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
• 负责人: Amir A. Zeki
• 金额: $ 48.24万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10161825
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Actins; Address; Adult; Agonist; Asthma; Bronchoalveolar Lavage; Bronchoconstriction; Bronchodilator Agents; CCL26 gene; Cells; Chronic; Coenzyme A; Complex; Cytoskeletal Proteins; Disease model; Dyspnea; F-Actin; Functional disorder; Gene Silencing; Genes; Goals; Histamine; House Dust Mite Allergens; Human; IL17 gene; IL6 gene; IL8 gene; Inflammation; Inhalation; Interleukin-13; Leukotriene Antagonists; Lung; Mass Spectrum Analysis; Measurement; Measures; Mediating; Methods; Mus; Muscarinic Antagonists; Muscle Contraction; Muscle Tonus; Muscle relaxation phase; Myosin Light Chains; Oxidoreductase; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Phosphotransferases; Plasma; Production; Property; Proteins; Rho-associated kinase; Role; Slice; Smooth Muscle Myocytes; Stress Fibers; Stretching; Structure of parenchyma of lung; Symptoms; TNF gene; Treatment Efficacy; airway hyperresponsiveness; airway inflammation; airway remodeling; asthma exacerbation; asthmatic; cell immortalization; cysteinyl leukotriene receptor; cytokine; desensitization; disabling symptom; empowered; experimental study; hydrophilicity; inhibitor/antagonist; knock-down; lipophilicity; methacholine; mevalonate; mouse model; myosin light chain 2; neonatal mice; optimal treatments; rab GTP-Binding Proteins; receptor; respiratory smooth muscle; small hairpin RNA; transcription factor; transcriptome sequencing

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.

项目摘要 在哮喘恶化期间，气道的呼吸症状令人衰弱 肌肉（ASM）收缩。为了放松ASM，当前的疗法是针对拮抗取包的 ASM受体（例如毒蕈碱拮抗剂，白细胞三烯受体）或激活促促促血液 松弛剂ASM受体（例如2激动剂）。尽管使用了宽度，但这些疗法仍然不足 控制符号。而不是针对复杂，间接和的接收器介导的途径 容易脱敏的前提是，治疗哮喘的更强大的策略是直接 针对ASM收缩设备。为了破坏ASM收缩设备，我们发现了一个 在3-羟基-3-甲基戊二酰辅酶A降低酶（HMGCR）抑制剂“汀类药物”中引人入胜的动作 Mevalonate（MA）途径。首先，使用人ASM细胞和人类精确切割肺切片（PCL），我们 观察到他汀类药物抑制了基础，组胺和方法氨（MCH）诱导的ASM收缩 它们的理化特性（即亲水性汀类药物），最明显的作用是 由亲脂性他汀类药物Pitavastatin授予。其次，我们观察到pitavastatin的ASM - 雷克斯效应 通过抑制Rho激酶（岩石）-1活性，肌球蛋白轻链（MLC）-2磷酸化和F-肌动蛋白发生。 应力纤维，通过Ma-和geranylgeranylylophophate（GGPP）依赖性机制。第三，pitavastatins的 效果被添加到2激动剂中。第四，独立于其ASM - 雷克斯效应，pitavastatin也抑制ASM 增殖，IL13诱导的Eotaxin-3和IL17/TNF诱导的IL6和IL8产生。 依赖机制。最后，在MCH诱导的气道高音的非炎性小鼠模型中 反应性（AHR），气管内（I.T.）对pitavastatin的滴注抑制了48％的支气管收缩。 在这些发现的授权下，我们假设pitavastatin在气管内交付时可以提供 通过改善ASM收缩和ASM注射，可用于支气管收缩的最佳治疗。 目标1：确定pitavastatin抑制ASM收缩和支气管收缩的潜力。 目标2：确定pitavastatin抑制ASM收缩和炎症的机制。 目标3：检查哮喘病理生物学对pitavastatin疗法有效性的影响。 长期影响：通过抑制ASM功能障碍的两个关键标志特征 - 收缩和 炎症 - 遗传的pitavastatin可能优于或增强电流掺入的支气管扩张剂疗法 哮喘的治疗。