Division of Pulmonary Infection and Critical Care, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
Graduate Institute of Clinical Medicine Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Sci Rep. 2019 Aug 12;9(1):11713. doi: 10.1038/s41598-019-47276-4.
Fat embolism (FE) is a lethal medical emergency often caused by fracture of long bones and amputation of limbs. Vascular endothelial growth factor (VEGF) promotes angiogenesis and increases vascular permeability. We tested the hypothesis that VEGF plays a critical role in FE-induced acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Fat tissues were collected from male Sprague-Dawley rats, and animal oil was extracted and mixed with water to form fatty micelles. The micelles were then injected into the tail vein to produce FE and ALI in rats. Lung weight gain was measured as the index of pulmonary edema. The expression of pulmonary VEGF was evaluated by real-time PCR and western blot analysis. Inducible nitric oxide synthase (iNOS) and phosphorylation of mitogen-activated protein kinase (MAPK) were determined by western blot analyses. Interleukin-1β (IL-1β) was quantified by ELISAs. Hematoxylin and eosin staining was used to evaluate the pathological damage of ALI. In this study, we found that animal oil-induced FE significantly increased pulmonary VEGF expression and MAPK phosphorylation. We also evaluated the inflammatory response after FE and found that iNOS and IL-1β significantly increased after FE. Systemic administration of SU-1498, an antagonist of VEGF receptor 2 (VEGFR-2), significantly attenuated the FE-induced inflammatory response and histological damage. This study suggested that VEGF is involved in FE-induced ARDS via the VEGFR-2 and MAPK cascades, which induce IL-1β release and iNOS upregulation. Blockade of could be used to treat FE-induced pulmonary damage.
脂肪栓塞（FE）是一种致命的医学急症，通常由长骨骨折和四肢截肢引起。血管内皮生长因子（VEGF）促进血管生成并增加血管通透性。我们测试了 VEGF 在 FE 诱导的急性呼吸窘迫综合征（ARDS）和急性肺损伤（ALI）中起关键作用的假设。从雄性 Sprague-Dawley 大鼠中收集脂肪组织，并提取动物油并与水混合形成脂肪胶束。然后将胶束注入尾静脉，在大鼠中产生 FE 和 ALI。肺重量增加作为肺水肿的指标进行测量。通过实时 PCR 和 Western blot 分析评估肺 VEGF 的表达。通过 Western blot 分析测定诱导型一氧化氮合酶（iNOS）和丝裂原活化蛋白激酶（MAPK）的磷酸化。通过 ELISA 定量白细胞介素-1β（IL-1β）。苏木精和伊红染色用于评估 ALI 的病理损伤。在这项研究中，我们发现动物油诱导的 FE 显著增加了肺 VEGF 的表达和 MAPK 的磷酸化。我们还评估了 FE 后的炎症反应，发现 FE 后 iNOS 和 IL-1β 明显增加。VEGF 受体 2（VEGFR-2）拮抗剂 SU-1498 的全身给药显著减弱了 FE 诱导的炎症反应和组织学损伤。这项研究表明，VEGF 通过 VEGFR-2 和 MAPK 级联参与 FE 诱导的 ARDS，从而诱导 IL-1β 释放和 iNOS 上调。阻断可能用于治疗 FE 引起的肺损伤。
