Antidotes against HCI-induced chronic lung injury
Antidotes against HCI-induced chronic lung injury
批准号:
10471329
负责人:
John D Catravas
金额:
$44.0万
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
项目状态:
已结题
起止时间:
2020-08-20 至 2024-08-31
关键词:
AcuteAftercareAnimal ModelAnimalsAnti-Inflammatory AgentsAntidotesAntineoplastic AgentsAreaCessation of lifeChemical WarfareChlorineChronicChronic Lung InjuryClinicalClinical TrialsDangerousnessDataDevelopmentDisease ProgressionDoseEffectivenessEventExhibitsExposure toFunctional disorderGasesHeat-Shock Proteins 70Heat-Shock Proteins 90HourHumanHydrochloric AcidIllicit DrugsIncidenceInflammatoryKnockout MiceLaboratoriesLeadLungLung diseasesModelingMolecular ChaperonesMusOilsOryctolagus cuniculusOximesPharmaceutical PreparationsPhosgenePirfenidonePlantsProfibrotic signalPulmonary FibrosisRoleSignal TransductionSiteSwimming PoolsTherapeuticUp-Regulationclinical investigationhuman modelidiopathic pulmonary fibrosisindium-bleomycininhibitorirritationlewisitelung injurynintedanibside effecttreatment optimization
中文摘要
总结
暴露于盐酸(HCl)可导致严重的急性和慢性、潜在致命的肺损伤。
由于其频繁和多次使用,接触盐酸的发生率一直在增加。此外,委员会认为,
HCl也牵涉到化学战中,既作为引发剂,也更经常地作为化学战的有毒产物。
光气、光气肟、路易氏剂和氯气暴露。尽管有大量的
关于盐酸急性效应的数据,对更严重的、潜在致命的慢性后遗症的了解要少得多。
暴露在HCl中,并且没有解毒剂存在于最危险的,不可逆的和潜在的致命的这些
肺纤维化(PF)。普遍存在的促炎分子伴侣热休克蛋白90
热休克蛋白90(HSP 90)调节几种促纤维化因子的活化,并在PF中上调。
假设HSP 90抑制剂,已经在临床试验中作为抗癌剂,可能被证明是有用的,
盐酸诱导的慢性肺损伤和肺纤维化(PF)的对策。在初步研究中,
我们已经描述了盐酸诱导的小鼠PF中的关键信号事件,并证明了治疗后
(HCl给药后24小时开始)与HSP 90抑制剂一起,AUY-922有效地阻断了HSP 90抑制剂的作用。
重要的促纤维化信号的上调,以及肺纤维化和
慢性肺功能障碍在当前的应用中,我们建议在三个方面扩展我们的初步发现:
1)确定临床上使用的HSP 90抑制剂,其在小鼠中作为HCl诱导的PF的解毒剂是最有效的,2)
研究HSP 70在HSP 90抑制剂的解毒作用中的潜在治疗作用; 3)
证明了HSP 90抑制剂在另一种HCl诱导的PF动物模型中类似地抑制HCl诱导的PF的能力。
诱发PF,兔子。这些研究结果将为进一步的发展提供所需的信息
HSP 90特异性抑制剂作为盐酸诱导的肺纤维化和慢性肺功能障碍的解毒剂。
英文摘要
SUMMARY
Exposure to hydrochloric acid (HCl) can cause severe acute and chronic, potentially lethal, pulmonary injury.
Because of its frequent and multiple uses, the incidence of exposure to HCl has been increasing. Furthermore,
HCl is also implicated in chemical warfare both as an initiating agent and more often as a toxic product of
phosgene, phosgene oxime, Lewisite and chlorine exposure. Even though there is considerable amount of
data on the acute effects of HCl, much less is known about the more severe, potentially lethal chronic sequels
of exposure to HCl and no antidotes exist to the most dangerous, irreversible and potentially lethal of these
effects, namely pulmonary fibrosis (PF). The ubiquitous pro-inflammatory chaperone, heat shock protein 90
(HSP90) regulates the activation of several pro-fibrotic factors and is upregulated in PF. We therefore
hypothesized that HSP90 inhibitors, already in clinical trials as anti-cancer agents, may prove useful as
countermeasures against HCl-induced chronic lung injury and pulmonary fibrosis (PF). In Preliminary Studies,
we have described key signaling events in HCl-induced PF in mice and have demonstrated that post-treatment
(beginning 24 hours after HCl administration) with the HSP90 inhibitor, AUY-922 effectively blocks the
upregulation of important pro-fibrotic signals, as well as the development of both pulmonary fibrosis and
chronic lung dysfunction. In the current application, we propose to expand on our initial findings in three areas:
1) identify the clinically used HSP90 inhibitor which is most effective as antidote in HCl-induced PF in mice, 2)
investigate a potential therapeutic role of HSP70 in the antidotal effects of HSP90 inhibitors and 3)
demonstrate the ability of HSP90 inhibitors to similarly inhibit HCl-induced PF in another animal model of HCl-
induced PF, the rabbit. Results from these studies will provide needed information for the further development
of a specific HSP90 inhibitor as antidote against HCl-induced lung fibrosis and chronic lung dysfunction.
