Asthma Sample Collection Protocol: Defining the Role of Apolipoprotein Pathways in Asthma
哮喘样本采集方案:定义载脂蛋白通路在哮喘中的作用
基本信息
- 批准号:10929167
- 负责人:
- 金额:$ 187.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:ADP Ribose TransferasesAirway DiseaseAlveolar MacrophagesApicalApolipoproteinsAsthmaAttenuatedBlood specimenBronchoalveolar LavageBronchoalveolar Lavage FluidBronchoscopyBrush CellCD14 geneCell membraneCellsChemotaxisCiliated Bronchial Epithelial CellClinical ImmunologyCollectionCytokine ReceptorsDendritic CellsEpithelial CellsEpitheliumExtrinsic asthmaFastingGenesHLA-DR AntigensHigh Density LipoproteinsHumanHypersensitivityITGAX geneImmuneInflammasomeInflammationInflammatoryInflammatory ResponseInterleukin-1LengthLigandsLinkLipidsLiquid substanceLungMAP3K7 geneMAP3K8 geneMAPK8 geneMacrophageMediatingMembraneMicrofluidicsMinorModificationMyelogenousNeutrophil ActivationNutrientPathway interactionsPeripheral Blood Mononuclear CellPhenotypePopulationProductionProtocols documentationPyroglyphidaeRANTESRegulationResearchRoleSamplingSerumSeverity of illnessSignal PathwaySignal TransductionSputumSteroidsTLR4 geneTh2 CellsTimeTissue ProcurementsTranscriptTriglyceridesTumor Necrosis Factor ReceptorVLDL receptorViraladaptive immune responseairway epitheliumairway inflammationasthmaticasthmatic patientbronchial epitheliumchemokinecytokineeosinophileosinophilic asthmaexosomehuman RNA sequencinghuman neutrophil peptide 1mRNA Expressionmouse modelnanoscaleneutrophilparticlepatient subsetsperipheral bloodpoint of carereceptorsample collectionsoluble TNF receptor type Ivesicular releasevolunteer
项目摘要
The progress achieved under this protocol is summarized as follows:
1. The structural cell populations obtained by this protocol have been utilized to characterize the expression of ARTS-1 in lung cell populations. Bronchial epithelial cells that have been obtained by bronchial brushings have been utilized to demonstrate co- localization of membrane-associated ARTS-1 and TNFR1 in the apical cell membrane of ciliated bronchial epithelial cells.
2. Bronchoalveolar lavage fluid obtained by this protocol has been utilized to identify exosome-like vesicle release as a new mechanism by which soluble cytokine receptors can be generated, independent of ectodomain cleavage by receptor sheddases. The majority of soluble type I TNF receptor (TNFR1) in bronchoalveolar lavage fluid was found to be full-length, 55-kDa, exosome-associated TNFR1, whereas the 28-kDa cleaved TNFR1 ectodomain represented only a minor fraction. Thus, release of exosome-associated TNFR1 (i.e., eTNFR1) represents an important alternative mechanism for the release of soluble TNF receptors.
3. BAL fluid from asthmatic patients has been utilized in studies investigating the ADP-ribosyltransferase-specific modification of human neutrophil peptide-1.
4. Expression of the VLDL receptor was demonstrated for the first time on circulating CD11c+/CD14-/HLA-DR+ dendritic cells. This confirmed our result in a murine model that the VLDL receptor is expressed by dendritic cells and attenuates house dust mite-induced airway inflammation by suppressing dendritic cell-mediated adaptive immune responses.
5. BAL fluid cells have been used to show that expression of CD163 is reduced on alveolar macrophages from asthmatics as compared to normal subjects.
6. Induced sputum cells have been used to develop components of a nanoscale microfluidic flow cytometer that will liquefy sputum samples for point-of-care inflammatory phenotyping of asthmatic patients.
7. Myeloid dendritic cell subsets from patients with eosinophil-high asthma were shown to have lower levels of LRP-1 expression than those from healthy nonasthmatic subjects and that a negative correlation exists between LRP-1 expression by myeloid dendritic cell subsets and peripheral blood eosinophil counts in asthmatic patients.
8. HDL particles were shown to be negatively correlated, whereas serum triglycerides were shown to be positively correlated, with blood eosinophils in atopic asthmatics. This supports the concept that serum levels of HDL and triglycerides may be linked to systemic type 2 inflammation in atopic asthma. (J Lipid Research 2017 Aug; 58(8): 1713-1721. PMID: 28655726.)
9. Human peripheral blood myeloid DC subsets from patients with eosinophilic asthma have lower LRP-1 expression than cells from healthy nonasthmatic subjects. (JACI 2018 Oct; 142(4):1066-1079.e6. DOI: 10.1016/j.jaci.2017.10.044. PMID: 29274414.)
