JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers.
JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers.
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DOI：
10.1186/s40169-016-0117-2
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发表时间：
2016-12
影响因子：
10.6
通讯作者：
Schafer PH
中科院分区：
文献类型：
--
作者：
van der Velden JL;Ye Y;Nolin JD;Hoffman SM;Chapman DG;Lahue KG;Abdalla S;Chen P;Liu Y;Bennett B;Khalil N;Sutherland D;Smith W;Horan G;Assaf M;Horowitz Z;Chopra R;Stevens RM;Palmisano M;Janssen-Heininger YM;Schafer PH
肺重塑和肺纤维化是由慢性重度哮喘和特发性肺纤维化（IPF）等疾病引起的严重、危及生命的疾病。临床前证据表明，JNK酶功能是肺纤维化过程中关键步骤所必需的。然而，尚未在具有临床相关生物标志物的肺纤维化转化模型或IPF患者中研究选择性JNK抑制剂。JNK抑制剂CC-930在室内尘螨诱导的纤维化气道小鼠模型中、在I期健康志愿者药效学研究中以及随后在轻度/中度IPF（n = 28）的II期多中心研究中进行评估，具有4周、安慰剂对照、双盲、顺序递增剂量期（50 mg QD、100 mg QD、100 mg BID）和52周开放标签治疗扩展期。在临床前模型中，CC-930减弱胶原1A1基因表达、支气管周围胶原沉积、棒状细胞中气道粘蛋白MUC5B表达以及肺、支气管肺泡灌洗液和血清中MMP-7表达。在I期研究中，CC-930减少了皮肤中由UV辐射诱导的c-Jun磷酸化。在II期IPF研究中，MMP-7和SP-D血浆蛋白水平降低存在CC-930剂量依赖性趋势。最常报告的不良事件为ALT升高、AST升高和上呼吸道感染（各6例受试者，21.4%）。共有13例受试者（46.4%）发生导致研究药物停药的不良事件。在本研究中，28例受试者中有9例发生疾病进展。在100 mg QD和100 mg BID剂量下，26 - 32周后平均FVC（%预测值）下降。MMP-7、SP-D和腱生蛋白-C的变化与FVC（%预测值）的变化显著相关。这些结果说明JNK酶活性参与肺纤维化，并支持全身生物标志物用于跟踪疾病进展和这种新型干预措施在IPF中的潜在临床获益。试用注册www.example.com NCT01203943本文的在线版本（doi：10.1186/s40169 - 016 - 0117 - 2）包含补充材料，可供授权用户使用。
Lung remodeling and pulmonary fibrosis are serious, life-threatening conditions resulting from diseases such as chronic severe asthma and idiopathic pulmonary fibrosis (IPF). Preclinical evidence suggests that JNK enzyme function is required for key steps in the pulmonary fibrotic process. However, a selective JNK inhibitor has not been investigated in translational models of lung fibrosis with clinically relevant biomarkers, or in IPF patients. The JNK inhibitor CC-930 was evaluated in the house dust mite-induced fibrotic airway mouse model, in a phase I healthy volunteer pharmacodynamic study, and subsequently in a phase II multicenter study of mild/moderate IPF (n = 28), with a 4-week, placebo-controlled, double-blind, sequential ascending-dose period (50 mg QD, 100 mg QD, 100 mg BID) and a 52-week open-label treatment-extension period. In the preclinical model, CC-930 attenuated collagen 1A1 gene expression, peribronchiolar collagen deposition, airway mucin MUC5B expression in club cells, and MMP-7 expression in lung, bronchoalveolar lavage fluid, and serum. In the phase I study, CC-930 reduced c-Jun phosphorylation induced by UV radiation in skin. In the phase II IPF study, there was a CC-930 dose-dependent trend in reduction of MMP-7 and SP-D plasma protein levels. The most commonly reported adverse events were increased ALT, increased AST, and upper respiratory tract infection (six subjects each, 21.4 %). A total of 13 subjects (46.4 %) experienced adverse events that led to discontinuation of study drug. Nine out of 28 subjects experienced progressive disease in this study. The mean FVC (% predicted) declined after 26–32 weeks at doses of 100 mg QD and 100 mg BID. Changes in MMP-7, SP-D, and tenascin-C significantly correlated with change in FVC (% predicted). These results illustrate JNK enzymatic activity involvement during pulmonary fibrosis, and support systemic biomarker use for tracking disease progression and the potential clinical benefit of this novel intervention in IPF. Trial registration ClinicalTrials.gov NCT01203943 The online version of this article (doi:10.1186/s40169-016-0117-2) contains supplementary material, which is available to authorized users.