Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Uijeongbu St Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Republic of Korea.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Uijeongbu St Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Republic of Korea
In Vivo. 2024 May-Jun;38(3):1127-1132. doi: 10.21873/invivo.13547.
BACKGROUND/AIM: Patients with pneumonia after prolonged neutropenia are at increased risk for acute respiratory distress syndrome (ARDS). The key molecule of endothelial barrier breakdown in sepsis is lipopolysaccharide (LPS), which is a component of the outer membrane of gram-negative bacterial cell walls. Maintaining increased cyclic adenosine monophosphate (cAMP) levels in endothelial cells is effective in preventing endothelial dysfunction and microvascular permeability. The aim of this study was to elucidate whether roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor, is effective in LPS-induced acute lung injury (ALI) during neutropenia recovery in a murine model.
To induce neutropenia, all mice were administered intraperitoneal cyclophosphamide. On day 2 after neutropenia, mice were administered LPS by intra-tracheal instillation. In the prevention group, roflumilast was given orally on day 0, when neutropenia was induced. In the treatment group, roflumilast was administered orally 1 hour after LPS injection.
Roflumilast attenuated histopathological changes associated with LPS-induced lung injury. The accumulation of neutrophils and the concentrations of inflammatory cytokines IL-1β, TNF-α, and IL-6 in bronchoalveolar lavage fluids were inhibited effectively by roflumilast. Also, MMP-9 and TGF-β expression was attenuated in the roflumilast group.
Roflumilast significantly attenuated LPS-induced ALI during neutropenia recovery.
背景/目的：中性粒细胞减少症持续时间较长的肺炎患者发生急性呼吸窘迫综合征（ARDS）的风险增加。脓毒症内皮屏障破裂的关键分子是脂多糖（LPS），它是革兰氏阴性细菌细胞壁外膜的组成部分。维持内皮细胞中增加的环磷酸腺苷（cAMP）水平可有效预防内皮功能障碍和微血管通透性。本研究旨在阐明磷酸二酯酶-4（PDE-4）抑制剂罗氟司特在中性粒细胞减少症恢复期 LPS 诱导的急性肺损伤（ALI）中的作用。
所有小鼠均腹腔内注射环磷酰胺以诱导中性粒细胞减少症。在中性粒细胞减少症发生后第 2 天，通过气管内滴注 LPS 诱导 ALI。在预防组中，在诱导中性粒细胞减少症的第 0 天口服给予罗氟司特。在治疗组中，在 LPS 注射后 1 小时口服给予罗氟司特。
罗氟司特减轻了与 LPS 诱导的肺损伤相关的组织病理学变化。罗氟司特有效抑制了中性粒细胞积聚和支气管肺泡灌洗液中炎症细胞因子 IL-1β、TNF-α 和 IL-6 的浓度。此外，罗氟司特组 MMP-9 和 TGF-β 的表达也减弱。
罗氟司特显著减轻了中性粒细胞减少症恢复期 LPS 诱导的 ALI。
