Division of Pulmonary Medicine, Tri-Service General Hospital, Institute of Undersea and Hyperbaric Medicine, National Defense Medical Center, Taipei, Taiwan.
Department of Critical Care Medicine, Li-Shin Hospital, Tao-Yuan County, Taiwan.
J Surg Res. 2019 Sep;241:24-30. doi: 10.1016/j.jss.2019.03.028. Epub 2019 Apr 17.
Pulmonary air embolism (PAE)-induced acute lung injury (ALI) can be caused by massive air entry into the lung circulation. PAE can occur during diving, aviation, and some iatrogenic invasive procedures. PAE-induced ALI presents with severe inflammation, hypoxia, and pulmonary hypertension, and it is a serious complication resulting in significant morbidity and mortality. Phosphodiesterase-4 (PDE4) inhibitors can regulate inflammation and are therefore expected to have a therapeutic effect on ALI. However, the effect of the PDE4 inhibitor roflumilast on PAE-induced ALI is unknown.
The PAE model was undertaken in isolated-perfused rat lungs. Four groups (n = 6 in each group) were defined as follows: control, PAE, PAE + roflumilast 2.5 mg/kg, and PAE + roflumilast 5 mg/kg. Induction of PAE-induced ALI was achieved via the infusion of 0.7 cc air through the pulmonary artery. Roflumilast was administered via perfusate. All groups were assessed for pulmonary microvascular permeability, lung histopathology changes, pulmonary edema (lung weight/body weight, lung wet/dry weight ratio), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-17, nuclear factor-kappa B (NF-κB), and inhibitor of NF-κB alpha (IκB-α).
After the induction of air, PAE-induced ALI presented with pulmonary edema, pulmonary microvascular hyperpermeability, and lung inflammation with neutrophilic sequestration. The PAE-induced ALI also presented with increased expressions of IL-1β, IL-6, IL-8, IL-17, TNF-α, and NF-κB and decreased expression of IκB-α. The administration of roflumilast decreased pulmonary edema, inflammation, cytokines, NF-κB, and restored IκB-α level.
PAE-induced ALI presents with lung inflammation with neutrophilic sequestration, pulmonary edema, hyperpermeability, increased cytokine levels, and activation of the NF-κB pathway. Roflumilast attenuates lung edema and inflammation and downregulates the NF-κB pathway and cytokines.
肺空气栓塞（PAE）引起的急性肺损伤（ALI）可由大量空气进入肺循环引起。PAE 可发生在潜水、航空和一些医源性侵入性操作中。PAE 引起的 ALI 表现为严重的炎症、缺氧和肺动脉高压，是导致发病率和死亡率显著增加的严重并发症。磷酸二酯酶 4（PDE4）抑制剂可调节炎症，因此有望对 ALI 产生治疗作用。然而，PDE4 抑制剂罗氟司特对 PAE 引起的 ALI 的影响尚不清楚。
采用离体灌注大鼠肺模型。将 4 组（每组 6 只）定义为：对照组、PAE 组、PAE+罗氟司特 2.5mg/kg 组和 PAE+罗氟司特 5mg/kg 组。通过肺动脉输注 0.7cc 空气诱导 PAE 诱导的 ALI。罗氟司特通过灌流液给药。所有组均评估肺微血管通透性、肺组织病理学变化、肺水肿（肺重/体重、肺湿/干重比）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、白细胞介素-17（IL-17）、核因子-κB（NF-κB）和 NF-κB 抑制剂-α（IκB-α）。
空气诱导后，PAE 诱导的 ALI 出现肺水肿、肺微血管高通透性和中性粒细胞浸润性肺炎症。PAE 诱导的 ALI 还表现出 IL-1β、IL-6、IL-8、IL-17、TNF-α和 NF-κB 表达增加，IκB-α表达减少。罗氟司特的给药减少了肺水肿、炎症、细胞因子、NF-κB，并恢复了 IκB-α 水平。
PAE 诱导的 ALI 表现为肺炎症伴中性粒细胞浸润、肺水肿、高通透性、细胞因子水平升高和 NF-κB 途径激活。罗氟司特减轻肺水肿和炎症，并下调 NF-κB 途径和细胞因子。
