Posey Janelle N, Jordan Mariah, Lewis Caitlin V, Sul Christina, Dobrinskikh Evgenia, Swindle Delaney, Denorme Frederik, Irwin David, Di Paola Jorge, Stenmark Kurt, Nozik Eva S, Delaney Cassidy
Cardiovascular Pulmonary Research Laboratory, University of Colorado Anschutz Medical Campus, Aurora, CO.
Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO.
Blood Adv. 2025 Apr 8;9(7):1571-1584. doi: 10.1182/bloodadvances.2024013880.
Inflammation drives the initiation and progression of pulmonary hypertension (PH). Platelets, increasingly recognized as immune cells, are activated and increased in the lungs of patients with PH. Platelet activation leads to the release of α-granule chemokines, many of which are implicated in PH. We hypothesized that hypoxia-induced secretion of platelet α-granule-stored proteins and PH would be prevented in Neurobeachin-like 2 knockout (Nbeal2-/-) α-granule-deficient mice. Wild-type (WT) and Nbeal2-/- mice were maintained in normoxia or exposed to 10% hypobaric hypoxia for 3, 14, 21, or 35 days. We observed macrothrombocytopenia, increased circulating neutrophils and monocytes, and increased lung interstitial macrophages (IMs) in Nbeal2-/- mice at baseline. Hypoxia-induced platelet activation was attenuated, and hypoxia-induced increase in lung platelet factor 4 (PF4) and platelets was delayed in Nbeal2-/- mice compared with in WT mice. Finally, although pulmonary vascular remodeling (PVR) and PH were attenuated at day 21, Nbeal2-/- mice were not protected against hypoxia-induced PVR and PH at day 35. Although this mutation also affected circulating monocytes, neutrophils, and lung IMs, all of which are critical in the development of experimental PH, we gained further support for the role of platelets and α-granule proteins, such as PF4, in PH progression and pathogenesis and made several observations that expand our understanding of α-granule-deficient mice in chronic hypoxia.
炎症驱动肺动脉高压（PH）的发生和发展。血小板越来越被认为是免疫细胞，在PH患者的肺部被激活且数量增加。血小板激活导致α-颗粒趋化因子的释放，其中许多与PH有关。我们假设，在缺乏α-颗粒的类神经海滩蛋白2基因敲除（Nbeal2-/-）小鼠中，缺氧诱导的血小板α-颗粒储存蛋白的分泌和PH将得到预防。将野生型（WT）和Nbeal2-/-小鼠置于常氧环境中或暴露于10%的低压缺氧环境中3天、14天、21天或35天。我们观察到，在基线时，Nbeal2-/-小鼠存在大血小板减少、循环中性粒细胞和单核细胞增加以及肺间质巨噬细胞（IM）增加。与WT小鼠相比，Nbeal2-/-小鼠中缺氧诱导的血小板激活减弱，缺氧诱导的肺血小板因子4（PF4）和血小板增加延迟。最后，尽管在第21天时肺血管重塑（PVR）和PH有所减轻，但在第35天时，Nbeal2-/-小鼠并未免受缺氧诱导的PVR和PH的影响。尽管这种突变也影响循环单核细胞、中性粒细胞和肺IM，所有这些在实验性PH的发展中都至关重要，但我们进一步支持了血小板和α-颗粒蛋白（如PF4）在PH进展和发病机制中的作用，并得出了一些观察结果，扩展了我们对慢性缺氧条件下α-颗粒缺陷小鼠的理解。
