Expression and regulation of a disintegrin and metalloproteinase (ADAM) 8 in experimental asthma
Expression and regulation of a disintegrin and metalloproteinase (ADAM) 8 in experimental asthma
复制标题
DOI：
10.1165/rcmb.2004-0026oc
复制
发表时间：
2004-09-01
影响因子：
6.4
通讯作者：
Rothenberg, ME
中科院分区：
文献类型：
--
作者：
King, NE;Zimmermann, N;Rothenberg, ME
尽管正在进行大量研究，但哮喘是一种复杂的慢性炎症性肺部疾病，其发病率仍在上升。为了阐明哮喘发病机制中涉及的新途径，我们在小鼠哮喘模型中使用了转录表达谱。采用不同过敏原（卵清蛋白和烟曲霉）诱导的哮喘模型，我们发现了 ADAM8（解整合素和金属蛋白酶 (ADAM) 家族的成员）的参与。小鼠肺部的原位杂交显示，在过敏原攻击后，支气管周围和血管周围炎症细胞以及细支气管上皮细胞中 ADAM8 被强烈诱导。对肺 ADAM8 cDNA 的序列分析鉴定出 ADAM8 的一种新剪接变体，其中包含与跨膜结构域并置的额外外显子。过敏原诱导的 ADAM8 mRNA 在肺部的积累具有剂量和时间依赖性。将白细胞介素 (IL)-4 或 IL-13 转基因或药物递送至肺部会导致 ADAM8 表达显着增加。基因靶向小鼠研究表明，卵清蛋白诱导的 ADAM8 在很大程度上依赖于信号转导子和转录激活子 (STAT) 6 以及 IL-4 受体 a 链。因此，ADAM8 是实验性哮喘肺中过敏原、IL-4 和 IL-13 诱导的基因。结合 ADAM33 在哮喘中的作用，这些结果表明过敏性肺部反应涉及 ADAM 家族不同成员的相互作用。
Asthma, a complex chronic inflammatory pulmonary disorder, is on the rise despite intense ongoing research. To elucidate novel pathways involved in asthma pathogenesis, we used transcript expression profiling in a murine model of asthma. Employing asthma models induced by different allergens (ovalbumin and Aspergillus fumigatus) we uncovered the involvement of ADAM8, a member of a disintegrin and metalloproteinase (ADAM) family. In situ hybridization of mouse lungs revealed strong ADAM8 induction in peribronchial and perivascular inflammatory cells as well as in bronchiolar epithelial cells following allergen challenge. Sequence analysis of lung ADAM8 cDNA identified a novel splice variant of ADAM8 that contained an additional exon in juxtaposition to the transmembrane domain. Allergen-induced ADAM8 mRNA accumulation in the lung was dose- and time-dependent. Transgenic or pharmacologic delivery of interleukin (IL)-4 or IL-13 to the lungs resulted in a marked increase of ADAM8 expression. Gene-targeted mice studies revealed that ovalbumin-induced ADAM8 was largely dependent upon signal transducer and activator of transcription (STAT) 6 and the IL-4 receptor a-chain. Thus, ADAM8 is an allergen-, IL-4-, and IL-13-induced gene in the experimental asthmatic lung. Taken together with the role of ADAM33 in asthma, these results suggest that allergic lung responses involve the interplay of diverse members of the ADAM family.