Transglutaminase 2, a novel regulator of eicosanoid production in asthma revealed by genome-wide expression profiling of distinct asthma phenotypes.
Transglutaminase 2, a novel regulator of eicosanoid production in asthma revealed by genome-wide expression profiling of distinct asthma phenotypes.
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DOI：
10.1371/journal.pone.0008583
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发表时间：
2010-01-05
期刊：
影响因子：
3.7
通讯作者：
Henderson WR
中科院分区：
文献类型：
--
作者：
Hallstrand TS;Wurfel MM;Lai Y;Ni Z;Gelb MH;Altemeier WA;Beyer RP;Aitken ML;Henderson WR
哮喘的一种常见表现，运动诱发的支气管收缩（EIB），发生在30-50%的哮喘患者中，其特征在于炎性类二十烷酸释放增加。本研究的目的是鉴定EIB中差异表达的基因，并了解这些基因在哮喘生物学中的功能。在基线和运动激发后，对两组有和无EIB的哮喘受试者（每组n =7）进行诱导痰获得的气道白细胞和上皮细胞的全基因组表达谱分析。 基于基因表达研究的结果，与正常对照组（n = 10）进行了额外的比较。 对另外一组EIB哮喘患者（n = 3）的上皮刷检和活检进行定位研究。 哮喘患者运动后β-类胰蛋白酶和羧肽酶A3等上皮修复和肥大细胞浸润相关基因表达上调。哮喘发病机制的新基因，转氨酶2（TGM 2），在两组之间的基线表达差异最大。体内研究证实了TGM 2在气道细胞和气道衬里液中的表达增加，并证明TGM 2在哮喘气道上皮中强烈表达。使用重组人酶的体外研究表明，TGM 2增强分泌型磷脂酶A2（PLA 2）X组（sPLA 2-X）的酶活性，sPLA 2-X是一种最近与哮喘发病机制有关的酶。本研究发现，TGM 2是一种新的哮喘发病机制的介质，在哮喘气道中过表达，并具有增加sPLA 2-X酶活性的功能。由于PLA 2是类花生酸形成的第一个限速步骤，因此这些结果表明，TGM 2可能是哮喘气道炎症级联反应的关键启动子。
A frequent manifestation of asthma, exercise-induced bronchoconstriction (EIB), occurs in 30–50% of asthmatics and is characterized by increased release of inflammatory eicosanoids. The objective of this study was to identify genes differentially expressed in EIB and to understand the function of these genes in the biology of asthma. Genome-wide expression profiling of airway leukocytes and epithelial cells obtained by induced sputum was conducted in two groups of subjects with asthma with and without EIB (n = 7 per group), at baseline and following exercise challenge. Based on the results of the gene expression study, additional comparisons were made with a normal control group (n = 10). Localization studies were conducted on epithelial brushings and biopsies from an additional group of asthmatics with EIB (n = 3). Genes related to epithelial repair and mast cell infiltration including β-tryptase and carboxypeptidase A3 were upregulated by exercise challenge in the asthma group with EIB. A gene novel to asthma pathogenesis, transglutaminase 2 (TGM2), was the most differentially expressed at baseline between the groups. In vivo studies confirmed the increased expression of TGM2 in airway cells and airway lining fluid, and demonstrate that TGM2 is avidly expressed in the asthmatic airway epithelium. In vitro studies using recombinant human enzymes reveal that TGM2 augments the enzymatic activity of secreted phospholipase A2 (PLA2) group X (sPLA2-X), an enzyme recently implicated in asthma pathogenesis. This study found that TGM2, a mediator that is novel to asthma pathogenesis, is overexpressed in asthmatic airways and functions to increase sPLA2-X enzymatic activity. Since PLA2 serves as the first rate-limiting step leading to eicosanoid formation, these results suggest that TGM2 may be a key initiator of the airway inflammatory cascade in asthma.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
30.5
作者：
Karp, CL;Grupe, A;Wills-Karp, M
通讯作者：
Wills-Karp, M
影响因子：
4.4
作者：
Hess A;Iyer H
通讯作者：
Iyer H
DOI：
10.1073/pnas.0604844103
发表时间：
2006-12-05
影响因子：
11.1
作者：
Antonyak, Marc A.;Jansen, Jaclyn M.;Cerione, Richard A.
通讯作者：
Cerione, Richard A.
DOI：
10.1164/rccm.200412-1667oc
发表时间：
2005-09-15
影响因子：
24.7
作者：
Hallstrand, TS;Moody, MW;Aitken, ML
通讯作者：
Aitken, ML