第一部分 异位淋巴样结构与非特异性间质性肺炎临床及预后相关性研究目的：异位淋巴样结构（ELS）与肺部疾病临床和预后的关系尚不明确，本部分旨在探讨ELS与非特异性间质性肺炎（NSIP）患者临床特征、疗效及预后的关系。方法：选取2003-4至2012-12北京协和医院经临床-影像-病理诊断为NSIP的患者，采集相关临床资料和随访资料，并对肺组织内ELS等相关结构进行数量和面积定量评估。根据治疗1年后用力肺活量（FVC）变化率分为改善、稳定和恶化组，根据5年生存情况分为生存组和死亡组，比较不同疗效组和不同预后组间病理指标差异。结果：共纳入60例NSIP患者中，男性19例（31.67%），平均年龄49±11岁，其中35例（58.33%）肺组织内出现ELS。传统治疗1年，FVC改善、稳定和恶化组人数分别为15例（28.30%）、34例（64.15%）和4例（7.55%），5年内死亡14例（23.33%）。自身免疫疾病相关NSIP与特发性NSIP患者在ELS特征上无统计学差异。ELS阳性组FVC和DLCO改善率显著低于ELS阴性组，ELS等相关结构的数量和平均面积在FVC恶化组中显著升高并与FVC改善率呈负相关。生存组与死亡组在ELS数量和面积上无显著差异。结论：ELS是NSIP患者肺部损伤的重要病理表现，并且可能与传统治疗效果不佳有关，其病理生理作用值得进一步研究。 第二部分 异位淋巴样结构在野百合碱大鼠肺损伤模型中的形成规律及生物标志物。 研究目的：野百合碱（MCT）可诱导肺组织慢性炎症。本部分旨在观察MCT肺损伤模型中异位淋巴样结构，并寻找相关血清和支气管肺泡灌洗液（BALF）标志物。方法：建立野百合碱SD大鼠腹腔注射肺损伤模型，并设置对照组，于建模后3-17周定期取材大鼠血清、BALF和肺组织，液相悬浮芯片技术检测血清和BALF炎症因子，肺组织H&E染色并定量评估淋巴滤泡数量和面积，分析淋巴滤泡与血清和BALF炎症因子对应关系。结果：模型大鼠淋巴滤泡自第3周于支气管基底部及肺血管周围形成，随时间延长数量增多、面积增大。与对照组相比，实验组血清和BALF多种炎症因子显著升高，血清IL-1b、IL-6和TNF-a三个因子含量于第7周达峰，早于BALF中的第9周达峰；血清IL-4和IFN-g两个因子含量于第13周达峰，晚于BALF中的第11周达峰。第5-9周淋巴滤泡形成与IL-6、TNF-a、IL-1b和IL-17含量升高相对应，第11-15周淋巴滤泡维持与进展阶段与IL-4和IFN-g含量升高相对应。结论：ELS的形成与MCT诱导的肺组织慢性炎症相关。外周血炎症因子与BALF中炎症因子在肺损伤过程中反应时相不同步，可能参与ELS的形成过程。

PART I: Clinical and Prognostic Relevance of Ectopic Lymphoid Structure in Nonspecific Interstitial Pneumonia： Objective: Clinical and prognostic relevance of ectopic lymphoid structure (ELS) in pulmonary disease remains unclear. This part explored the relationship between ELS structure and clinical manifestations, treatment response and prognosis of patients with nonspecific interstitial pneumonia (NSIP).Method: Baseline and follow-up data of patients who were diagnosed as NSIP by clinicradiologic-pathologic diagnosis in Peking Union Medical College Hospital from April 2003 to December 2012 were retrospectively collected. The number and average size of ELS and related structures were quantitatively assessed. According to change rate of forced vital capacity (FVC) after 1 year of treatment, patients were divided into improved, stable and worsened group. Survival group and death group were divided based on their 5-year status. Differences in pathological indexes among groups were compared. Results: A total of 60 patients with NSIP were enrolled in this study. Their mean age was 49±11 years and 19 (31.67%) of which were men. The proportions of ELS positivity was 58.33%. After 1 year of standard therapy, 15 (58.33%) patients improved and 4 (7.55%) patients worsened in FVC, and the other 34 (64.15%) patients remained stable. 14 (23.33%) patients died within 5 years. There was no significant difference in ELS features between autoimmune disease-related NSIP and idiopathic NSIP. The improvement rate of FVC and DLCO in ELS-positive group was significantly lower than that in ELS-negative group. Numbers and average size of ELS related structures were significantly increased in FVC worsened group and were negatively correlated with the change rate of FVC. No significant difference was seen in ELS number and size between survival group and death group. Conclusion: ELS is an important pathological manifestations of lung injury in NSIP patients and may predict less improvement in lung function after steroid treatment with or without immunosuppressant. Its pathophysiological mechanisms warrant further studies. PART II：Formation Regularities and Biomarkers of Ectopic Lymphoid Structure in Monocrotaline-induced Lung Injury Model： Objective: Monocrotaline (MCT) can induce chronic inflammation in lung tissue. This part aimed to observe ectopic lymphoid structures (ELS) in the MCT lung injury model and to search for relevant serum and bronchoalveolar lavage fluid (BALF) markers.Method: Lung injury model was established in SD rats by intraperitoneal injection of MCT. Serum, BALF and lung tissues were collected regularly from 3 to 17 weeks after modeling. LUMINEX xMAP was used to detect inflammatory factors in serum and BALF. Number and average size of ELS were quantitatively evaluated in H&E-stained lung tissues. The relationship between ELS and inflammatory factors was analyzed. Results: In MCT group, ELS formed on the basal side of bronchial epithelium and in the perivascular space as early as 3 weeks after modeling and increased with time. Compared with the control group, certain inflammatory factors significantly increased in serum and BALF. Serum levels of IL-1b, IL-6 and TNF-a reached their peaks 7 weeks after modeling, which was earlier than in BALF. Serum levels of IL-4 and IFN-g reached their peaks 13 weeks after modeling, which was later than in BALF. Formation of ELS during week 5-9 accorded with elevating levels of IL-1b, IL-6, TNF-a, and IL-17, and their maintenance and progression during week 11-15 corresponded with the increase in IL-4 and IFN-g.Conclusion: The formation of ELS is associated with MCT-induced chronic inflammation in lung tissue. Reaction phase of inflammatory factors in peripheral blood was out of sync with that in BALF, which may be involved in the formation of ELS.