10. Peripheral blood mononuclear cells from asthmatics were used to show that prolonged fasting blunts the NLRP3 inflammasome and Th2 cell activation in steroid-naive asthmatics as well as diminishes airway epithelial cell cytokine production. This identifies a potential role for nutrient level-dependent regulation of inflammation in asthma. (J Immunol 2018 Sep 1; 201(5):1382-1388. PMID 30021766).
11. Bronchoalveolar lavage macrophages from asthmatics were used to show that APOE can function as an endogenous, concentration-dependent pulmonary danger signal that primes and activates the NLPR3 inflammasome to secrete IL-1. This might represent a mechanism through which APOE amplifies pulmonary inflammatory responses when concentrations in the lung are increased to greater than normal levels, which can occur during viral exacerbations of HDM-induced asthma characterized by neutrophilic airway inflammation. (J Allergy Clinical Immunology 2019; 144(2):426-441.e3. DOI: https://doi.org/10.1016/jaci.2019.02.027).
12. RNA sequencing of human asthmatic bronchial brushing cells stimulated with APOE identified increased expression of mRNA transcripts encoding multiple proinflammatory genes, including CXCL5 (C-X-C motif chemokine ligand 5), an epithelial-derived chemokine that promotes neutrophil activation and chemotaxis. We subsequently characterized the APOE signaling pathway that induces CXCL5 secretion by human asthmatic small airway epithelial cells (SAECs). We showed that elevated levels of APOE in the airway may activate a TLR4/TAK1/IK/NF-B/TPL2/JNK signaling pathway that induces CXCL5 secretion by human asthmatic SAECs. These findings identify new roles for TLR4 and TPL2 in APOE-mediated proinflammatory responses in asthma. (Am J Resp Cell Mol Biol 2020; 63 (2): 185 - 197.)
根据本议定书取得的进展总结如下:
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Apolipoprotein E is a concentration-dependent pulmonary danger signal that activates the NLRP3 inflammasome and IL-1β secretion by bronchoalveolar fluid macrophages from asthmatic subjects.
- DOI:10.1016/j.jaci.2019.02.027
- 发表时间:2019-08
- 期刊:
- 影响因子:14.2
- 作者:Gordon, Elizabeth M.;Yao, Xianglan;Xu, Haitao;Karkowsky, William;Kaler, Maryann;Kalchiem-Dekel, Or;Barochia, Amisha V.;Gao, Meixia;Keeran, Karen J.;Jeffries, Kenneth R.;Levine, Stewart J.
- 通讯作者:Levine, Stewart J.
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Stewart Levine其他文献
Stewart Levine的其他文献
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{{ truncateString('Stewart Levine', 18)}}的其他基金
Characterization of the Role of NUCB2 in Asthma Pathogenesis
NUCB2 在哮喘发病机制中作用的表征
- 批准号:
8558006 - 财政年份:
- 资助金额:
$ 187.8万 - 项目类别:
Identification and Characterization of microRNA Genes in Asthma
哮喘中 microRNA 基因的鉴定和表征
- 批准号:
8939833 - 财政年份:
- 资助金额:
$ 187.8万 - 项目类别:
Study of Pioglitazone Hydrochloride in Severe, Refractory Asthma
盐酸吡格列酮治疗严重难治性哮喘的研究
- 批准号:
8344773 - 财政年份:
- 资助金额:
$ 187.8万 - 项目类别:
ID of Biomarkers in Exhaled Breath Condensates from Asthmatic Patients
哮喘患者呼出气体冷凝物中生物标志物的识别
- 批准号:
7734981 - 财政年份:
- 资助金额:
$ 187.8万 - 项目类别:
Development of Apolipoprotein-based Therapeutics for Asthma
基于载脂蛋白的哮喘疗法的开发
- 批准号:
8149566 - 财政年份:
- 资助金额:
$ 187.8万 - 项目类别:
ID of Biomarkers in Exhaled Breath Condensates from Asthmatic Patients
哮喘患者呼出气体冷凝物中生物标志物的识别
- 批准号:
7969044 - 财政年份:
- 资助金额:
$ 187.8万 - 项目类别:
Characterization of the Role of NUCB2 in Asthma Pathogenesis
NUCB2 在哮喘发病机制中作用的表征
- 批准号:
8344859 - 财政年份:
- 资助金额:
$ 187.8万 - 项目类别:
Identifying and Characterizing "Corticosteroid-unresponsive" Genes in Asthma
哮喘中“皮质类固醇无反应”基因的识别和特征分析
- 批准号:
8557924 - 财政年份:
- 资助金额:
$ 187.8万 - 项目类别:
Characterization of the Role of NUCB2 in Asthma Pathogenesis
NUCB2 在哮喘发病机制中作用的表征
- 批准号:
8746634 - 财政年份:
- 资助金额:
$ 187.8万 - 项目类别:
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