Therapeutic efficacies of neutrophil elastase and RIP1 inhibitors in acute lung injury
中性粒细胞弹性蛋白酶和RIP1抑制剂治疗急性肺损伤的疗效
基本信息
- 批准号:10311120
- 负责人:
- 金额:$ 23.18万
- 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:2020-12-02 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAcute Lung InjuryAdverse effectsAffectAlveolarAmericanAnimal ModelApoptosisAttenuatedBacteriaBiochemicalBreathingCASP8 geneCell DeathCell SurvivalCessation of lifeClinical ResearchClinical TrialsConsensusDevelopmentEffectivenessEndotheliumEnzymesEventFDA approvedGeneticGoalsHumanHuman bodyHypoxemiaIncidenceInflammationInjuryInvadedJapaneseKnock-outKnockout MiceLethal Dose 50Leukocyte ElastaseLeukocytesLipopolysaccharidesLungMeasuresMediatingMetalloproteasesModelingMolecularMulticenter StudiesMusNeutrophil ActivationPathway interactionsPeptide HydrolasesPerinatalPharmacologyPhasePhase III Clinical TrialsPhosphotransferasesPlayProteinsPulmonary EdemaPulmonary InflammationRIPK1 geneRIPK3 geneReactive Oxygen SpeciesReceptor InhibitionRespiratory FailureRoleStainsStudy modelsSyndromeTNF geneTissuesTreatment EfficacyTreatment ProtocolsUbiquitinationUnited StatesVentilatorexperimental studyimprovedin vivoinflammatory milieuinhibitorinsightinterstitialkinase inhibitorlung injurymortalitymouse modelneutrophilneutrophil elastase inhibitornovelnovel therapeutic interventionpathogenpreventpublic health relevancepulmonary functionsmall molecular inhibitorventilation
项目摘要
5. Project Summary/Abstract
Acute lung injury (ALI) is a syndrome of respiratory failure characterized by protein-rich pulmonary edema that
causes severe hypoxemia and labored breathing. In the United States, the annual incidence of ALI is about
200,000 with a mortality rate of 30-40%; yet, there is no FDA-approved pharmacological therapy for ALI.
Neutrophils are the most abundant circulating white blood cells in the human body and provide the first line of
defense against invading pathogens. In the lung, while neutrophils are essential for pathogen elimination,
exuberant accumulation and prolonged survival of neutrophils in the interstitial and alveolar spaces contribute
to ALI by releasing a variety of injurious molecules, including neutrophil elastase (NE), metalloproteases,
reactive oxygen species (ROS), and other proteolytic enzymes. Although all these injurious molecules
contribute to ALI, an increasing body of studies have demonstrated that NE is the most potent hydrolytic
enzyme that plays a key role in lung alveolar injury, and that inhibition of NE with small molecular inhibitors
[e.g. Sivelestat (Siv)] reduces measures of lung injury and inflammation in animal models of ALI. However,
clinical studies have not yet provided a clear consensus. Whereas in Japanese phase III clinical trials, Siv
improved pulmonary functions, in North American multicenter studies, Siv rather increased long-term mortality
by unknown mechanisms. Thus, identification of molecular events associated with adverse effects of Siv in ALI
is an important task for the development of novel and combination treatment regimens. Recently, in unbiased
functional protease purification experiments, we discovered that NE cleaves receptor interacting protein 1
(RIP1), and that inhibition of NE with Siv leads to RIP1-dependent necroptosis in mouse and human
neutrophils following treatment with lipopolysaccharide (LPS) or TNFα. Such RIP1-induced necroptosis can be
inhibited by RIP1 kinase inhibitors (e.g. Nec-1s) or knockout (KO) of RIP3. We found that LPS/Siv-induced
necroptosis was significantly inhibited in RIP3 KO neutrophils. Importantly, in a mouse model of ALI induced by
50% lethal dose of LPS, Siv in combination with Nec-1s resulted in 90% survival of the mice (P=0.001),
whereas neither Siv nor Nec-1s alone afforded significant protection against the death. Thus, we hypothesize
that inhibition of NE with Siv in ALI leads to RIP1-mediated necroptosis in neutrophils, which causes secondary
inflammation and lung injury, and that inhibition of RIP1-mediated necroptosis significantly improves the
effectiveness of NE inhibitors in ALI. Aim-1. Determine the therapeutic efficacies of RIP1 and NE inhibitors in
lung injury and inflammation using mouse models of ALI. Aim-2. Determine how genetic ablation of NE or RIP3
affects lung injury and inflammation in ALI mice.
