Reducing Airway Smooth Muscle Tone Using Inhaled Statins
使用吸入他汀类药物降低气道平滑肌张力
基本信息
- 批准号:10394390
- 负责人:
- 金额:$ 47.4万
- 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
- 起止时间:2020-05-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-hydroxy-3-methylglutaryl-coenzyme AActinsAddressAdultAgonistAsthmaBronchoalveolar LavageBronchoconstrictionBronchodilator AgentsCCL26 geneCellsChronicCoenzyme AComplexCytoskeletal ProteinsDisease modelDyspneaF-ActinFunctional disorderGene SilencingGenesGoalsHistamineHouse Dust Mite AllergensHumanIL17 geneIL6 geneIL8 geneInflammationInhalationInterleukin-13Leukotriene AntagonistsLungMass Spectrum AnalysisMeasurementMeasuresMediatingMethodsMusMuscarinic AntagonistsMuscle ContractionMuscle TonusMuscle relaxation phaseMyosin Light ChainsOxidoreductasePathway interactionsPharmaceutical PreparationsPharmacologyPhosphorylationPhosphotransferasesPlasmaProductionPropertyProteinsRho-associated kinaseRoleSliceSmooth Muscle MyocytesStress FibersStretchingStructure of parenchyma of lungSymptomsTNF geneTreatment Efficacyairway hyperresponsivenessairway inflammationairway remodelingasthma exacerbationasthmaticcell immortalizationcysteinyl leukotriene receptorcytokinedesensitizationdisabling symptomempoweredexperimental studyhydrophilicityinhibitorknock-downlipophilicitymethacholinemevalonatemouse modelmyosin light chain 2neonatal miceoptimal treatmentsrab GTP-Binding Proteinsreceptorrespiratory smooth musclesmall hairpin RNAtranscription factortranscriptome sequencing
项目摘要
PROJECT SUMMARY
During an asthma exacerbation, the debilitating symptoms of breathlessness is largely driven by airway smooth
muscle (ASM) contraction. To relax the ASM, current therapies are directed either at antagonizing pro-contractile
ASM receptors (e.g. muscarinic antagonists, cysteinyl leukotriene receptor antagonists), or activating pro-
relaxant ASM receptors (e.g. 2-agonists). Despite their widespread use, these therapies remain inadequate in
controlling symptoms. Rather than targeting receptor-mediated pathways that are complex, indirect, and
susceptible to desensitization, our key premise is that a more robust strategy for treating asthma is to directly
target the ASM contractile apparatus. To disrupt the ASM contractile apparatus, we have discovered a
compelling action for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors, ‘statins’, in the
mevalonate (MA) pathway. First, using human ASM cells and human precision cut lung slices (PCLS), we
observed that statins inhibit basal-, histamine-, and methacholine (MCh)-induced ASM contraction according to
their physiochemical properties (i.e. lipophilic versus hydrophilic statins), and the most pronounced effect is
conferred by the lipophilic statin, pitavastatin. Second, we observed that the ASM-relaxing effects of pitavastatin
occurs by inhibiting Rho kinase (ROCK)-1 activity, myosin light chain (MLC)-2 phosphorylation, and F-actin
stress fibers, by a MA- and geranylgeranylpyrophosphate (GGPP)-dependent mechanism. Third, pitavastatins’
effect is additive to 2−agonists. Fourth, independent of its ASM-relaxing effect, pitavastatin also inhibits ASM
proliferation, and IL13-induced eotaxin-3 and IL17/TNF-induced IL6 and IL8 production by a MA/GGPP-
dependent mechanism. Finally, in a non-inflammatory mouse model of MCh-induced airway hyper-
responsiveness (AHR), intratracheal (i.t.) instillation of pitavastatin inhibited bronchoconstriction by 48%.
Empowered by these findings, we hypothesize that pitavastatin when delivered intratracheally can provide
optimal therapy for bronchoconstriction by ameliorating ASM contraction and ASM inflammation.
AIM 1: Establish the potential of pitavastatin to inhibit ASM contraction and bronchoconstriction.
AIM 2: Determine pitavastatin’s mechanisms for inhibiting ASM contraction and inflammation.
AIM 3: Examine the effects of asthma pathobiology on the efficacy of pitavastatin therapy.
Long-Term Impact: By inhibiting two key hallmark features of ASM dysfunction in asthma – contraction and
inflammation – inhaled pitavastatin may be superior to or enhance current inhaled bronchodilator therapies for
the treatment of asthma.
