Development of therapeutics for chlorine-induced airway and lung injury

描述（由申请人提供）：人体吸入氯气和其他有毒气体会导致几种急性和慢性呼吸系统异常，包括急性肺损伤（ALI）、反应性气道功能障碍综合征（RADS）和气道腔内纤维化（AIF）。目前还没有已知的治疗方法来预防化学品吸入后这些疾病的发展。在AIF的情况下，在理解管腔内纤维化病变如何刺激和发展方面也存在根本性的差距。我们在此次更新申请中的目标是制定医疗对策，以防止在氯暴露后给药时发生ALI、RADS和AIF。该建议的中心假设是：1）化学诱导的ALI和RADS可以通过暴露后给予iNOS抑制剂GW 274150来预防; 2）化学诱导的AIF可以通过抑制特异性受体酪氨酸激酶信号传导途径来预防; 3）暴露后气道上皮修复可以通过用抗肿瘤药物刺激气道上皮干细胞的存活和增殖来增强。这些假设是基于在前一个U01奖项的3年期间产生的强有力的初步数据，并将在三个具体目标中进行测试：1）开发GW 274150作为氯诱导的ALI和RADS的人类治疗剂，2）鉴定特异性酪氨酸激酶抑制剂，其防止导致急性肺损伤的间充质细胞增殖、血管生成和纤维化。 AIF，和3）鉴定促进上皮stm细胞存活和增殖的现有药物。在第一个目标中，GW 274150是一种特异性iNOS抑制剂，已经在III期人体临床试验中测试了其他适应症，将在小鼠和试验性大型动物中进行氯诱导的ALI和RADS的疗效研究。如果证明有效，则将对GW 274150进行监管批准所需的额外研究，包括收集药代动力学和毒性数据、使用当前药品生产质量管理规范生产GW 274150以及确定性大型动物疗效研究。一旦完成，将根据FDA动物规则寻求批准GW 274150用于人用。在第二个目标中，已经在原理验证研究中验证的抑制特异性酪氨酸激酶信号传导途径的策略将通过确定特异性酪氨酸激酶抑制剂在氯诱导的AIF的新型鼠模型中的功效而转化为临床效用。在第三个目标中，刺激上皮干细胞增殖和分化的候选治疗剂将在小分子和FDA批准的药物的新的体外筛选中鉴定B。将对已经鉴定的两种化合物以及沿着的其他命中物进行验证和有效性测试 在上皮细胞修复的小鼠模型中。拟议研究的成功完成将导致FDA批准的第一种治疗氯诱导的ALI和RADS的疗法，第一种治疗氯诱导的AIF的临床前验证，以及识别刺激化学吸入后上皮再生的现有药物。 公共卫生相关性：拟议的研究与公共卫生有关，因为确定和开发治疗化学品引起的肺损伤的疗法将显着改善通过意外或故意释放暴露于高毒性化学品的个人的健康和福祉。因此，拟议中的研究与NIH的使命有关，即促进疾病的治疗，使个人能够活得更长，更充实的生活。

DESCRIPTION (provided by applicant): Human inhalation of chlorine and other toxic gasses leads to several acute and chronic respiratory abnormalities including Acute Lung Injury (ALI), Reactive Airways Dysfunction Syndrome (RADS), and Airway Intraluminal Fibrosis (AIF). There is currently no known therapy to prevent the development of these disorders after chemical inhalation. In the case of AIF, there is also a fundamental gap in understanding how intraluminal fibrotic lesions are stimulated and develop. Our objective in this renewal application is to develop medical counter-measures that will prevent the development of ALI, RADS, and AIF when administered after chlorine exposure. The central hypotheses of this proposal are that 1) chemical-induced ALI and RADS can be prevented by post-exposure administration of the iNOS inhibitor GW274150; 2) chemical-induced AIF can be prevented by inhibiting specific receptor tyrosine kinase signaling pathways; and 3) post-exposure airway epithelial repair can be enhanced by stimulating the survival and proliferation of airway epithelial stem cells with existin drugs. These hypotheses are based on strong preliminary data generated during the 3 years of a previous U01 award and will be tested in three specific aims: 1) to develop GW274150 as a human therapeutic for chlorine induced ALI and RADS, 2) to identify specific tyrosine kinase inhibitors that prevent the mesenchymal cell proliferation, angiogenesis, and fibrosis that lead to AIF, and 3) to identify existing drugs that promote the survival and proliferation of epithelial stm cells. In the first aim, GW274150, a specific iNOS inhibitor that has already been tested in phase III human clinical trials for other indications, will be examined in murine and pilot large animal efficacy stuidies of chlorine-induced ALI and RADS. If proven efficacious, GW274150 will be subjected to additional studies necessary for regulatory approval, including collection of pharmacokinetic and toxicity data, production of GW274150 using current good manufacturing practices, and definitive large animal efficacy studies. Once completed, approval of GW274150 for human use will be sought under the FDA animal rule. In the second aim, the strategy of inhibiting specific tyrosine kinase signaling pathways, which has already been validated in proof-of-principle studies, will be translated to clinical utility by determining the efficacy of specifi tyrosine kinase inhibitors in a novel murine model of chlorine-induced AIF. In the third aim, candidate therapeutics that stimulate epithelial stem cell proliferation and differentiation will b identified in a novel in vitro screen of small molecules and FDA approved drugs. Two compounds already identified, along with additional hits, will be validated and tested for efficacy in a murine model of epithelial cell repair. The successful completion of the proposed studies will result in the first FDA-approved therapy for chlorine-induced ALI and RADS, preclinical validation of the first therapy for chlorine-induced AIF, and the identification of existing drugs that stimulate epithelial regeneration after chemical inhalation. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because identifying and developing therapeutics to treat chemical-induced lung injury will markedly improve the health and well being of individuals exposed to highly toxic chemicals via accidental or intentional release. The proposed research is thus relevant to the NIH's mission of promoting the treatment of disease so that individuals can live longer and more fulfilling lives.