5.项目总结/摘要
急性肺损伤(ALI)是一种以富含蛋白质的肺水肿为特征的呼吸衰竭综合征,
会导致严重的低氧血症和呼吸困难在美国,ALI的年发病率约为
20万例,死亡率为30-40%;然而,没有FDA批准的药物治疗ALI。
嗜中性粒细胞是人体中最丰富的循环白色血细胞,并提供了第一道免疫屏障。
防御入侵的病原体。在肺中,虽然中性粒细胞对病原体的清除至关重要,
中性粒细胞在间质和肺泡腔中的大量积聚和延长的存活有助于
通过释放多种有害分子,包括中性粒细胞弹性蛋白酶(NE),金属蛋白酶,
活性氧(ROS)和其它蛋白水解酶。尽管所有这些有害分子
由于NE对ALI的作用,越来越多的研究表明NE是最有效的水解酶,
在肺泡损伤中起关键作用的酶,以及用小分子抑制剂抑制NE
[e.g. Sivelestat(Siv)]减少ALI动物模型中肺损伤和炎症的测量。然而,在这方面,
临床研究尚未提供明确的共识。而在日本的III期临床试验中,
改善肺功能,在北美多中心研究中,Siv反而增加了长期死亡率
未知的机制。因此,鉴定与Siv在ALI中的不良反应相关的分子事件,
是开发新的联合治疗方案的重要任务。最近,在无偏见的
功能蛋白酶纯化实验中,我们发现NE切割受体相互作用蛋白1
(RIP 1),并且用Siv抑制NE导致小鼠和人中RIP 1依赖性坏死性凋亡
用脂多糖(LPS)或TNFα处理后的中性粒细胞。这种RIP 1诱导的坏死性凋亡可以是
受RIP 1激酶抑制剂(例如Nec-1 s)或RIP 3敲除(KO)抑制。我们发现LPS/Siv诱导的
在RIP 3 KO中性粒细胞中,坏死性凋亡被显著抑制。更重要的是,在小鼠ALI模型中,
50%致死剂量LPS、Siv联合Nec-1 s组小鼠存活率为90%(P=0.001),
而Siv和Nec-1 s都不能单独对死亡提供显著的保护。因此,我们假设
在ALI中用Siv抑制NE导致RIP 1介导的中性粒细胞坏死性凋亡,这引起继发性
炎症和肺损伤,抑制RIP 1介导坏死性凋亡显著改善了
NE抑制剂在ALI中的有效性。目标一确定RIP 1和NE抑制剂在
肺损伤和炎症。目标二确定NE或RIP 3的基因消融
影响ALI小鼠的肺损伤和炎症。
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 }}
HASEM HABELHAH其他文献
HASEM HABELHAH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('HASEM HABELHAH', 18)}}的其他基金
The roles of TRAF2 and RIP1 in breast cancer cell survival
TRAF2 和 RIP1 在乳腺癌细胞存活中的作用
- 批准号:
10363270 - 财政年份:2022
- 资助金额:
$ 23.18万 - 项目类别:
The roles of TRAF2 and RIP1 in breast cancer cell survival
TRAF2 和 RIP1 在乳腺癌细胞存活中的作用
- 批准号:
10619506 - 财政年份:2022
- 资助金额:
$ 23.18万 - 项目类别:
HtrA2-mediated RIP1 cleavage regulates neuronal inflammation and death
HtrA2介导的RIP1裂解调节神经元炎症和死亡
- 批准号:
9371476 - 财政年份:2017
- 资助金额:
$ 23.18万 - 项目类别:
RIP1 Cleavage by Caspase-8 is Essential for TRAIL-induced NF-kB Activation
Caspase-8 裂解 RIP1 对于 TRAIL 诱导的 NF-kB 激活至关重要
- 批准号:
8033152 - 财政年份:2010
- 资助金额:
$ 23.18万 - 项目类别:
RIP1 Cleavage by Caspase-8 is Essential for TRAIL-induced NF-kB Activation
Caspase-8 对 RIP1 的切割对于 TRAIL 诱导的 NF-kB 激活至关重要
- 批准号:
8403529 - 财政年份:2010
- 资助金额:
$ 23.18万 - 项目类别:
RIP1 Cleavage by Caspase-8 is Essential for TRAIL-induced NF-kB Activation
Caspase-8 裂解 RIP1 对于 TRAIL 诱导的 NF-kB 激活至关重要
- 批准号:
7887290 - 财政年份:2010
- 资助金额:
$ 23.18万 - 项目类别:
RIP1 Cleavage by Caspase-8 is Essential for TRAIL-induced NF-kB Activation
Caspase-8 裂解 RIP1 对于 TRAIL 诱导的 NF-kB 激活至关重要
- 批准号:
8206767 - 财政年份:2010
- 资助金额:
$ 23.18万 - 项目类别:
