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
• 负责人: Amir A. Zeki
• 金额: $ 46.99万
• 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/10621162
• 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; Geranylgeranyl-diphosphate geranylgeranyltransferase; 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; Phosphorylation; Phosphotransferases; Plasma; Predisposition; Production; Proliferating; Property; Proteins; Relaxation; Rho-associated kinase; Role; Slice; Smooth Muscle Myocytes; Stress Fibers; Stretching; Structure of parenchyma of lung; Symptoms; Treatment Efficacy; airway hyperresponsiveness; airway inflammation; airway remodeling; asthma exacerbation; asthmatic; constriction; cysteinyl leukotriene receptor; cytokine; desensitization; disabling symptom; empowerment; experimental study; geranylgeranyl pyrophosphate; hydrophilicity; inhibitor; knock-down; lipophilicity; methacholine; mevalonate; mouse model; myosin light chain 2; neonatal mice; optimal treatments; pharmacologic; 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.

项目概要 在哮喘恶化期间，呼吸困难的衰弱症状很大程度上是由气道通畅引起的 为了放松 ASM，目前的治疗方法要么是对抗促收缩。 ASM 受体（例如毒蕈碱拮抗剂、半胱氨酰白三烯受体拮抗剂）或激活亲 松弛剂 ASM 受体（例如 2 激动剂）尽管广泛使用，但这些疗法在治疗中仍然不足。 控制症状，而不是针对复杂、间接的受体介导的途径。 容易受到脱敏的影响，我们的关键前提是治疗哮喘的更强有力的策略是直接 瞄准 ASM 收缩装置 为了破坏 ASM 收缩装置，我们发现了一个 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 首先，我们使用人类 ASM 细胞和人类精密切割肺切片 (PCLS)。 观察到他汀类药物可抑制基础、组胺和乙酰甲胆碱 (MCh) 诱导的 ASM 收缩，根据 它们的理化特性（即亲脂性与亲水性他汀类药物），最明显的效果是 其次，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-肌动蛋白来发生 第三，匹伐他汀通过 MA 和香叶基香叶基焦磷酸 (GGPP) 依赖性机制。 第四，与 ASM 松弛作用无关，匹伐他汀也能抑制 ASM。 MA/GGPP- 的增殖、IL13 诱导的嗜酸细胞活化趋化因子 3 和 IL17/TNFα 诱导的 IL6 和 IL8 产生 最后，在 MCh 诱导的气道亢进的非炎症小鼠模型中。 根据反应性 (AHR)，气管内 (i.t.) 滴注匹伐他汀可抑制支气管收缩 48%。 受这些发现的支持，我们勇敢地说匹伐他汀在气管内给药时可以提供 通过改善 ASM 收缩和 ASM 炎症来实现支气管收缩的最佳治疗。 目标 1：确定匹伐他汀抑制 ASM 收缩和支气管收缩的潜力。 目标 2：确定匹伐他汀抑制 ASM 收缩和炎症的机制。 目标 3：检查哮喘病理学对匹伐他汀治疗效果的影响。 长期影响：通过抑制哮喘 ASM 功能障碍的两个关键特征——收缩和收缩 炎症 – 吸入匹伐他汀可能优于或增强目前的吸入支气管扩张剂疗法 哮喘的治疗。