项目总结
在哮喘加重期间,气促的衰弱症状主要是由畅通的呼吸道引起的。
肌肉(ASM)收缩。为了放松ASM,目前的治疗方法要么是针对拮抗前收缩
ASM受体(如M受体拮抗剂,半胱氨酰白三烯受体拮抗剂),或激活前-
舒张剂ASM受体(如-2激动剂)。尽管它们被广泛使用,但这些疗法仍然不足以
控制症状。而不是针对受体介导的复杂、间接和
易受脱敏影响,我们的关键前提是更有力的治疗哮喘的策略是直接
瞄准ASM收缩装置。为了扰乱ASM收缩装置,我们发现了一种
3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)抑制剂他汀类药物在
甲氧戊酸(MA)途径。首先,使用人类ASM细胞和人类精密切割肺切片(PCLS),我们
观察到他汀类药物抑制基础、组胺和乙酰甲胆碱(MCH)诱导的ASM收缩
它们的物理化学性质(即亲脂性与亲水性的他汀类药物),最显著的作用是
由亲脂的他汀类药物匹伐他汀授予。第二,我们观察到匹伐他汀的ASM松弛作用
通过抑制Rho激酶(ROCK)-1活性、肌球蛋白轻链(MLC)-2磷酸化和F-肌动蛋白而发生
应激纤维,通过MA和香叶基焦磷酸(GGPP)依赖的机制。第三,Pitavastatins‘
-2−激动剂的作用是相加的。第四,与其ASM松弛作用无关,匹伐他汀也抑制ASM。
IL-13诱导的嗜酸性粒细胞趋化因子-3和IL-17/肿瘤坏死因子诱导MA/GGPP产生IL-6和IL-8
依赖机制。最后,在MCH诱导的呼吸道高反应的非炎症性小鼠模型中,
反应性(AHR)、气管内(I.T.)滴入匹伐他汀可抑制48%的支气管收缩。
根据这些发现,我们假设匹伐他汀在气管内给药时可以提供
改善ASM收缩和ASM炎症是治疗支气管收缩的最佳方法。
目的1:研究匹伐他汀对ASM收缩和支气管收缩的抑制作用。
目的2:确定匹伐他汀抑制ASM收缩和炎症的机制。
目的3:探讨哮喘病理生物学因素对匹伐他汀疗效的影响。
长期影响:通过抑制哮喘ASM功能障碍的两个关键特征-收缩和
炎性吸入的匹伐他汀可能优于或加强目前的吸入支气管扩张剂治疗
哮喘的治疗。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Amir A. Zeki其他文献
Amir A. Zeki的其他文献
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{{ truncateString('Amir A. Zeki', 18)}}的其他基金
Reducing Airway Smooth Muscle Tone Using Inhaled Statins
使用吸入他汀类药物降低气道平滑肌张力
- 批准号:
9974238 - 财政年份:2020
- 资助金额:
$ 47.4万 - 项目类别:
Reducing Airway Smooth Muscle Tone Using Inhaled Statins
使用吸入他汀类药物降低气道平滑肌张力
- 批准号:
10161825 - 财政年份:2020
- 资助金额:
$ 47.4万 - 项目类别:
Reducing Airway Smooth Muscle Tone Using Inhaled Statins
使用吸入他汀类药物降低气道平滑肌张力
- 批准号:
10621162 - 财政年份:2020
- 资助金额:
$ 47.4万 - 项目类别:
Statin Lipophilicity as a Determinant of Drug Airway Distribution: A Pilot Study to Identify the Most Potent Statin(s) for the Treatment of Severe Asthma.
他汀类药物的亲脂性是药物气道分布的决定因素:一项旨在确定治疗严重哮喘最有效的他汀类药物的初步研究。
- 批准号:
9900756 - 财政年份:2019
- 资助金额:
$ 47.4万 - 项目类别:
Isoprenoid Biology in Asthma: Proof-of-Principle and Method Development
哮喘中的类异戊二烯生物学:原理验证和方法开发
- 批准号:
9810509 - 财政年份:2019
- 资助金额:
$ 47.4万 - 项目类别:
Isoprenoid Biology in Asthma: Proof-of-Principle and Method Development
哮喘中的类异戊二烯生物学:原理验证和方法开发
- 批准号:
10015331 - 财政年份:2019
- 资助金额:
$ 47.4万 - 项目类别:
The Modulation of Eotaxin Expression by Statins: Implications for Asthma Therapy
他汀类药物对嗜酸细胞活化趋化因子表达的调节:对哮喘治疗的影响
- 批准号:
8991504 - 财政年份:2014
- 资助金额:
$ 47.4万 - 项目类别:
The Modulation of Eotaxin Expression by Statins: Implications for Asthma Therapy
他汀类药物对嗜酸细胞活化趋化因子表达的调节:对哮喘治疗的影响
- 批准号:
8635699 - 财政年份:2014
- 资助金额:
$ 47.4万 - 项目类别:
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