Lamanna Emma, Kropf Zoe F, Luong Raymond, Narayan Matthew, Richards Elizabeth A, Cardwell Bailey, Royce Simon G, Nold-Petry Claudia A, Bourke Jane E
Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology University, Bundoora, Victoria, Australia.
Am J Respir Cell Mol Biol. 2025 Jul;73(1):26-36. doi: 10.1165/rcmb.2024-0249OC.
Acute respiratory distress syndrome (ARDS) results in decreased quality of life, including increased risk of pulmonary hypertension (PH). In animal models, ARDS can be induced by LPS, which can disrupt the pulmonary endothelium and epithelium and induce inflammation. We tested whether administration or treatment with LPS alters the reactivity of intrapulmonary arteries and airways to constrictors relevant to both ARDS and PH, using the precision-cut lung slice (PCLS) technique. Mice were administered LPS (10 μg/50 μl, intranasal) or saline daily for 4 days before collection of BAL fluid or preparation of PCLSs. Alternatively, PCLSs from naive mice were left untreated or treated with LPS (10 μg/ml) or TNF (10 ng/ml) for 18 hours. Contraction to endothelin-1, U46619 (a stable mimetic of thromboxane A), or serotonin was quantified. LPS administration increased BAL total inflammatory cells 5-fold, neutrophils 125-fold, and protein 2-fold, as well as the thickness of the pulmonary arterial smooth muscle layer. After LPS, contraction of intrapulmonary arteries in PCLSs to endothelin-1 and U46619, but not serotonin, increased, whereas bronchoconstrictor responses were unchanged. In PCLSs treated with LPS , these differential effects on pulmonary artery and airway contraction were maintained Although LPS increased TNF secretion from PCLSs, TNF treatment only increased U46619-induced vasoconstriction. This study demonstrates the potential contributions of LPS-induced inflammation and vascular remodeling to altered intrapulmonary artery reactivity to specific agonists, with implications for ARDS-associated PH.
急性呼吸窘迫综合征（ARDS）会导致生活质量下降，包括肺动脉高压（PH）风险增加。在动物模型中，脂多糖（LPS）可诱发ARDS，它会破坏肺内皮和上皮并引发炎症。我们使用精密切割肺片（PCLS）技术，测试了给予LPS或用LPS治疗是否会改变肺内动脉和气道对与ARDS和PH相关的收缩剂的反应性。在收集支气管肺泡灌洗（BAL）液或制备PCLS之前，给小鼠每日鼻内给予LPS（10μg/50μl）或生理盐水，持续4天。或者，对来自未处理小鼠的PCLS不进行处理，或用LPS（10μg/ml）或肿瘤坏死因子（TNF，10ng/ml）处理18小时。对内皮素-1、U46619（血栓素A的稳定类似物）或5-羟色胺的收缩反应进行定量分析。给予LPS使BAL中的总炎症细胞增加5倍，中性粒细胞增加125倍，蛋白质增加2倍，同时肺动脉平滑肌层厚度增加。给予LPS后，PCLS中肺内动脉对内皮素-1和U46619的收缩反应增加，但对5-羟色胺的收缩反应未增加，而支气管收缩反应未改变。在用LPS处理的PCLS中，对肺动脉和气道收缩的这些差异效应得以维持。虽然LPS增加了PCLS中TNF的分泌，但TNF处理仅增加了U46619诱导的血管收缩。本研究证明了LPS诱导的炎症和血管重塑对肺内动脉对特定激动剂反应性改变的潜在作用，这对ARDS相关的PH具有重要意义。
