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REGULATION OF THE MACROPHAGE INFLAMMATORY PHENOTYPE IN ARDS

ARDS 中巨噬细胞炎症表型的调节

基本信息

批准号：
10650813
负责人：
John W Christman
金额：
$ 55.44万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650813
关键词：
Ablation Acute Respiratory Distress Syndrome Address Affect Alveolar Alveolar Macrophages Amino Acids Arachidonic Acids Bacteremia Berlin Blood capillaries COVID-19 Calcineurin Calcineurin inhibitor Capillary Permeability Cell Communication Cell model Cells Complication Critical Illness Data Development Disease Endocytosis Enzymes Epithelial Cells Escherichia coli Functional disorder Genetic Goals Health Human Inflammation Inflammation Mediators Inflammatory Injury Intensive Care Units Interleukin-6 Intravenous Knowledge Lead Life Lipids Lipopolysaccharides Liquid substance Lung Lung Lavage Fluid Macrophage Measures Mediating Mediator Metabolism Modeling Molecular Molecular Target Mus Outcome PTGS2 gene Pathogenesis Pathway interactions Patients Peptides Permeability Pharmacological Treatment Phenotype Prevention approach Property Proteins Proteolysis Public Health Publishing Pulmonary Edema Pulmonary Inflammation Regulation Research Resistance Resolution Role Route Safety Severity of illness Staphylococcus aureus Structure Supportive care T-Cell Activation TNF gene Testing Transcriptional Activation Vascular Endothelium Ventilator-induced lung injury Work absorption alveolar epithelium cecal ligation puncture cell type cellular targeting clinically relevant current pandemic cytokine cytokine release syndrome efficacy evaluation efficacy testing extracellular vesicles improved inhibitor lipid mediator lipid metabolism lung injury lung microvascular endothelial cells meetings mortality mouse model neutrophil new therapeutic target novel novel strategies nuclear factors of activated T-cells pharmacokinetics and pharmacodynamics pharmacologic pre-clinical prevent transcription factor NF-AT c3 treatment response ventilation

项目摘要

Our published data show that genetic ablation and pharmacologic inhibition of NFATc3 in macrophages is beneficial in maintaining alveolar-capillary barrier function, prevents inflammatory cytokine release and neutrophilic inflammation, improved arterial oxygenation and survival in the LPS and cecal ligation puncture mouse models of ARDS. Here, we propose to determine the granular details of the downstream molecular targets of NFATc3 using a 2-hit mouse model, human lung macrophages, and BALF from patients with ARDS. Our team has developed a novel non-toxic cell permeable calcineurin inhibitory (CNI) peptide (CNI103) that blocks activation of NFATc3 in macrophages and mitigates ARDS in mice. We propose to determine the molecular targets of NFATc3 using a pre-clinical 2-hit mouse model, human lung macrophages, and BALF from patients meeting the Berlin criterion for ARDS. Our central hypothesis is that activation of calcineurin-dependent NFAT in macrophages regulates the development of ALI/ARDS, and inhibition of NFAT activation by a novel peptide calcineurin inhibitor (CNI) lessens disease severity. We propose two specific aims: Specific Aim 1: To delineate the downstream molecular targets of NFATc3-Calcineurin activation pathway in pulmonary macrophages during ALI/ARDS. Novel preliminary data show that the lipid content of extracellular vesicles (EVs) in BALF are NFATc3 dependent and mediate disruption of barrier function in lung microvascular endothelial cells (MVEC). In SA1, we will 1) determine the spectrum of NFAT regulated lipids mediators and enzymes involved in lipid metabolism, 2) determine whether these mediators are packaged in extracellular vesicles, 3) assess whether EVs mediate the the cell-to-cell communication that results in permeability pulmonary edema and 4) determine whether blocking NFAT activation prevents lung injury and inflammation in clinically relevant mouse and cellular models of ARDS. Specific Aim 2: To determine the efficacy and safety of an optimized cell permeable calcineurin inhibitor, which prevents NFAT activation, in clinically relevant infectious and non-infectious mouse models of ALI/ARDS. We will test whether cell permeable calcineurin peptide inhibitors prevent and reverse lung injury and inflammation in mouse models of ARDS. We will also assess the pharmacokinetic and pharmacodynamics (PK/PD) properties, cellular selectivity, safety, efficacy, and potency in preventing and reversing lung injury in preclinical mouse models of ARDS. These studies will advance knowledge about the essential role of NFATc3 activation in macrophages and other lung cell types in the pathogenesis of ALI/ARDS. We anticipate that knowledge gained from these studies will establish NFATc3 as a novel therapeutic target that regulates EV-mediated cell-cell interactions by governing the composition of biologically active lipid and protein mediators.

我们发表的数据表明，巨噬细胞中NFATc3的基因消融和药物抑制是有效的

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Early Titration of Oxygen During Mechanical Ventilation Reduces Hyperoxemia in a Pilot, Feasibility, Randomized Control Trial for Automated Titration of Oxygen Levels.

DOI：
10.1097/cce.0000000000000704
发表时间：
2022-06
期刊：
Critical care explorations
影响因子：
0
作者：
Pannu, Sonal R.;Exline, Matthew;Klamer, Brett;Brock, Guy;Crouser, Elliott D.;Christman, John W.;Diaz, Philip
通讯作者：
Diaz, Philip

Workforce, Workload, and Burnout in Critical Care Organizations: Survey Results and Research Agenda.

DOI：
10.1097/ccm.0000000000004552
发表时间：
2020-11
期刊：
Critical care medicine
影响因子：
8.8
作者：
Lilly CM;Oropello JM;Pastores SM;Coopersmith CM;Khan RA;Sessler CN;Christman JW;Academic Leaders in Critical Care Medicine Task Force of the Society of Critical Care Medicine
通讯作者：
Academic Leaders in Critical Care Medicine Task Force of the Society of Critical Care Medicine

Is the cellular response to cigarette smoke predictive of the phenotypic variation of COPD?

DOI：
10.1152/ajplung.00108.2011
发表时间：
2011-06-01
期刊：
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
影响因子：
4.9
作者：
Park, Gye Young;Christman, John W.
通讯作者：
Christman, John W.

Exosomal Transfer of DNA Methyl-Transferase mRNA Induces an Immunosuppressive Phenotype in Human Monocytes.

DOI：
10.1097/shk.0000000000001928
发表时间：
2022-06-01
期刊：
Shock (Augusta, Ga.)
影响因子：
0
作者：
通讯作者：

Airway Epithelial Cell-Derived Colony Stimulating Factor-1 Promotes Allergen Sensitization.

DOI：
10.1016/j.immuni.2018.06.009
发表时间：
2018-08-21
期刊：
Immunity
影响因子：
32.4
作者：
Moon HG;Kim SJ;Jeong JJ;Han SS;Jarjour NN;Lee H;Abboud-Werner SL;Chung S;Choi HS;Natarajan V;Ackerman SJ;Christman JW;Park GY
通讯作者：
Park GY

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John W Christman其他文献

62 - NOSl-Derived Nitric Oxide Promotes NF-kB Transcriptional Activity Through Inhibition of Suppressor of Cytokine Signaling (SOCS-1)

DOI：
10.1016/j.freeradbiomed.2015.10.101
发表时间：
2015-10-01
期刊：
Conference abstract
影响因子：
作者：
Marcelo G Bonini;Sofia V Zaichik;Mao Mao;Peter C Hart;Saurabh Chatterjee;Asrar B. Malik;John W Christman;Michelle L. Block;Richard D Minshall;Benjamin N Gantner
通讯作者：
Benjamin N Gantner