher than in controls, although the prevalence of these antibodies was too low for them to be use

10、d as biomarkers. Another candidate bio-marker was serum IgG to tissue transglutaminase (tTG), because the prevalence of serum specific IgG to tTG was significantly higher in patients with TDI-OA than in controls. The hum

11、an leukocyte antigen (HLA) DRB1*1501-DQB1*0602-DPB1*0501 haplotype may be used as a genetic marker for TDI-OA in Koreans via enhanced specific IgE sensitization in exposed subjects. The genetic polymorphisms of catenin a

12、lpha 3, alpha-T catenin (CTNNA3) were significantly associated with TDI-OA. Additionally, examining the neurokinin 2 receptor (NK2R) 7853G>A and 11424 G>A polymor-phisms, the NK2R 7853GG genotype had higher serum v

13、ascular endothelial growth factor (VEGF) levels than the GA or AA genotypes among Korean workers exposed to TDI. To identify new serologic markers using a proteomic approach, differentially expressed proteins between sub

14、jects with MDI-OA and asymptomatic exposed controls in a Korean population showed that the optimal serum cutoff levels were 69.8 ng/mL for ferritin and 2.5 µg/mL for transferrin. When these two parameters were combi

15、ned, the sensitivity was 71.4% and the specificity was 85.7%. The serum cyto-kine matrix metalloproteinase-9 (MMP-9) level is a useful biomarker for identifying cases of TDI-OA among exposed workers. Despite these possi-

16、ble biomarkers, more effort should be focused on developing early diagnostic biomarkers using a comprehensive approach based on the pathogenic mechanisms of isocyanate-induced OA.Key Words: Isocyanate; toluene diisocyana

17、te; biomarkers; 4,4-diphenylmethane diisocyanate; occupational asthmaThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licen

18、ses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Correspondence to: Hae-Sim Park, MD, PhD, Department of Allergy a

19、nd Rheumatology, Ajou University School of Medicine, San-5 Wonchun-dong, Yeongtong-gu, Suwon 443-721, Korea. Tel: +82-31-219-5196; Fax: +82-31-219-5154; E-mail: hspark@ajou.ac.kr Received: May 18, 2010; Accepted: June

20、1, 2010.?Nami Shrestha Palikhe and Joo-Hee Kim contribute equally for this manuscript. ?There are no financial or other issues that might lead to conflict of interest.Biomarkers for Isocyanate-Induced Asthma AAIR Allergy

21、 Asthma Immunol Res. 2011 January;3(1):21-26. doi: 10.4168/aair.2011.3.1.21 23 http://e-aair.orgtrix 500K SNP chip. The genetic polymorphisms of catenin al-pha 3, alpha-T catenin (CTNNA3) were significantly associated wi

22、th TDI-OA. Carriers with the minor haplotype, HT2 [GG], of two genetic polymorphisms (rs10762058 and rs7088181) had significantly lower PC20 methacholine levels and lower mRNA expression of CTNNA3 than non-carriers. A ge

23、netic polymor-phism in the 3’-downstream region of CTNNA3 (rs1786929) was significantly associated with the TDI-OA phenotype and the prevalence of serum specific IgG to CK19.25 The small sam-ple size for genome-wide asso

24、ciation is one limitation of this study. Nevertheless, as TDI-OA is quite rare in developed coun-tries, this study should be replicated in other populations. Fur-thermore, the detailed functions of this gene remain to be

25、 de-termined. In conclusion, this study provides an important con-tribution for Asian populations by identifying CTNNA3 as a po-tential biomarker for predicting genetic susceptibility to TDI-in-duced asthma.Additionally,

26、 a study of a Korean population examined two single nucleotide polymorphisms (SNPs) of the neurokinin 2 receptor: NK2R 7853G>A (Gly231Glu) and 11424 G>A (Ar-g375His). No significant difference in allele, genotype,

27、or haplo-type frequencies of these two SNPs was seen, but subjects with the NK2R 7853GG genotype had higher serum vascular endo-thelial growth factor (VEGF) levels than those with GA or AA among the TDI-exposed workers,

28、suggesting that the NK2R 7853GG genotype contributes to increased serum VEGF levels, resulting in airway inflammation after TDI exposure, which may be mediated by neurogenic ROS.26 These results suggest that the NK2R 785

29、3G>A polymorphism is a candidate biomarker for TDI OA. However, this study needs to be repeated using larger cohorts. Additionally, the indirect relationship between serum VEGF and NK2R 7853G>A needs to be investig

30、ated to deter-mine whether there is a functional association between the two, which could assist in determining whether this may be used as a biomarker.Several studies have focused on anti-oxidant gene markers. Wikman et

31、 al.27 showed an association of N-acetyltransferase genotypes as modifiers of the diisocyanate exposure-associat-ed asthma risk. They showed that slow acetylator N-acetyltrans-ferase 1 (NAT1) genotypes had a 2.5-fold gre

32、ater risk of diisocy-anate-induced asthma. This was the first result to suggest that glutathione S-transferases (GSTs) and NATs play an important role in the inception of asthmatic reactions related to occupa-tional expo

33、sure to diisocyanates. A study in a Swedish popula-tion showed that the glutathione S-transferase pi (GSTP1) gen-otype should be considered when evaluating biomarkers of TDI exposure in urine and plasma. A protective eff

34、ect of GSTP1 105 Val was seen in TDI-related asthma.28 As this study has not been replicated, no conclusion can yet be drawn regarding these bio-markers.More recently, our unpublished data showed that the adren-ergic bet

35、a-2, ADRB2 46A>G, 252G>A, and 523C>A SNPs and haplotype 1 [TTACGC] were significantly associated with spe-cific IgE antibodies to the TDI-HSA conjugate in TDI-exposed subjects. Exposed workers with the AA genoty

36、pe of the 46 A>G polymorphism had significantly higher serum specific IgE lev-els than those with the GG genotype, suggesting that ADRB2 polymorphisms may affect IgE-specific sensitization to TDI-HSA conjugate in TDI

37、exposed workers. As TDI-OA is a complex process, ADRB2 polymorphisms with further environmental or Table 2. Genetic and protein biomarkers for isocyanate-induced asthmaGene Full name Genotype Association PopulationGeneti

38、c biomarkersHLA Human leukocyte antigen DRB1*1501-DQB1*0602-DPB1* Yes KoreanHLA Human leukocyte antigen DQB1*0503 Yes EuropeanHLA Human leukocyte antigen DQB1*05 Yes SwedishHLA Human leukocyte antigen DQB1*0501 No Europe

39、anCTNNA3 Catenin alpha 3, alpha-T catenin HT2 [GG] Yes KoreanNK2R Neurokinin2 receptor 7853G>A, 11424G>A Yes KoreanNAT1 N-acetyl transferase Slow acetylator Yes FinnishGSTP1 Glutathione S-transferase pi 105 Val (pr