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Mechanistic role of membrane pore formation in lung-endothelial barrier failure due to blood-borne pathogens.

膜孔形成在血源性病原体导致的肺内皮屏障衰竭中的机制作用。

基本信息

批准号：
10687230
负责人：
Jahar Bhattacharya
金额：
$ 75.09万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-06-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10687230
关键词：
Actins Acute Lung Injury Acute Respiratory Distress Syndrome Address Alveolar Macrophages Bacteremia Bacteria Biological Blood-Borne Pathogens CASP1 gene Calcineurin Caspase Cell membrane Cells Confocal Microscopy Cytosol Dimensions Disease Dose Endothelial Cells Endothelium Enhancers Event F-Actin Failure Flagella Gap Junctions Goals Inflammasome Inhalation Injections Intravenous Knowledge Lung Membrane Modeling Molecular Mus N-terminal Pathogenesis Pathology Peritonitis Permeability Phase Process Proteins Pseudomonas aeruginosa Pseudomonas aeruginosa infection Pulmonary Inflammation Research Role Sepsis Severities System Systemic infection Tail Text Therapeutic Time Transfection Veins acronyms effective therapy genetic manipulation intraperitoneal lung injury mortality neutrophil novel opportunistic pathogen repaired response sepsis induced ARDS septic sex

项目摘要

PROJECT SUMMARY Significance. The overall goals are to define mechanisms and therapies for the acute respiratory distress syndrome (ARDS) due to septic bacteremia of the opportunistic pathogen, Pseudomonas aeruginosa (PA). These mechanisms remain undefined. Our premise is that blood-borne PA cause ARDS by rapidly internalizing in the lung endothelium. Consequently, there is activation of the gasdermin D mechanism of membrane pore formation. Ca2+ enters the endothelial cytosol through the pores, destabilizing f-actin, and thereby inducing barrier failure – the major cause of ARDS. Approach. We will evaluate the premise in two Specific Aims by means of real-time confocal microscopy (RCM) of live mouse lungs, as well as other general approaches. In SA1, we will determine the effects of LPS transfection of the lung endothelium, a model of PA-associated LPS internalization. In SA2, we will determine lung-endothelial effects of bacteremia, modeled by intravenous PA injection, and extra-pulmonary sepsis by intraperitoneal PA infection. The premise will be evaluated in genetically manipulated mice to evaluate (i) the gasdermin D and other hypotheses of membrane pore formation; (ii) mechanisms of pore repair by the ESCRT- III system; (iii) the role of pore-induced Ca2+ and f-actin mechanisms in barrier failure; (iv) effects of PA internalization in the lung endothelium; and (v) the efficacy of endothelial actin enhancement by cell- permeable proteins as effective therapy against ARDS due to PA peritonitis induced. Impact. Our studies will for the first time, reveal the importance of lung-endothelial pore formation as a mechanism of the endothelial barrier failure that underlies sepsis-induced ARDS due to extra-pulmonary infection by PA. The endothelial internalization of PA will be understood as the critical mechanism in this pathology. The dynamics and mechanisms of endothelial pore formation will be revealed for the first time. Molecular strategies directed against endothelial pore formation, therefore barrier failure, will be evaluated as therapies for ARDS due to PA sepsis. Outstandingly novel understanding will be achieved in mechanisms and therapies of sepsis-induced ARDS due to PA-induced pore formation.

项目摘要意义总体目标是确定急性呼吸窘迫的机制和治疗方法急性呼吸窘迫综合征（ARDS）是由条件致病菌铜绿假单胞菌（PA）的脓毒性菌血症引起的。这些机制仍然不明确。我们的前提是，血源性PA通过快速地内化在肺内皮细胞中。因此，存在Gasdermin D机制的激活，膜孔形成Ca 2+通过孔进入内皮细胞胞质溶胶，使f-肌动蛋白不稳定，从而引起屏障失效--ARDS的主要原因。 Approach.我们将通过实时共聚焦显微镜来评估两个特定目标的前提 (RCM)活鼠肺以及其他常规方法。在SA 1中，我们将确定LPS的作用肺内皮的转染，PA相关LPS内化的模型。在SA 2中，我们将确定通过静脉PA注射建模的菌血症的肺内皮效应，以及通过腹膜内PA感染。将在遗传操作的小鼠中评价前提，以评价（i） gasdermin D和膜孔形成的其他假设;（ii）ESCRT-1介导的孔修复机制。 III系统;（iii）孔诱导的Ca 2+和f-肌动蛋白机制在屏障失效中的作用;（iv）PA的影响在肺内皮细胞的内化;和（v）内皮肌动蛋白增强细胞的功效- 渗透性蛋白是治疗PA腹膜炎所致ARDS的有效药物。冲击我们的研究将首次揭示肺内皮孔形成作为一种内皮屏障功能衰竭是脓毒症诱导的肺外呼吸窘迫综合征的基础， PA感染。PA的内皮内化将被理解为其中的关键机制。病理将首次揭示内皮孔形成的动力学和机制。针对内皮孔形成（因此屏障失效）的分子策略将被评价为治疗由于PA败血症引起的ARDS。将在机制和治疗由于PA诱导的孔隙形成引起的脓毒症诱导的ARDS。

项目成果

期刊论文数量（71）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechano-oxidative coupling by mitochondria induces proinflammatory responses in lung venular capillaries.

线粒体的机械氧化耦合诱导肺小静脉毛细血管的促炎症反应。

DOI：
10.1172/jci17271
发表时间：
2003
期刊：
The Journal of clinical investigation.
影响因子：
0
作者：
Ichimura,Hideo;Parthasarathi,Kaushik;Quadri,Sadiqa;Issekutz,AndrewC;Bhattacharya,Jahar
通讯作者：
Bhattacharya,Jahar

Pulmonary surfactant and drug delivery: Vehiculization, release and targeting of surfactant/tacrolimus formulations.

DOI：
10.1016/j.jconrel.2020.11.042
发表时间：
2021-01-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Hidalgo A;Garcia-Mouton C;Autilio C;Carravilla P;Orellana G;Islam MN;Bhattacharya J;Bhattacharya S;Cruz A;Pérez-Gil J
通讯作者：
Pérez-Gil J

Acid contact in the rodent pulmonary alveolus causes proinflammatory signaling by membrane pore formation.