The Function and Potential Application of Extracellular Vesicle Derived Clara Cell Protein 16 in Gram-negative Bacterial Pneumonia
细胞外囊泡衍生的 Clara 细胞蛋白 16 在革兰氏阴性细菌性肺炎中的功能和潜在应用
基本信息
- 批准号:10905165
- 负责人:
- 金额:$ 50.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Lung InjuryAllergensAlveolarAlveolar wallAnti-Inflammatory AgentsAntibioticsAntiinflammatory EffectAsthmaBacterial InfectionsBacterial PneumoniaBiogenesisBiologicalBlood capillariesBronchoalveolar Lavage FluidCellsChronic Obstructive Pulmonary DiseaseClara cellClinicalCommunicable DiseasesDNA DamageDNA RepairDNA Repair PathwayDataDiseaseDoseEdemaEngineeringEpithelial CellsExposure toFreezingGoalsGram-Negative BacteriaHospitalsHumanHypoxemiaInfectionInflammationInflammatoryInflammatory ResponseInhalationInjuryKlebsiella pneumoniaeKnockout MiceKnowledgeLength of StayLipopolysaccharidesLungLung ComplianceLung diseasesLung infectionsMeasuresMediatingMicro Array DataMusN-terminalNatural ImmunityNebulizerNosocomial pneumoniaOxidative StressOzonePathogenesisPatientsPeptide Signal SequencesPermeabilityPharmaceutical PreparationsPlayPneumoniaPredispositionPropertyProtein SecretionProteinsRNARecombinantsRegulationReportingResearchResearch Project GrantsResistanceRoleRunawaySarcoidosisSignal PathwaySignal TransductionStimulusStructure of parenchyma of lungSystemTestingTherapeuticTherapeutic AgentsTherapeutic EffectToxic effectUltrasonicsUnited StatesVirusWild Type Mouseaerosolizedbactericidecell regenerationcell typecigarette smokecomparativecostepithelial injuryexosomeextracellular vesiclesidiopathic pulmonary fibrosisimmunogenicityinsightlung injurynovelnovel therapeutic interventionnovel therapeuticsoverexpressionpotential biomarkerprotective effectresponsesingle-cell RNA sequencingstable cell linetreatment strategyventilator-associated pneumonia
项目摘要
PROJECT SUMMARY/ABSTRACT
Gram-negative (G-) bacteria are the leading cause of hospital-acquired pneumonia (HAP) in the United States.
Nearly 300,000 episodes of HAP occur in U.S. hospitals each year. HAP on average increases the length of
hospital stay from 7 to 9 days, at an additional cost of more than $40,000 per patient; it is responsible for one-
fourth of all ICU infections and half of all antibiotic use. The devastating damage caused by G- bacteria results
from the imbalance of bactericidal effects and overwhelming inflammation. Despite decades of research, the
underlying mechanisms by which the runaway inflammation is developed remain incompletely understood.
Thus, there is an urgent need to develop novel therapeutic strategies against this devastating disease.
Clara Cell Protein 16 (CC16) is the major protein secreted by Clara cells and the most abundant protein in
bronchoalveolar lavage fluid (BALF). Dysregulation of CC16 has been reported to be associated with various
lung disorders and several studies have demonstrated that CC16 could serve as a potential biomarker of lung
epithelial injury in numerous disease states including idiopathic pulmonary fibrosis, sarcoidosis, COPD,
asthma, acute lung injury, etc. Functionally, CC16 has anti-inflammatory activities in lung tissues exposed to
ozone, allergens, viruses and cigarette smoke. This protective role is confirmed by studies using genetically
modified mice, showing that Cc16 deficiency is associated with increased susceptibility of the lung to infectious
stimuli and oxidative stress. However, the role of CC16 in acute lung injury is still not clear.
Our preliminary study showed that CC16 can be secreted in an extracellular vesicle (EV)-dependent manner.
To explore the function of EV-derived CC16 (EV-CC16), we generated a stable cell line overexpressing CC16
and collected secreted EV-CC16 from cells. We observed that EV-CC16 suppresses NF-κB signaling
activation and has a strong anti-inflammatory effect against lipopolysaccharide (LPS) and Klebsiella
pneumoniae (K. pneu) induced inflammation. Notably, considering the dose of CC16 and its protective effect
against LPS-induced lung injury, EV-CC16 is over 50,000 times more efficient than recombinant CC16
(rCC16). Besides, our data also indicated EV-CC16 is much more resistant to freeze-thaw than rCC16, making
EV-CC16 a potential novel therapeutic agent for the treatment of lung injury. Using microarray, we found EV-
CC16 strikingly activated multiple DNA repair signaling pathways. Consistently, we observed more severe DNA
damage in lungs from Cc16 knockout mice than wild-type mice. Thus, we aim to further investigate the
mechanism by which CC16 protects lung tissues from injury. Our ultimate goal is to test whether the delivery of
aerosolized EV-CC16 via nebulization can provide protective effects against G- bacterial-induced pneumonia.
Successful completion of the aims proposed in this application may not only provide new insights into the field
of innate immunity, by filling gaps in our knowledge about the role of CC16 in G- bacterial pneumonia but also
might provide a novel therapeutic strategy for the treatment of pulmonary infection.
项目总结/文摘
项目成果
期刊论文数量(0)
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Duo Zhang其他文献
Duo Zhang的其他文献
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{{ truncateString('Duo Zhang', 18)}}的其他基金
Lincenc1 regulates the lipopolysaccharide-induced inflammatory response in macrophages
Linncec1 调节脂多糖诱导的巨噬细胞炎症反应
- 批准号:
10186789 - 财政年份:2020
- 资助金额:
$ 50.15万 - 项目类别:
Lincenc1 regulates the lipopolysaccharide-induced inflammatory response in macrophages
Linncec1 调节脂多糖诱导的巨噬细胞炎症反应
- 批准号:
10432039 - 财政年份:2020
- 资助金额:
$ 50.15万 - 项目类别:
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