Division of Environmental Medicine, Department of Medicine, New York University Grossman School of Medicine (NYUGSoM), New York, NY 10016, USA.
Division of Pulmonary, Critical Care and Sleep, Department of Medicine, New York University Grossman School of Medicine (NYUGSoM), New York, NY 10016, USA.
Int J Mol Sci. 2023 Jul 25;24(15):11918. doi: 10.3390/ijms241511918.
Pulmonary hypertension (PH) has a high mortality and few treatment options. Adaptive immune mediators of PH in mice challenged with antigen/particulate matter (antigen/PM) has been the focus of our prior work. We identified key roles of type-2- and type-17 responses in C57BL/6 mice. Here, we focused on type-2-response-related cytokines, specifically resistin-like molecule (RELM)α, a critical mediator of hypoxia-induced PH. Because of strain differences in the immune responses to type 2 stimuli, we compared C57BL/6J and BALB/c mice. A model of intraperitoneal antigen sensitization with subsequent, intranasal challenges with antigen/PM (ovalbumin and urban ambient PM) or saline was used in C57BL/6 and BALB/c wild-type or RELMα-/- mice. Vascular remodeling was assessed with histology; right ventricular (RV) pressure, RV weights and cytokines were quantified. Upon challenge with antigen/PM, both C57BL/6 and BALB/c mice developed pulmonary vascular remodeling; these changes were much more prominent in the C57BL/6 strain. Compared to wild-type mice, RELMα-/- had significantly reduced pulmonary vascular remodeling in BALB/c, but not in C57BL/6 mice. RV weights, RV and RV -receptor were significantly increased in BALB/c wild-type mice, but not in BALB/c-RELMα-/- or in C57BL/6-wild-type or C57BL/6-RELMα-/- mice in response to antigen/PM. RV systolic pressures (RVSP) were higher in BALB/c compared to C57BL/6J mice, and RELMα-/- mice were not different from their respective wild-type controls. The RELMα-/- animals demonstrated significantly decreased expression of RELMβ and RELMγ, which makes these mice comparable to a situation where human RELMβ levels would be significantly modified, as only humans have this single RELM molecule. In BALB/c mice, RELMα was a key contributor to pulmonary vascular remodeling, increase in RV weight and RV cytokine responses induced by exposure to antigen/PM, highlighting the significance of the genetic background for the biological role of RELMα.
肺动脉高压（PH）死亡率高，治疗选择有限。我们之前的工作重点是研究在抗原/颗粒物（antigen/PM）刺激的小鼠中，适应性免疫介质对 PH 的影响。我们在 C57BL/6 小鼠中发现了 2 型和 17 型反应的关键作用。在这里，我们专注于 2 型反应相关的细胞因子，特别是抵抗素样分子（RELM）α，它是缺氧诱导 PH 的关键介质。由于对 2 型刺激的免疫反应存在品系差异，我们比较了 C57BL/6J 和 BALB/c 小鼠。使用腹腔内抗原致敏，随后用抗原/PM（卵清蛋白和城市环境 PM）或生理盐水进行鼻腔内挑战的模型，在 C57BL/6 和 BALB/c 野生型或 RELMα-/- 小鼠中进行。通过组织学评估血管重塑；右心室（RV）压力、RV 重量和细胞因子进行定量。在抗原/PM 挑战后，C57BL/6 和 BALB/c 小鼠均发生肺血管重塑；C57BL/6 品系的变化更为明显。与野生型小鼠相比，RELMα-/- 小鼠的 BALB/c 肺部血管重塑明显减少，但在 C57BL/6 小鼠中没有减少。BALB/c 野生型小鼠的 RV 重量、RV 和 RV 受体在抗原/PM 刺激后显著增加，但 BALB/c-RELMα-/-或 C57BL/6-野生型或 C57BL/6-RELMα-/-小鼠则没有增加。与 C57BL/6J 小鼠相比，BALB/c 小鼠的 RV 收缩压（RVSP）更高，而 RELMα-/- 小鼠与其相应的野生型对照没有差异。RELMα-/- 动物的 RELMβ 和 RELMγ 表达明显减少，这使得这些小鼠与人类 RELMβ 水平发生显著改变的情况相当，因为只有人类才有这种单一的 RELM 分子。在 BALB/c 小鼠中，RELMα 是抗原/PM 暴露诱导的肺血管重塑、RV 重量增加和 RV 细胞因子反应的关键因素，这突显了遗传背景对 RELMα 生物学作用的重要性。
