Complement Mediated Remodeling in Pulmonary Vascular Disease

肺动脉高压(PAH)困扰着不同性别和不同年龄的患者，发病率很高。 如果不及时诊断和适当治疗，是致命的。尽管对ITS的理解取得了进展 美国食品和药物管理局批准的14种疗法的发病机制和开发 美国食品和药物管理局(FDA)在过去2-30年里，它仍然与显著的发病率和死亡率有关。这个 PPG的基本前提是PAH在临床参数方面具有高度的异质性，包括 启动因素、临床表现、进展速度和治疗反应。重要的是，病人对- 患者的异质性，涉及肺血管病变的类型和相应的内型(即， 驱动特定疾病表现的潜在分子过程)，我们的团队已经发现 这也是疾病发病机制高度复杂的基础。对这些更广泛的问题的调查很少 异质性的各个方面导致对导致特定亚种的具体因素缺乏了解 多环芳烃的表型--对更有针对性(和个体化)治疗的发展产生负面影响。 这些局限性表现在一些患者依靠目前可用的治疗方法存活了多年- 然而，他们的疾病没有治愈--而另一些人则从发病到移植迅速而无情地进展 或者死亡。这项提议试图揭示与肺血管炎症有关的新的致病过程， 肺血管重构和肺血管病变的分子基础，同时认识到关键 该病的病理和病理生物学异质性。要在此测试的中心前提是 建议早期和持久的局部、肺血管特异性激活补体导联 持续的血管周围炎症和细胞外基质的变化，从而形成前馈 促炎症/促重塑血管周围微环境循环，导致血管病变的发生 pH值这项应用代表着朝着识别新的生物标记物和更有效的方向迈出了重要的一步 个体化治疗，这是非常需要的。

Pulmonary arterial hypertension (PAH) afflicts patients of both sexes and across a broad age range and is highly lethal, if not promptly diagnosed and appropriately treated. Despite advances in the understanding of its pathogenesis and the development of 14 therapies approved by the United States Food and Drug Administration (FDA) over the past 2-3 decades, it continues to be associated with significant morbidity and mortality. The fundamental premise in this PPG is that PAH is highly heterogeneous regarding clinical parameters including initiating factors, clinical presentation, rate of progression, and response to therapy. Importantly, patient-to- patient heterogeneity, involving the types of pulmonary vascular lesions and the corresponding endotypes (i.e., underlying molecular processes driving the specific disease presentation), has been uncovered by our group and underlies the high complexity of disease pathogenesis. The paucity of investigations of these broader aspects of heterogeneity has resulted in a lack of understanding of specific factors contributing to particular sub- phenotypes of PAH – negatively impacting the development of more targeted (and individualized) therapies. These limitations manifest in the fact that some patients live many years on currently available treatments – however without cure of their disease -, while others progress rapidly and inexorably from onset to transplantation or death. This proposal seeks to uncover novel pathogenetic processes linking pulmonary vascular inflammation, remodeling, and molecular underpinnings of pulmonary vascular lesions in PH, while recognizing the key pathological and pathobiological heterogeneity of the disease. The central premise to be tested in this proposal is that early and persistent local, pulmonary vascular-specific activation of complement leads to persistent perivascular inflammation and extracellular matrix changes, thus shaping a feed-forward loop of pro- inflammatory/pro-remodeling perivascular microenvironment, leading to development of PH. This application represents a major step towards identifying new biomarkers and more effective individualized treatments, which are critically needed.