Impact of alcohol on lung fibroblast regulation of the alveolar epithelial barrier
酒精对肺成纤维细胞调节肺泡上皮屏障的影响
基本信息
- 批准号:9896468
- 负责人:
- 金额:$ 7.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdult Respiratory Distress SyndromeAlcoholsAlveolarAlveolar MacrophagesAnimalsAttenuatedAutomobile DrivingBleomycinCell Differentiation processCell physiologyChronicChronic Obstructive Airway DiseaseChronic lung diseaseCoculture TechniquesCollagenCommunicationComplexCytokine SignalingDataDepositionDown-RegulationEndotoxinsEpithelialEpithelial CellsEpitheliumEthanolExperimental ModelsExtracellular MatrixExtracellular Matrix ProteinsFailureFibroblastsFibronectinsFoundationsFunctional disorderFutureGoalsGrowth FactorHomeostasisImpairmentIndividualInjuryInterstitial Lung DiseasesLaboratoriesLeadLungLung diseasesMeasuresMesenchymalMicroRNAsModalityMolecularMorbidity - disease rateNormal tissue morphologyOrganOxidative StressPathologicPhagocytosisPhasePopulations at RiskPreventive InterventionProcessProductionProteinsQuality of lifeRecoveryRegulationResistanceResolutionRiskRoleSignal PathwaySignal TransductionSignaling MoleculeSurvivorsTestingTherapeuticTherapeutic InterventionTight JunctionsTissuesTransforming Growth Factor betaUp-Regulationalcohol effectalcohol exposurealveolar epitheliumcell injurycell motilitycell typechronic alcohol ingestioncytokinedesignequilibration disorderexosomeextracellular vesiclesinsightintercellular communicationlung injurylung repairmortalitynovelpreventproblem drinkerrepairedresponserestorationtissue injurytissue repairwound
项目摘要
Project Summary
Tissue disrepair following injury leads to organ dysfunction and increases morbidity and mortality of
those who survive the initial insult. In the lung, the disrepair process is associated with excessive collagen
deposition along with failure of both re-epithelialization and epithelial cell tight junction formation. Tissue
disrepair is associated with dysregulation of TGFβ signaling in a variety of pulmonary diseases including the
acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and interstitial
lung disease (ILD). Our laboratory utilizes experimental models of chronic alcohol ingestion and bleomycin-
induced lung injury to assess the molecular mechanisms of lung repair and identify novel preventative and
therapeutic interventions. We have previously shown that alcohol induces excessive and persistent TGFβ
expression in the lung. Additionally, we demonstrated that in the lung of chronic alcohol-exposed animals,
TGFβ is a critical molecule driving many cellular anomalies by increasing airway oxidative stress, decreasing
alveolar macrophages phagocytosis, and priming the lung for fibroproliferative disrepair following acute injury.
Our preliminary data show that alcohol-exposed lung fibroblasts interfere with epithelial cell barrier formation
likely through induction of epithelial-mesenchymal transition (EMT). Additionally, inhibition of TGFβ signaling
attenuates the effect of alcohol-exposed fibroblasts on epithelial cells. Interestingly, we also showed that
fibroblasts influence epithelial cells indirectly via fibroblast-derived exosomes rather than direct secretion of
cytokines or growth factors. Furthermore, we showed that alcohol disturbs the balance of pro- and anti-fibrotic
microRNA (miR) expression. Specifically, alcohol increases pro-fibrotic miR-21 and attenuates anti-fibrotic
miRNA-1946a in lung fibroblasts. These data lead us to hypothesize that alcohol exposure disrupts alveolar
epithelial cell tight junction formation and barrier function following injury through an imbalance of miR-21 and
miR-1946a in exosomes secreted by lung fibroblasts. The experimental approaches are designed to test this
hypothesis, and these studies are expected to provide a firm scientific basis for the underlying mechanism(s)
by which alcohol interferes with normal repair following lung injury. The results from this proposal will set the
basis for future studies to investigate potential therapeutic strategies to prevent or mitigate tissue injury and
disrepair in the at-risk population (i.e., alcoholic individuals).
