呼吸系统的分子病理学.pptx

呼吸系统疾病的分子病理学 2015-9-28张雪,博士、副教授、博士生导师浙江大学医学部基础医学院病理与病理生理学系个人简介个人简介呼吸系统疾病的分子病理学机制研究；炎症与损伤在呼吸系统疾病中的作用及其分子机制；炎症因子及趋化因子的谷胱甘肽化修饰后的功能及其在肺部炎症中的作用研究领域研究领域浙江大学紫金港校区科研楼A310,0571-联系方式联系方式Outline呼吸系统的发育和生物学基础常见呼吸系统疾病及其分子病理学机制 感染性疾病 免疫炎症性疾病 遗传性疾病 呼吸系统肿瘤研究方法举例 1.1.呼吸系统呼吸系统的发育的发育A:7-8 week embryonic human lungs.The mainstem bronchi have already branched into lobar and segmental bronchi.There are three lobes in the right lung and two in the leftB:lung embryonic day 12 murine lungs.There are four lobes in the right lung and one in the left lung.人与小鼠的肺发育进程对比人与小鼠的肺发育进程对比胚胎期、假腺管期、小管期、囊泡期、肺泡期Pulmonary organogenesisBranching morphogenesisAlveolarization小鼠肺发育的主要过程小鼠肺发育的主要过程E17-18Nkx2.1In the mouse,large conducting airways(trachea and bronchi)are lined by a pseudostratified epithelium consisting primarily of goblet,basal,Clara(secretory),and ciliated cells.Peripheral conducting airways(bronchioles-acinar ducts,proximal to the alveoli)are lined by a simple columnar epithelium comprised primarily of ciliated and nonciliated cells(Clara cells).Pulmonary neuroendocrine cells(PNEC),some clustered in neuroendocrine bodies(NEBs),are a relatively rare cell type that express serotonin,bombesin,calcitonin gene-related peptide(CGRP),and other neuroendocrine peptides(toppanel).气道气道上皮细胞的分类及其相关的转录因子上皮细胞的分类及其相关的转录因子The distribution of transcription factorsvaries among distinct cell types alongthe cephalocaudal axis of the lung.GFI-1,HES,MASH,and RB influence differentiation/growth of neuroendocrine cellsAlveolar type II cells,but not type I cells,express TTF-1,FOXA1/2,C/EBP,NF-1,ERM,and GATA-6.TTF-1,SOX familymembers,p63,FOXJ1,SPDEF,and othertranscription factors vary in concentrationalong the airways where they influence epithelial cell differentiation and gene expression.转录因子在呼吸道上皮细胞中的分布情况转录因子在呼吸道上皮细胞中的分布情况The morphologically similar Nkx2.1 and Shh null mutant phenotypes in which the trachea fails to separate dorso-ventrally from the esophagus,forming a tracheo-esophageal tube from the sides of which grossly hypoplastic and dysplastic epithelial bags arise.The compound null Gli2-/-,Gli3-/-mutant phenotype in which the primitive lung anlage completely fails to arise from the primitive foregut endoderm.Gli2-/-null mutation and Gli2 gene dosage reduction result in abnormalities of lung lobation.The FGF-10-/-phenotype in which the larynx and trachea form and separate dorso-ventrally from the esophagus;but the primary bronchial branches completely fail to arise from the trachea.The phenotype in transgenic mice that misexpress a dominant negative,tyrosine kinase deleted FGFR under the control of the SP-C promoter/enhancer.Bronchial morphogenesis is abrogated distal to the primary bronchi.基因敲基因敲除小鼠的表型揭示某些基因在肺发育中的作用除小鼠的表型揭示某些基因在肺发育中的作用调控肺发育主要的信号通路调控肺发育主要的信号通路a,FGF10(green),possibly induced byhomeotic transcription factors,is secreted by visceral mesenchyme and induces FGFR2b(red)expression in the cells at the tip of the primordial buds or in the buds of subsequent generations.b,FGFR2b signaling induces Spry2,which forms a negative-feedback loop by inhibiting FGFR2b signaling.Wnt5a(blue)expressed in the surrounding mesenchyme inducesBMP4,which antagonizes FGF10 in an autocrine manner but has a paracrine agonistic effect on budding.Netrin1,4(pink)restricts FGFR2b signaling to the tip of the growing bud.参与肺泡远端发育的主要信号调控方式参与肺泡远端发育的主要信号调控方式2.2.肺部疾病的生物学及免疫学基础肺部疾病的生物学及免疫学基础气道上皮细胞杯状细胞Clara 细胞肺泡上皮细胞（I和II）肺成纤维细胞肺单核/巨噬细胞淋巴细胞树突状细胞 中性粒细胞血管内皮细胞血管平滑肌细胞3.3.急性肺损伤急性肺损伤Acute Lung Injury(ALI)Acute Respiratory Distress Syndrome(ARDS)病因：病因：直接损伤（肺炎、烟雾和有毒气体吸入、淹溺等）间接损伤（脓毒症、输血、休克等）急性肺损伤的病理学特征急性肺损伤的病理学特征Diffuse alveolar damageInflux of neutrophils and macrophages A protein rich exudate in the alveolar spaces Endothelial and epithelial injury急性肺损伤病理机制急性肺损伤病理机制研究急性肺损伤的动物模型及其分子机制研究急性肺损伤的动物模型及其分子机制细菌(LPS-inducedALI)病毒颗粒性吸入物O antigen(or O polysaccharide)Arepetitiveglycanpolymer；Variesfromstraintostrain(over160differentOantigenstructures);Atargetforrecognitionbyhostantibodies;TheabsenceorreductionofO-chainsLPSroughhydrophobicCoreoligosaccharideLipid AAveryconservedcomponent;AnchortheLPSintothebacterial;ToxicityLPS signaling pathwayGAB2 and LPS-induced lung injuriesWASPb b-actinGab2 N/+Gab2N/NGab2 KOLess leucocytes infiltrated in Gab2 N/N More cytokines releasedin Gab2 N/NImpaired leucocytes adhesion in Gab2 N/N 4.4.哮喘哮喘平滑肌收缩粘液分泌增加血管通透性增高炎症细胞浸润气道炎症气道高反应性哮喘发病的分子病理机制哮喘发病的分子病理机制哮喘发病期的组织形态哮喘发病期的组织形态气道杯状细胞化生气道杯状细胞化生AsthmaChronicobstructivepulmonarydisease(COPD)ChronicbronchitisCysticfibrosis(CF)Lungcancerrelateddiseasesinflammatorydisordersderegulatedmucinproduction&哮喘中后期的气道重塑哮喘中后期的气道重塑气气道重塑的组织形态道重塑的组织形态研究哮喘的动物模型研究哮喘的动物模型014212827OVA i.h.OVA i.p.OVASacAtomization OVA、HDM、花粉、粉尘等A novel role for Gab2:induction of mucin expression and goblet cell hyperplasia杯状细胞化生的分子调控机制杯状细胞化生的分子调控机制 Loss of Gab2 enhances SOCS3 binding with TYK2,resulting in attenuated IL-13-mediated STAT6 activation 正常肺泡纤维化肺泡n原因不明的慢性炎症性间质性肺部、弥漫性肺泡结构损伤及纤维化重构n进行性肺功能下降、不可逆呼吸衰竭n病因不明，缺乏有效治疗手段n高死亡率，中位生存期甚至低于大多数恶性肿瘤特发性肺纤维化特发性肺纤维化 。