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DOI:
10.3390/ijms22168833
发表时间:
2021-08-17
期刊:
International journal of molecular sciences
影响因子:
5.6
作者:
[Colunga Biancatelli RML, Solopov P, Dimitropoulou C, Catravas JD]
通讯作者:
Catravas JD
DOI:
10.3390/cells11061046
发表时间:
2022-03-19
期刊:
Cells
影响因子:
6
作者:
[Colunga Biancatelli RML, Solopov P, Dimitropoulou C, Gregory B, Day T, Catravas JD]
通讯作者:
Catravas JD
DOI:
10.3390/cells10061489
发表时间:
2021-06-13
期刊:
Cells
影响因子:
6
作者:
[Colunga Biancatelli RML, Solopov P, Gregory B, Catravas JD]
通讯作者:
Catravas JD
DOI:
10.3390/nu13103599
发表时间:
2021-10-14
期刊:
Nutrients
影响因子:
5.9
作者:
[Solopov P, Colunga Biancatelli RML, Dimitropoulou C, Catravas JD]
通讯作者:
Catravas JD
Sex-Related Differences in Murine Models of Chemically Induced Pulmonary Fibrosis.
化学诱导的肺纤维化的鼠模型中的性别相关差异。
DOI:
10.3390/ijms22115909
发表时间:
2021-05-31
期刊:
International journal of molecular sciences
影响因子:
5.6
作者:
[Solopov P, Colunga Biancatelli RML, Dimitropoulou C, Catravas JD]
通讯作者:
Catravas JD
Antidotes against HCI-induced chronic lung injury
-
批准号:10015581
-
项目类别:
-
资助金额:$45.88万
-
财政年份:2020
-
负责人:John D Catravas
-
依托单位:
Antidotes against HCI-induced chronic lung injury
-
批准号:10241958
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项目类别:
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资助金额:$45.28万
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财政年份:2020
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负责人:John D Catravas
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依托单位:
Antidotes against mustard-induced chronic lung injury
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批准号:9789315
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项目类别:
-
资助金额:$19.38万
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财政年份:2018
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负责人:John D Catravas
-
依托单位:
Human Tissue & Animal Core Unit
-
批准号:8198069
-
项目类别:
-
资助金额:$38.74万
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财政年份:2011
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负责人:John D Catravas
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依托单位:
Therapeutic Mechanisms of RhoA Inhibition In Acute Lung Injury
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批准号:8198063
-
项目类别:
-
资助金额:$35.02万
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财政年份:2011
-
负责人:John D Catravas
-
依托单位:
VASCULAR ANTI-INFLAMMATORY ACTIONS OF HSP90 INHIBITORS
-
批准号:8231387
-
项目类别:
-
资助金额:$36.38万
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财政年份:2010
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负责人:John D Catravas
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依托单位:
VASCULAR ANTI-INFLAMMATORY ACTIONS OF HSP90 INHIBITORS
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批准号:8426147
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项目类别:
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资助金额:$15.45万
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财政年份:2010
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负责人:John D Catravas
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依托单位:
VASCULAR ANTI-INFLAMMATORY ACTIONS OF HSP90 INHIBITORS
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批准号:8054846
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资助金额:$36.75万
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财政年份:2010
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负责人:John D Catravas
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依托单位:
VASCULAR ANTI-INFLAMMATORY ACTIONS OF HSP90 INHIBITORS
-
批准号:8852348
-
项目类别:
-
资助金额:$19.18万
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财政年份:2010
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负责人:John D Catravas
-
依托单位:
VASCULAR ANTI-INFLAMMATORY ACTIONS OF HSP90 INHIBITORS
-
批准号:7889057
-
项目类别:
-
资助金额:$36.75万
-
财政年份:2010
-
负责人:John D Catravas
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依托单位:
REGULATION OF sGC IN sGC/Hsp90/NOS COMPLEXES
-
批准号:7024541
-
项目类别:
-
资助金额:$31.42万
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财政年份:2003
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负责人:John D Catravas
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依托单位:
REGULATION OF sGC IN sGC/Hsp90/NOS COMPLEXES
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批准号:6739012
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项目类别:
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资助金额:$32.18万
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财政年份:2003
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负责人:John D Catravas
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依托单位:
REGULATION OF sGC IN sGC/Hsp90/NOS COMPLEXES
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批准号:6574052
-
项目类别:
-
资助金额:$32.2万
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财政年份:2003
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负责人:John D Catravas
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依托单位:
REGULATION OF sGC IN sGC/Hsp90/NOS COMPLEXES
-
批准号:6853510
-
项目类别:
-
资助金额:$32.18万
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财政年份:2003
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负责人:John D Catravas
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依托单位:
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批准号:7008666
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资助金额:$8.5万
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财政年份:2001
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负责人:John D Catravas
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TRAINING IN INTEGRATIVE CARDIOVASCULAR BIOLOGY
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批准号:6490763
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项目类别:
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资助金额:$27.54万
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财政年份:2001
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负责人:John D Catravas
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依托单位:
POST-DOCTORAL TRAINING PROGRAM IN INTEGRATIVE CARDIOVASCULAR BIOLOGY
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批准号:7437420
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项目类别:
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资助金额:$33.22万
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财政年份:2001
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负责人:John D Catravas
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依托单位:
POST-DOCTORAL TRAINING PROGRAM IN INTEGRATIVE CARDIOVASCULAR BIOLOGY
-
批准号:7872793
-
项目类别:
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资助金额:$22.67万
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财政年份:2001
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负责人:John D Catravas
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依托单位:
Training in Integrative Cardiovascular Biology
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资助金额:$29.38万
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财政年份:2001
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依托单位:
海外基金