Mesenchymal Stromal Cell Conditioning by Carbon Monoxide
Mesenchymal Stromal Cell Conditioning by Carbon Monoxide
批准号:
8225579
负责人:
Mark A PERRELLA
金额:
$49.48万
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
已结题
起止时间:
2011-08-15 至 2016-06-30
关键词:
Acute Lung InjuryAnimal ModelAnimalsAnti-Inflammatory AgentsAnti-inflammatoryApoptosisAutomobile DrivingBacteriaBiologicalBiological AssayBone MarrowCarbon MonoxideCell CommunicationCell TherapyCell surfaceCellsCessation of lifeCoculture TechniquesComplexConditioned Culture MediaDeath RateDiagnosisDiseaseEarly treatmentEffector CellEventExposure toFailureFibroblastsFunctional disorderGasesGoalsHarvestHematopoieticHemeHome environmentHomeostasisHomingHourHumanHypotensionHypoxiaImmuneImmune Cell ActivationImmune responseImmune systemInfectionInflammationInflammatoryInflammatory ResponseInjuryInvadedKnockout MiceLaboratoriesLeadLigationLungLymphocyteMediator of activation proteinMedicalMesenchymalMolecularMusOrganOrgan SurvivalOrganismOutcomeOxygenasesPatientsPhagocytesPhagocytosisProcessPropertyPulmonary CirculationPuncture procedureRefractoryResolutionRespiratory FailureRoleSepsisSeptic ShockSeveritiesSiteStagingStromal CellsTherapeuticTimeTransgenic MiceWound Healingantimicrobialbaseconditioningheme oxygenase-1improvedimproved functioningin vivoinnovationinsightlung injurymacrophagemicrobialmicroorganismmonocyteneutrophilnovelnovel strategiesnovel therapeuticsoverexpressionparacrinepathogenpre-clinicalpreventresponse
中文摘要
项目概述(见说明):
英文摘要
PROJECT SUMMARY (See instmctions):
Sepsis is a disease process representing the systemic response to severe infection. The infectious insult activates immune cells of the host, including neutrophils, monocytes/macrophages, and lymphocytes. Early activation of immune cells triggers a pro-inflammatory response that contributes to eradication of the invading microorganism(s). If the pathogens are not eradicated, sepsis may progress to severe sepsis (sepsis plus organ dysfunction, such as lung injury and respiratory failure) and septic shock (severe sepsis
plus refractory hypotension and circulatory failure), which frequently leads to death. Once the invading microorganism(s) are eradicated, then resolution of the immune response is critical, as continued systemic inflammation will lead to organ injury. Unfortunately, this early pro-inflammatory response may also be followed by a later state of immunoparalysis, due in part to apoptosis of immune effector cells. The cascade of biologic events that occur during sepsis is complex, and therapeutic strategies need to be tailored depending upon the stage of sepsis at the time of diagnosis. Multipotent mesenchymal stromal cells (MSCs) are considered to be a promising platform for cell-based therapy. MSCs are known to have immunomodulatory
properties, and recently it has been suggested that MSCs are beneficial during the early proinflammatory stage of cecal ligation and puncture in mice. We hypothesize that MSCs, when administered to mice after the onset of polymicrobial or single organism sepsis, will adapt to the specific stage of sepsis and lead to an improved outcome. Prior studies in our laboratory demonstrated that heme oxygenase (H0)-1-derived carbon monoxide (CO), a known anti-inflammatory molecule, also has anti-microbial properties during sepsis. Thus, we also hypothesize that conditioning MSCs with CO ex vivo will improve their function In vivo, and increase the beneficial effects of MSCs after the onset of sepsis in mice. Gaining insight into the mechanisms responsible for this enhanced response of MSCs conditioned with CO will allow us to further understand MSCs as a cell-based therapy, and to develop novel therapeutic strategies for this devastating disease process. MSCs ¿ CO conditioning will also be studied in mice with a "humanized" immune system.
Finally we will advance the understanding of the human immune response to sepsis by assessing phagocytic function of neutrophils and monocytes harvested from patients with sepsis or sepsis plus acute lung injury, compared with cells from control patients. We will determine whether the administration of MSCs ¿ CO ex vivo can improve phagocyte function. These functional assays will be correlated with patient outcome.
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科研奖励(0)
会议论文
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负责人:Mark A PERRELLA
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DNA Minor Groove-binding Drugs and Food-borne Pathogens
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DNA Minor Groove-binding Drugs and Food-borne Pathogens
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DNA Minor Groove-binding Drugs and Food-borne Pathogens
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资助金额:$40.44万
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DNA Minor Groove-binding Drugs and Food-borne Pathogens
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Role of APEG-1 in Vascular Smooth Muscle Biology
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资助金额:$36.53万
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财政年份:2001
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依托单位:
Role of APEG-1 in Vascular Smooth Muscle Biology
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项目类别:
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资助金额:$36.53万
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财政年份:2001
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依托单位:
Role of APEG-1 in Vascular Smooth Muscle Biology
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项目类别:
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资助金额:$36.53万
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财政年份:2001
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依托单位:
HEME OXYGENASE-1 GENE EXPRESSION IN ENDOTOXIC SHOCK
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依托单位:
海外基金