Division of Pulmonary and Critical Care, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
PLoS One. 2010 Jan 5;5(1):e8583. doi: 10.1371/journal.pone.0008583.
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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 beta-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 A(2) (PLA(2)) group X (sPLA(2)-X), an enzyme recently implicated in asthma pathogenesis.
CONCLUSIONS/SIGNIFICANCE: This study found that TGM2, a mediator that is novel to asthma pathogenesis, is overexpressed in asthmatic airways and functions to increase sPLA(2)-X enzymatic activity. Since PLA(2) 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.
哮喘的常见表现之一是运动诱发的支气管收缩（EIB），约 30-50%的哮喘患者会出现这种情况，其特征是炎症性类二十烷酸的释放增加。本研究的目的是确定 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。
方法/主要发现：通过诱导痰获取气道白细胞和上皮细胞进行全基因组表达谱分析，在两组哮喘患者中进行，一组有 EIB（每组 7 例），另一组无 EIB（每组 7 例），分别在基线和运动挑战后进行。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。对来自有 EIB 的哮喘患者的额外组（n = 3）的上皮刷检和活检进行了定位研究。在有 EIB 的哮喘组中，与上皮修复和肥大细胞浸润相关的基因，包括β-胰蛋白酶和羧肽酶 A3，在运动挑战后被上调。一种与哮喘发病机制相关的新基因，转谷氨酰胺酶 2（TGM2），在两组之间的基线水平上是最具差异表达的。体内研究证实了 TGM2 在气道细胞和气道衬里液中的表达增加，并表明 TGM2 在哮喘气道上皮中大量表达。使用重组人酶的体外研究表明，TGM2 增强了分泌型磷脂酶 A2（PLA2）组 X（sPLA2-X）的酶活性，这种酶最近与哮喘发病机制有关。
结论/意义：本研究发现，TGM2 是哮喘发病机制中的一种新的介质，在哮喘气道中过度表达，并发挥增加 sPLA2-X 酶活性的作用。由于 PLA2 是导致类二十烷酸形成的第一个限速步骤，这些结果表明 TGM2 可能是哮喘气道炎症级联反应的关键启动子。
