Noradrenergic mechanisms of IPF

摘要 伴随多种情况的肺纤维化以进行性瘢痕形成为特征。 成人肺。不管潜在的疾病状态如何，这种并发症的出现预示着 只有通过肺移植才能治愈的更糟糕的结果。已提出的致病机制表明 了解上皮细胞和成纤维细胞之间的相互作用，这是由微环境线索协调的。 了解纤维化微环境中的这些方面在疾病中尤其重要，例如 特发性肺纤维化(IPF)，患者既有且常为进展性疾病。AS 因此，确定可用于安全和有效治疗的可干预过程仍然是一个 严重的未得到满足的需求。因此，在一系列开创性的研究中，我们发现纤维化 肺中富含异位模式的肾上腺素能神经，这些神经通过释放NA来推动纤维化， NA引起的纤维化可以用α-1肾上腺素受体拮抗剂治疗。此轴活跃于IPF所在肺区 组织中肾上腺素能神经支配和NA的标志物丰富，患者接受α1肾上腺素受体治疗 拮抗剂可以改善临床结果。我们现在将确定NA在纤维化中是如何积聚的 并定义其致纤维化功能。例如，虽然我们发现肾上腺素能神经重塑 在结直肠癌中被缺失的依赖受体刺激，其机制(S) 观察是未知的。我们发现纤维化的肺巨噬细胞缺乏NA分解代谢。 但它们是否通过扰乱NA循环而导致纤维化尚未得到证实。最后，我们 已发现纤维化患者成纤维细胞增殖与α-1肾上腺素受体亚型ADRA1D有关 在小鼠模型和人类IPF中，这需要更多的研究。这个应用程序将探索机械影响 使用统一的视野和概念框架研究这些发现的治疗潜力 神经源性NA在肺内积聚，导致纤维化。我们提出了一个综合项目，以追求 三个独立的目标使用一个翻译平台结合两个动物模型，操作肾上腺素能 神经、神经工程、细胞特异性基因敲除小鼠、遗传和药理学上的得失 方法、人体细胞和组织的体外研究、单细胞测序和微CT。第一个目标是 探讨肾上腺素能神经重塑和纤维刺激性NA蓄积是否需要表达 结直肠癌(DCC)依赖受体缺失依赖于肺内肾上腺素能神经。第二个目标 将确定巨噬细胞干扰的NA循环是否会加剧动物模型和人类的纤维化 细胞和组织。第三个目标将使用细胞特异性基因敲除小鼠和原代人类细胞和组织来 确定NA相关的肺纤维化需要ADRA1D表达的成纤维细胞。如果成功，我们的项目 将产生范式转变的结果，将改变我们看待-和治疗-成人肺纤维化的方式。

ABSTRACT The pulmonary fibrosis that accompanies many conditions is characterized by progressive scar formation in the adult human lung. Regardless of the underlying disease state, the presence of this complication portends a worse outcome that is curable only by lung transplantation. Proposed pathogenic mechanisms suggest a poorly understood interaction between epithelial cells and fibroblasts that is orchestrated by microenvironmental cues. Understanding these aspects in the fibrotic microenvironment is of particular importance in diseases such as Idiopathic Pulmonary Fibrosis (IPF) where patients present with established and often progressive disease. As a result, identification of intervenable processes that can be targeted for safe and effective therapies remains a critical unmet need. It is therefore relevant that in a groundbreaking set of studies we have found that fibrotic lungs are enriched for ectopically patterned adrenergic nerves, that these nerves drive fibrosis by releasing NA, that NA driven fibrosis can be treated with α1 adrenoreceptor antagonists. This axis is active in IPF where lung tissues are enriched for markers of adrenergic innervation and NA, and patients treated with α1 adrenoreceptor antagonists experience improved clinical outcomes. We will now determine how NA accumulates in fibrotic lungs and define its fibrogenic functions. For example, while we have found that adrenergic nerve remodeling is stimulated by the dependence receptor deleted in colorectal carcinoma (DCC), the mechanism(s) of this observation are unknown. We have found that fibrotic lung macrophages are deficient in NA catabolism machinery, but whether they contribute to fibrosis via perturbed NA recycling has not been shown. Finally, we have found an association between fibroblast proliferation and α1 adrenoreceptor subtype ADRA1D in fibrotic mouse models and in human IPF that requires more study. This application will explore the mechanistic impact and therapeutic potential of these findings using a unified vision and conceptual framework that will study how nerve-derived NA accumulates in the lung and causes fibrosis. We propose an integrated project that pursues three independent aims using a translational platform combining two animal models, manipulation of adrenergic nerves, neuroengineering, cell specific knockout mice, genetic and pharmacologic gain and loss of function approaches, ex vivo study of human cells and tissues, single cell sequencing, and microCT. The first aim will probe whether adrenergic nerve remodeling and accumulation of fibrostimulatory NA requires expression of the dependence receptor deleted in colorectal carcinoma (DCC) on adrenergic nerves in the lung. The second aim will determine if perturbed NA recycling by macrophages exacerbates fibrosis in animal models and in human cells and tissues. The third aim will use cell specific knockout mice and primary human cells and tissues to determine wither NA-associated lung fibrosis requires ADRA1D-expressing fibroblasts. If successful, our project will produce paradigm shifting results that will change the way we view – and treat – fibrosis in the adult lung.