A murine model of Pseudomonas aeruginosa pneumonia secondary to hemorrhagic shock
失血性休克继发铜绿假单胞菌肺炎小鼠模型
基本信息
- 批准号:9294349
- 负责人:
- 金额:$ 8.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-01-10 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdaptor Signaling ProteinAddressAdhesivesAdult Respiratory Distress SyndromeAffinityAnimal ModelAnimalsAnti-Bacterial AgentsAntibiotic TherapyAttenuatedBacteriaBacterial PneumoniaBindingBiologyBlood CirculationBlood VesselsCause of DeathCellsComplementComplicationContainmentCritical IllnessCytoplasmic TailDoseDrug resistanceElementsEmigrationsEndotheliumEquilibriumExtracellular MatrixGoalsHemorrhageHemorrhagic ShockHost DefenseHypovolemicsImmuneImmune System DiseasesImmune System and Related DisordersImmune systemImmunityImmunosuppressionInfectionInflammatory ResponseInnate Immune ResponseIntegrinsLeadLigand BindingLigandsLungMediatingMediator of activation proteinModelingMusNatural ImmunityNeutrophil InfiltrationNosocomial pneumoniaPathogenesisPatientsPeritoneumPlayPneumoniaPredispositionPseudomonas aeruginosaPseudomonas aeruginosa pneumoniaPulmonary EdemaRecruitment ActivityRegulationRespiratory Tract InfectionsRoleSecondary toTalinTestingTherapeuticTherapeutic InterventionTimeTissuesTraumaTrauma patientTreatment EfficacyWorkadhesion receptorclinically relevantdrug resistant bacteriaexperimental studyimmune functionimproved outcomeindexinginsightinterstitiallung injurymortalitymouse modelneutrophilpathogenpostcapillary venulepreventrespiratoryresponsesecondary infectionsmall moleculetargeted treatmenttooltraffickingvascular bed
项目摘要
Abstract
Secondary infections due to compromised immune function are a significant cause of mortality in
hospitalized trauma patients that have survived hemorrhagic shock. The Gram-negative bacterial pathogen
Pseudomonas aeruginosa is one of the most common causes of secondary pneumonia in these patients.
Neutrophil recruitment into the airspaces of the lung is critical for host defense against P. aeruginosa
pneumonia, and studies suggest that this element of innate immunity is compromised following hemorrhagic
shock. Animal models of critical illness and associated immune dysfunction have been developed to probe
pathogenesis of secondary infection and evaluate potential therapies. However, a mouse model of
pseudomonal pneumonia secondary to hemorrhagic shock has not been characterized. Here, we propose to
develop and characterize a mouse model of P. aeruginosa pneumonia secondary to hemorrhagic shock as a
more clinically relevant format to evaluate potential neutrophil-targeted therapeutic strategies. β2 integrins are
adhesion receptors that regulate neutrophil trafficking, and must become activated to bind to their ligands
expressed on endothelium or extracellular matrix. Our previous studies suggest a strategy of attenuating β2
integrin activation to promote neutrophil emigration from the pulmonary vasculature and recruitment into the
airspaces during acute respiratory P. aeruginosa infection in mice with a fully competent innate immune
response. In the second part of this study, we will use the new mouse model to evaluate the efficacy of
XVA143, a small molecule antagonist that prevents β2 integrins from achieving their highest ligand-binding
affinity. We will additionally assess the effects of modulating neutrophil recruitment on lung injury and
pulmonary edema, as neutrophils are also mediators of bystander tissue damage that can lead to acute
respiratory distress syndrome. These studies may identify regulators of β2 integrin activation as effective
therapeutics for promoting host defense of the lung against secondary bacterial pneumonia while maintaining
tissue protection.
摘要
由于免疫功能受损引起的继发性感染是老年人死亡的重要原因。
失血性休克幸存的住院创伤患者。革兰氏阴性细菌病原体
铜绿假单胞菌是这些患者继发性肺炎的最常见原因之一。
肺内的神经元募集对于宿主防御铜绿假单胞菌至关重要
研究表明,这种先天免疫的元素在出血性肺炎后受到损害。
冲击.已经开发了危重病和相关免疫功能障碍的动物模型来探索
继发感染的发病机制,并评估潜在的治疗方法。然而,
继发于失血性休克的假单胞菌肺炎还没有特征。在此,我们建议
开发并表征继发于失血性休克的铜绿假单胞菌肺炎小鼠模型,
更临床相关的格式,以评估潜在的嗜中性粒细胞靶向治疗策略。β2整合素是
调节中性粒细胞运输的粘附受体,必须被激活才能与其配体结合
在内皮或细胞外基质上表达。我们以前的研究提出了一种减弱β2的策略,
整合素活化促进中性粒细胞从肺血管移出并募集到肺血管中,
具有完全固有免疫能力的小鼠急性呼吸道铜绿假单胞菌感染期间的空气间隙
反应在本研究的第二部分,我们将使用新的小鼠模型来评估
XVA 143,一种阻止β2整联蛋白达到其最高配体结合的小分子拮抗剂
亲和力我们还将评估调节中性粒细胞募集对肺损伤的影响,
肺水肿,因为中性粒细胞也是旁观者组织损伤的介质,可导致急性肺水肿。
呼吸窘迫综合征这些研究可能会确定β2整合素激活的调节剂作为有效的
促进宿主肺防御继发性细菌性肺炎同时维持
组织保护
项目成果
期刊论文数量(0)
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CRAIG THOMAS LEFORT其他文献
CRAIG THOMAS LEFORT的其他文献
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{{ truncateString('CRAIG THOMAS LEFORT', 18)}}的其他基金
56th Annual Meeting of the Society for Leukocyte Biology
白细胞生物学学会第 56 届年会
- 批准号:
10752090 - 财政年份:2023
- 资助金额:
$ 8.05万 - 项目类别:
Selective Modulation of Neutrophils in Critical Illness
危重疾病中中性粒细胞的选择性调节
- 批准号:
10551956 - 财政年份:2017
- 资助金额:
$ 8.05万 - 项目类别:
Selective modulation of neutrophils in critical illness
危重疾病中中性粒细胞的选择性调节
- 批准号:
9750019 - 财政年份:2017
- 资助金额:
$ 8.05万 - 项目类别:
Selective modulation of neutrophils in critical illness
危重疾病中中性粒细胞的选择性调节
- 批准号:
9382234 - 财政年份:2017
- 资助金额:
$ 8.05万 - 项目类别:
Selective modulation of neutrophils in critical illness
危重疾病中中性粒细胞的选择性调节
- 批准号:
10220991 - 财政年份:2017
- 资助金额:
$ 8.05万 - 项目类别:














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