Department of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Front Immunol. 2023 Mar 13;14:1126574. doi: 10.3389/fimmu.2023.1126574. eCollection 2023.
Ozone and bacterial lipopolysaccharide (LPS) are common air pollutants that are related to high hospital admissions due to airway hyperreactivity and increased susceptibility to infections, especially in children, older population and individuals with underlying conditions. We modeled acute lung inflammation (ALI) by exposing 6-8 week old male mice to 0.005 ppm ozone for 2 h followed by 50 μg of intranasal LPS. We compared the immunomodulatory effects of single dose pre-treatment with CD61 blocking antibody (clone 2C9.G2), ATPase inhibitor BTB06584 against propranolol as the immune-stimulant and dexamethasone as the immune-suppressant in the ALI model. Ozone and LPS exposure induced lung neutrophil and eosinophil recruitment as measured by respective peroxidase (MPO and EPX) assays, systemic leukopenia, increased levels of lung vascular neutrophil regulatory chemokines such as CXCL5, SDF-1, CXCL13 and a decrease in immune-regulatory chemokines such as BAL IL-10 and CCL27. While CD61 blocking antibody and BTB06584 produced maximum increase in BAL leukocyte counts, protein content and BAL chemokines, these treatments induced moderate increase in lung MPO and EPX content. CD61 blocking antibody induced maximal BAL cell death, a markedly punctate distribution of NK1.1, CX3CR1, CD61. BTB06584 preserved BAL cell viability with cytosolic and membrane distribution of Gr1 and CX3CR1. Propranolol attenuated BAL protein, protected against BAL cell death, induced polarized distribution of NK1.1, CX3CR1 and CD61 but presented with high lung EPX. Dexamethasone induced sparse cell membrane distribution of CX3CR1 and CD61 on BAL cells and displayed very low lung MPO and EPX levels despite highest levels of BAL chemokines. Our study unravels ATPase inhibitor IF1 as a novel drug target for lung injury.
臭氧和细菌脂多糖（LPS）是常见的空气污染物，它们与气道高反应性和感染易感性增加有关，尤其是在儿童、老年人和有潜在疾病的人群中。我们通过使 6-8 周龄雄性小鼠暴露于 0.005 ppm 臭氧 2 小时，然后用 50 μg 鼻内 LPS 来模拟急性肺炎症（ALI）。我们比较了单次预先用 CD61 阻断抗体（克隆 2C9.G2）、ATP 酶抑制剂 BTB06584 与普萘洛尔（作为免疫刺激剂）和地塞米松（作为免疫抑制剂）在 ALI 模型中的免疫调节作用。臭氧和 LPS 暴露诱导肺中性粒细胞和嗜酸性粒细胞募集，分别通过过氧化物酶（MPO 和 EPX）测定法进行测量，引起全身白细胞减少，肺血管中性粒细胞调节趋化因子如 CXCL5、SDF-1、CXCL13 的水平增加，以及免疫调节趋化因子如 BAL IL-10 和 CCL27 的水平降低。虽然 CD61 阻断抗体和 BTB06584 使 BAL 白细胞计数、蛋白含量和 BAL 趋化因子的增加达到最大值，但这些治疗方法诱导肺 MPO 和 EPX 含量中度增加。CD61 阻断抗体诱导 BAL 细胞死亡的最大值，NK1.1、CX3CR1 和 CD61 的点状分布明显。BTB06584 保持 BAL 细胞活力，Gr1 和 CX3CR1 的细胞质和细胞膜分布。普萘洛尔减弱 BAL 蛋白，保护 BAL 细胞死亡，诱导 NK1.1、CX3CR1 和 CD61 的极化分布，但肺 EPX 水平很高。地塞米松诱导 BAL 细胞上 CX3CR1 和 CD61 的稀疏细胞膜分布，尽管 BAL 趋化因子水平最高，但肺 MPO 和 EPX 水平非常低。我们的研究揭示了 ATP 酶抑制剂 IF1 作为肺损伤的新药物靶点。
