Inducible HMGB1 antagonist for viral-induced acute lung injury.

十多年来，我们的工作重点是开发针对病毒和 细菌引起的急性肺损伤（ALI）和更严重的急性呼吸窘迫综合征（ARDS）。 值得注意的是，我们鉴定了Toll样受体4（TLR 4）信号通路作为宿主对Toll样受体4的应答的关键。 流感和流感后继发细菌感染。我们还确定了高迁移率组箱1 HMGB 1是一种宿主来源的“高迁移率相关分子模式”（DAMP），作为疾病严重程度的生物标志物， 多种呼吸道病毒，并在因严重呼吸道感染住院的患者血清中检测到水平大大升高。 流感和SARS-CoV-2感染。重要的是，我们的数据表明，HMGB 1是一个中央调解人， 流感引起的呼吸道疾病，通过刺激TLR 4/MD-2引起有效的炎症反应， 与ALI/ARDS相关的反应。TLR 4拮抗剂（例如，科洛尼亚和许多 其他）以及小分子HMGB 1拮抗剂，可减轻危及生命的肺部表现 急性肺损伤（ALI）和致死性的临床前啮齿动物模型。确定这些有前途的 治疗靶点的研究使我们提出了一个中心假设，即我们的发现可能适用于其他ALI， 诱导剂事实上，自从我们最早报道了TLR 4拮抗剂阿托莫兰在流感中的疗效以来， 在小鼠和棉鼠中诱导疾病（Sigmodon hispidus，一种独特地对非适应性疾病易感的物种， 人类病毒），该试剂已被报道在埃博拉病毒和登革热病毒的动物模型中减弱疾病， 导致细胞因子和趋化因子产生的减少和疾病症状的减轻。鉴于临床 SARS-CoV-2大流行暴露的ALI和ARDS的相关性，以及 流感和SARS-Cov-2诱导的由细胞因子风暴引起的ALI/ARDS之间的关系， 稳态，并最终导致多器官衰竭和死亡，我们建议，作为第一阶段STTR的中心目标， 为了评估我们新开发的，炎症诱导的，腺病毒载体编码 HMGB 1拮抗剂，“HMGB 1 Box A”，以减轻严重的流感诱导的炎症。我们将测试 我们在LPS诱导的肺部炎症和小鼠适应性流感的小鼠模型中的干预效果 感染，以及用非适应性人流感病毒株攻击的棉鼠，我们已经将其与 HMGB 1水平与疾病严重程度相关。我们预测，我们的创新战略将提供一种新的方法， 治疗由多种非感染性和感染性因子介导的炎性肺病， 引起ALI/ARDS。

For more than a decade, our work has focused on development of therapeutic interventions for viral- and bacterial-induced acute lung injury (ALI) and the more severe acute respiratory distress syndrome (ARDS). Significantly, we identified the Toll-like receptor 4 (TLR4) signaling pathway as key to the host response to influenza and secondary bacterial infection following influenza. We also identified High Mobility Group Box 1 (HMGB1), a host-derived “danger-associated molecular pattern” (DAMP), as a biomarker of disease severity for multiple respiratory viruses and detected greatly elevated levels in sera from patients hospitalized for severe influenza and SARS-CoV-2 infections. Importantly, our data indicate that HMGB1 is a central mediator of influenza-induced respiratory disease that acts by stimulating TLR4/MD-2 to elicit the potent inflammatory response associated with ALI/ARDS. Therapeutic administration of TLR4 antagonists (e.g., Eritoran and many others), as well as small molecule HMGB1 antagonists, mitigate the life-threatening pulmonary manifestations of acute lung injury (ALI) and lethality in preclinical rodent models. The identification of these promising therapeutic targets has led us to the central hypothesis that our findings may well be applicable to other ALI- inducing agents. Indeed, since our earliest reports of the efficacy of the TLR4 antagonist, Eritoran, in influenza- induced disease in both mice and cotton rats (Sigmodon hispidus, a species uniquely susceptible to non-adapted human viruses), this agent has been reported to blunt disease in animal models of Ebola virus and Dengue virus, leading to a reduction in cytokine and chemokine production and reduced disease symptoms. Given the clinical relevance of ALI and ARDS that has been exposed by the SARS-CoV-2 pandemic, and the striking similarities between influenza- and SARS-Cov-2-induced ALI/ARDS caused by a cytokine storm leading to loss of homeostasis and, ultimately, multiorgan failure and death, we propose, as the central goal of this phase I STTR, to evaluate the therapeutic efficacy of our newly developed, inflammation-inducible, adenoviral vector encoding the HMGB1 antagonist, “HMGB1 Box A,” to ameliorate severe influenza-induced inflammation. We will test the efficacy of our intervention in murine models of LPS-induced lung inflammation and mouse-adapted influenza infection, and in cotton rats challenged with non-adapted human influenza strains for which we have correlated HMGB1 levels with disease severity. We predict that our innovative strategy will provide a novel approach to treatment of inflammatory lung disease that is mediated by multiple non-infectious and infectious agents that cause ALI/ARDS.