蛋白靶标在儿童哮喘分型、病情及预后评估中的作用

Asthma is a common disease in children, which affects millions of children's health. Clinicaly asthma was evaluated by clinical menifestations and lung function, but lung function isn't a sensitive index to reflect the actual airway inflammation, especially in children, when the lung function decreases,the airway inflammation is already irreversible. Current studies showed that differentiating inflammation phenotypes is important to management of asthma , that helps to predict the disease prognosis. So far the prognosis of childhood asthma is still largely unknown due to lack of objective and acurate criteria clinically. Our team has already made some progress in biomarker disvorvery and clinical validation of the identified biomarkers associated with childhood asthma. By using proteomics method ,we identified a series of 4 novel plasma biomarkers which are crucial mediators in asthma inflammation pathways. Clinical validation of these biomarkers in a childhood asthma population showed that these markers are closely related to childhood asthma disease severity by using ELISA test.Our study indicated that these biomarkers may be associated with different inflammatory phenotypes,that helps us to understand the different prognosis of childhood asthma. We are planing to further conduct our study in children of different age groups in both case control and cohort studies to investigate the correlation of the biomarkers with different inflammatory phenotypes of childhood asthma, to explore the association between the dynamic changes of the 4 biomarkers with the prognosis and management of childhood ashma. If it goes well, we will find a novel clinical tool in monitoring the progress of childhood asthma and evaluating the prognosis of childhood asthma. This study will facilitate our understanding of pathogenesis and biological mechanisms of asthma,and highlight novel therapeutic stratergies.

儿童哮喘自然病程特点目前尚不清楚，预后难测。临床上以症状、肺功能来评估病情，但肺功能不够敏感，其降低时气道炎症已不可逆。另外，儿童哮喘有不同的炎症亚型，不同亚型可能具有不同的发病机制及预后。因此早期明确病情严重程度及分型对指导儿童哮喘治疗和预测预后有重要意义，但目前临床上缺乏能够准确评估哮喘病情及预后的客观指标。我们在前期国家自然科学基金（81072368）项目中，已发现4种与儿童哮喘病情直接相关的蛋白靶标：抗凝血酶III,补体C3,α2巨球蛋白和CD5L。它们均是哮喘炎症反应通路中的关键介质，与哮喘不同炎症亚型的炎症反应网络相关，对鉴别气道炎症亚型及预测预后有一定指导意义。本项目组拟在前期工作基础上，进一步通过对不同年龄段哮喘儿童的病例对照和队列研究，对上述靶标和炎症亚型进行深入分析，以期为临床找到一种较为精准和敏感的指标，动态监测哮喘进展、评估预后，并试图探索哮喘儿童具有不同转归的机制

根据纳入和排除标准，选择哮喘患者学龄前期35例、学龄期45例、青春期58例、成人期75例，正常对照组学龄前期30例、学龄期40例、青春期50例、成人期70例。用ELISA试剂盒检测各组人员血清蛋白靶标抗凝血酶III(ATIII)、补体C3(C3)、α2巨球蛋白(A2M)、CD5L的水平，检测肺功能，诱导痰并进行痰炎症分型，半年后随访，再次行上述检查。应用SPSS17.0统计学软件分析四种蛋白靶标在不同年龄组中哮喘组、正常组中的差异，分析四种蛋白靶标在哮喘患者不同年龄组间的差异，分析哮喘患者四种蛋白靶标与痰炎症分型之间的关联及与肺功能之间的关联。结果：1.血清抗凝血酶III在儿童时期时，哮喘病人表达水平高于正常人，而到成人哮喘患者，其表达水平与正常人无差异；血清抗凝血酶III的表达在青春期和成人期哮喘患者之间有差异，成人期哮喘患者表达血清抗凝血酶III水平下降；2. CD5L在学龄前期和成人期时，哮喘病人表达减低，且成人期哮喘CD5L的表达比学龄期、青春期哮喘儿童明显减低，差异有统计学意义；CD5L与嗜酸性粒细胞型痰炎症分型呈正相关；3. 补体C3、α2巨球蛋白在各个年龄组哮喘患者、正常人中表达均无差异，在哮喘患者各年龄组中表达也无差异，未提示其在哮喘判定中具有意义。但补体C3与抗凝血酶III、肺功能FEV1之间均存在负相关关系，α2巨球蛋白与中性粒细胞型痰炎症分型呈正相关。结论：1. 血清抗凝血酶III可能参与了儿童哮喘发病；2. CD5L可能与成人哮喘的发病相关，与α2巨球蛋白均有潜力作为鉴别痰炎症分型的蛋白靶标；3. 补体C3水平可间接反映哮喘患者肺功能情况，具有成为评估哮喘病情的靶标的潜力。由于实验周期短，入组病例少，以上得到的结论还需要扩大样本进行进一步的验证。后续试验中，我们将继续增加入组病例，继续进行血清中四种蛋白靶标水平的检测及痰炎症分型、肺功能检测，并进行相关性分析；另一方面，针对本研究中的小年龄组哮喘儿童，应进行更长时间的队列研究，继续进行跟踪随访至成人期，来检验相关指标的动态变化，进一步检验其与儿童哮喘预后及发病机制的相关性。

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