项目概要
损伤后组织失修导致器官功能障碍并增加发病率和死亡率
那些在最初的损伤中幸存下来的人,肺部的失修过程与过量的胶原蛋白有关。
沉积以及上皮细胞再形成和上皮细胞紧密连接组织形成的失败。
失修复与多种肺部疾病中 TGFβ 信号传导失调有关,包括
急性呼吸窘迫综合征 (ARDS)、慢性阻塞性肺疾病 (COPD) 和间质性肺病
肺部疾病(ILD)。我们的实验室利用慢性酒精摄入和博来霉素的实验模型。
诱导肺损伤以评估肺修复的分子机制并确定新的预防和治疗方法
我们之前已经表明,酒精会诱导过量且持续的 TGFβ。
我们还证明,在长期暴露于酒精的动物的肺部中,
TGFβ 是一种关键分子,通过增加气道氧化应激、减少气道氧化应激来驱动许多细胞异常。
肺泡巨噬细胞吞噬作用,并引发急性损伤后肺部纤维增殖失修。
我们的初步数据表明,暴露于酒精的肺成纤维细胞会干扰上皮细胞屏障的形成
可能是通过诱导上皮间质转化 (EMT),另外抑制 TGFβ 信号传导。
减弱暴露于酒精的成纤维细胞对上皮细胞的影响。
成纤维细胞通过成纤维细胞衍生的外泌体间接影响上皮细胞,而不是直接分泌
此外,我们发现酒精会扰乱促纤维化和抗纤维化的平衡。
具体来说,酒精会增加促纤维化的 miR-21 并减弱抗纤维化的作用。
肺成纤维细胞中的 miRNA-1946a 使我们能够解决酒精暴露会破坏肺泡的问题。
损伤后 miR-21 和 miR-21 失衡影响上皮细胞紧密连接形成和屏障功能
肺成纤维细胞分泌的外泌体中的 miR-1946a 旨在测试这一点。
假设,这些研究预计将为潜在机制提供坚实的科学基础
酒精会干扰肺损伤后的正常修复。该提案的结果将确定。
为未来研究调查预防或减轻组织损伤的潜在治疗策略奠定基础
高危人群(即酗酒者)的失修。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
VIRANUJ SUEBLINVONG其他文献
VIRANUJ SUEBLINVONG的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('VIRANUJ SUEBLINVONG', 18)}}的其他基金
Alcohol-mediated Clock genes interfere with lung injury and repair
酒精介导的时钟基因干扰肺损伤和修复
- 批准号:
10587621 - 财政年份:2023
- 资助金额:
$ 7.8万 - 项目类别:
Impact of alcohol on lung fibroblast regulation of the alveolar epithelial barrier
酒精对肺成纤维细胞调节肺泡上皮屏障的影响
- 批准号:
10263149 - 财政年份:2020
- 资助金额:
$ 7.8万 - 项目类别:
Alcohol Induced Oxidative Stress Inhibits Recovery From Acute Lung Injury
酒精引起的氧化应激会抑制急性肺损伤的恢复
- 批准号:
8541686 - 财政年份:2012
- 资助金额:
$ 7.8万 - 项目类别:
Alcohol Induced Oxidative Stress Inhibits Recovery From Acute Lung Injury
酒精引起的氧化应激会抑制急性肺损伤的恢复
- 批准号:
8352560 - 财政年份:2012
- 资助金额:
$ 7.8万 - 项目类别:
Alcohol Induced Oxidative Stress Inhibits Recovery From Acute Lung Injury
酒精引起的氧化应激会抑制急性肺损伤的恢复
- 批准号:
8702060 - 财政年份:2012
- 资助金额:
$ 7.8万 - 项目类别:
相似国自然基金
肺撞击伤的生物力学机理及其并发ARDS的病理机制研究
- 批准号:39370670
- 批准年份:1993
- 资助金额:5.3 万元
- 项目类别:面上项目
刺激性气体致成人呼吸窘迫综合征的机理及诊断防治研究
- 批准号:39270582
- 批准年份:1992
- 资助金额:4.0 万元
- 项目类别:面上项目
相似海外基金
Impact of alcohol exposure on unjamming the airway epithelium
酒精暴露对疏通气道上皮的影响
- 批准号:
10547794 - 财政年份:2021
- 资助金额:
$ 7.8万 - 项目类别:
Impact of alcohol exposure on unjamming the airway epithelium
酒精暴露对疏通气道上皮的影响
- 批准号:
10312710 - 财政年份:2021
- 资助金额:
$ 7.8万 - 项目类别:
Impact of Alcohol Misuse on Cognitive and Respiratory Outcomes in COVID-19-associated Acute Respiratory Failure
滥用酒精对 COVID-19 相关急性呼吸衰竭患者认知和呼吸结果的影响
- 批准号:
10391807 - 财政年份:2021
- 资助金额:
$ 7.8万 - 项目类别:
Microbiota-Mediated Bidirectional Interactions Between Alcohol Misuse and Post-COVID-19 Syndrome
微生物介导的酒精滥用与 COVID-19 后综合症之间的双向相互作用
- 批准号:
10392167 - 财政年份:2021
- 资助金额:
$ 7.8万 - 项目类别:
Impact of Alcohol Misuse on Cognitive and Respiratory Outcomes in COVID-19-associated Acute Respiratory Failure
滥用酒精对 COVID-19 相关急性呼吸衰竭患者认知和呼吸结果的影响
- 批准号:
10671588 - 财政年份:2021
- 资助金额:
$ 7.8万 - 项目类别: