Haitchi Hans Michael, Bassett David J P, Bucchieri Fabio, Gao Xiufeng, Powell Robert M, Hanley Neil A, Wilson David I, Holgate Stephen T, Davies Donna E
Division of Infection Inflammation and Immunity, Roger Brooke Laboratory, School of Medicine, University of Southampton, Southampton, UK.
J Allergy Clin Immunol. 2009 Sep;124(3):590-7, 597.e1-11. doi: 10.1016/j.jaci.2009.06.026. Epub 2009 Aug 8.
Asthma pathogenesis involves gene and environmental interactions. A disintegrin and metalloprotease 33 (ADAM33)/Adam33 is a susceptibility gene for asthma and bronchial hyperresponsiveness in human beings and mice. ADAM33 is almost exclusively expressed in mesenchymal cells, including mesenchymal progenitors in developing lungs.
Because maternal allergy is a risk factor for asthma, we hypothesized that an allergic environment affects ADAM33/Adam33 expression during human and mouse lung development.
Human embryonic/fetal lung (HEL) tissues were collected from first-trimester terminations of pregnancy. These were processed immediately or used for explant culture +/- IL-13. MF1 mice or ovalbumin-sensitized A/J mice (Bronchial hyperresponsivness (Bhr)1/Adam33 locus-positive) were time-mated and challenged with ovalbumin (A/J mice only) during pregnancy. Lungs were harvested at different times during gestation and post partum. ADAM33/Adam33 expression was analyzed by using reverse transcriptase quantitative polymerase chain reaction and Western blotting.
ADAM33 mRNA was detectable in HELs in the pseudoglandular stage of development and showed a significant increase from 7 to 9 weeks postconception. IL-13 significantly suppressed ADAM33 mRNA in HEL explants. In developing murine lungs, Adam33 mRNA and protein expression increased significantly in the early pseudoglandular stage and showed another large increase post partum. In A/J mice, maternal allergy significantly suppressed Adam33 mRNA in lungs of newborn pups, whereas processed Adam33 protein increased and several smaller isoforms were detected.
Adam33/Adam33 shows 2 significant increments in expression during lung morphogenesis, suggesting important developmental regulation. The ability of maternal allergy or exogenous IL-13 to suppress Adam33/ADAM33 mRNA but enhance Adam33 processing suggests a gene-environment interaction that may be relevant for asthma pathogenesis.
哮喘的发病机制涉及基因与环境的相互作用。解整合素金属蛋白酶33（ADAM33）/Adam33是人类和小鼠哮喘及支气管高反应性的一个易感基因。ADAM33几乎仅在间充质细胞中表达，包括发育中肺脏的间充质祖细胞。
由于母亲过敏是哮喘的一个危险因素，我们推测过敏环境会影响人和小鼠肺发育过程中ADAM33/Adam33的表达。
收集孕早期终止妊娠的人胚胎/胎儿肺（HEL）组织。这些组织立即进行处理或用于外植体培养（±白细胞介素-13）。MF1小鼠或卵清蛋白致敏的A/J小鼠（支气管高反应性（Bhr）1/Adam33基因座阳性）进行定时交配，并在孕期用卵清蛋白攻击（仅用于A/J小鼠）。在妊娠期间和产后的不同时间点采集肺组织。通过逆转录定量聚合酶链反应和蛋白质免疫印迹法分析ADAM33/Adam33的表达。
在发育的假腺期HEL中可检测到ADAM33 mRNA，且在受孕后7至9周显著增加。白细胞介素-13显著抑制HEL外植体中的ADAM33 mRNA。在发育中的小鼠肺脏中，Adam33 mRNA和蛋白表达在假腺早期显著增加，并在产后出现另一次大幅增加。在A/J小鼠中，母亲过敏显著抑制新生幼崽肺中的Adam33 mRNA，而加工后的Adam33蛋白增加，并检测到几种较小的异构体。
Adam33/Adam33在肺形态发生过程中表达有2次显著增加，提示其在发育过程中有重要调控作用。母亲过敏或外源性白细胞介素-13抑制Adam33/ADAM33 mRNA但增强Adam33加工的能力提示了一种可能与哮喘发病机制相关的基因-环境相互作用。