Regulation of TRAF2 Activity in Normal and Tumor Cells
正常细胞和肿瘤细胞中 TRAF2 活性的调节
- 批准号:
7339874 - 财政年份:2006
- 资助金额:
$ 23.18万 - 项目类别:
Regulation of TRAF2 Activity in Normal and Tumor Cells
正常细胞和肿瘤细胞中 TRAF2 活性的调节
- 批准号:
7187428 - 财政年份:2006
- 资助金额:
$ 23.18万 - 项目类别:
Regulation of TRAF2 Activity in Normal and Tumor Cells
正常细胞和肿瘤细胞中 TRAF2 活性的调节
- 批准号:
7034445 - 财政年份:2006
- 资助金额:
$ 23.18万 - 项目类别:
相似海外基金
Combinatorial cytokine-coated macrophages for targeted immunomodulation in acute lung injury
组合细胞因子包被的巨噬细胞用于急性肺损伤的靶向免疫调节
- 批准号:
10648387 - 财政年份:2023
- 资助金额:
$ 23.18万 - 项目类别:
Lung epithelial cell-derived C3 in acute lung injury
肺上皮细胞衍生的 C3 在急性肺损伤中的作用
- 批准号:
10720687 - 财政年份:2023
- 资助金额:
$ 23.18万 - 项目类别:
Examining the role of TRMT1 and tRNA methylation in acute lung injury and ARDS
检查 TRMT1 和 tRNA 甲基化在急性肺损伤和 ARDS 中的作用
- 批准号:
10719249 - 财政年份:2023
- 资助金额:
$ 23.18万 - 项目类别:
Inducible HMGB1 antagonist for viral-induced acute lung injury.
诱导型 HMGB1 拮抗剂,用于治疗病毒引起的急性肺损伤。
- 批准号:
10591804 - 财政年份:2023
- 资助金额:
$ 23.18万 - 项目类别:
MAP2K1 AND MAP2K2 IN ACUTE LUNG INJURY AND RESOLUTION
MAP2K1 和 MAP2K2 在急性肺损伤中的作用及缓解
- 批准号:
10741574 - 财政年份:2023
- 资助金额:
$ 23.18万 - 项目类别:
Development of a new treatment for COVID-19-related acute lung injury targeting the microbiota-derived peptide corisin
针对微生物群衍生肽 corisin 开发治疗 COVID-19 相关急性肺损伤的新疗法
- 批准号:
23K07651 - 财政年份:2023
- 资助金额:
$ 23.18万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Probing immunovascular mechanobiology in pneumonia-associated acute lung injury at the single capillary level
在单毛细血管水平探讨肺炎相关急性肺损伤的免疫血管力学生物学
- 批准号:
10679944 - 财政年份:2023
- 资助金额:
$ 23.18万 - 项目类别:
The amyloid precursor protein protects against acute lung injury
淀粉样前体蛋白可预防急性肺损伤
- 批准号:
10575258 - 财政年份:2023
- 资助金额:
$ 23.18万 - 项目类别:
Role of macrophages and miRNA in regulating lung macrophage polarization and lung pathogenesis during respiratory virus-induced acute lung injury in normal and diabetic Syrian hamsters.
正常和糖尿病叙利亚仓鼠呼吸道病毒引起的急性肺损伤期间巨噬细胞和 miRNA 在调节肺巨噬细胞极化和肺部发病机制中的作用。
- 批准号:
10701207 - 财政年份:2023
- 资助金额:
$ 23.18万 - 项目类别:
Roles of N-glycans on neutrophil beta2 integrins in progression of acute lung injury
N-聚糖对中性粒细胞β2整合素在急性肺损伤进展中的作用
- 批准号:
10837431 - 财政年份:2023
- 资助金额:
$ 23.18万 - 项目类别:














{{item.name}}会员




