New Therapeutic Targets in Idiopathic Pulmonary Fibrosis Aiming to Rein in Runaway Wound-Healing Responses
New Therapeutic Targets in Idiopathic Pulmonary Fibrosis Aiming to Rein in Runaway Wound-Healing Responses
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DOI：
10.1164/rccm.201403-0509pp
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发表时间：
2014-10-15
影响因子：
24.7
通讯作者：
Tager, Andrew M.
中科院分区：
文献类型：
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作者：
Ahluwalia, Neil;Shea, Barry S.;Tager, Andrew M.
特发性肺纤维化（IPF）是一种毁灭性疾病，自诊断之日起中位生存期短至3年，且美国食品和药物管理局尚未批准药物治疗。为了解决对有效的特发性肺纤维化治疗的巨大未满足的需求，许多新药最近已经或正在进行临床试验评估。大多数这些治疗候选药物的理论基础是基于IPF发病机制的当前范式，其中认为肺泡上皮的复发性损伤驱动异常伤口愈合反应，导致纤维化而不是修复。在这里，我们讨论了最近完成或目前正在进行的II期和III期IPF临床试验中的药物，这些药物的假定作用机制和异常修复过程被认为是靶向的：先天免疫激活和极化，成纤维细胞蓄积和肌成纤维细胞分化，或细胞外基质沉积和硬化。在这种情况下，最近完成的吡非尼酮和尼达尼布试验的积极结果，以及正在进行的其他药物试验的结果，除了为IPF患者提供获益外，还应提供对该疾病仍然神秘的发病机制的有价值的见解。
Idiopathic pulmonary fibrosis (IPF) is a devastating disease, with a median survival as short as 3 years from the time of diagnosis and no pharmacological therapies yet approved by the U.S. Food and Drug Administration. To address the great unmet need for effective IPF therapy, a number of new drugs have recently been, or are now being, evaluated in clinical trials. The rationales for most of these therapeutic candidates are based on the current paradigm of IPF pathogenesis, in which recurrent injury to the alveolar epithelium is believed to drive aberrant wound healing responses, resulting in fibrosis rather than repair. Here we discuss drugs in recently completed or currently ongoing phase II and III IPF clinical trials in the context of their putative mechanisms of action and the aberrant repair processes they are believed to target: innate immune activation and polarization, fibroblast accumulation and myofibroblast differentiation, or extracellular matrix deposition and stiffening. Placed in this context, the positive results of recently completed trials of pirfenidone and nintedanib, and results that will come from ongoing trials of other agents, should provide valuable insights into the still-enigmatic pathogenesis of this disease, in addition to providing benefits to patients with IPF.