Abstract
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.
Highlights
Fat embolism (FE) is a serious clinical complication in patients associated with long-bone fractures or amputation
The present study clearly demonstrated that FE induced severe pulmonary edema and damage, which is mediated by overexpression of Vascular endothelial growth factor (VEGF), and activated the VEGF receptor 2 (VEGFR-2) and mitogen-activated protein kinase (MAPK) cascades
Our results suggested that FE induced a pulmonary inflammatory response, which included IL-1β and Inducible nitric oxide synthase (iNOS) overproduction
Summary
Fat embolism (FE) is a serious clinical complication in patients associated with long-bone fractures or amputation. Intravasation of fat or fatty acids from long-bone fractures and other sources leads to FE, which always induces severe lung injury and acute respiratory distress syndrome (ARDS)[1,2]. VEGF functions as a potent proinflammatory cytokine in many physiological and pathological immune responses[16]. Numerous signals, such as IL-1, IL-6, and insulin-like growth factor I, are known to stimulate VEGF www.nature.com/scientificreports/. Plasma VEGF levels and its receptors were shown to increase under severe sepsis conditions, and the VEGF levels correlated with the severity and mortality, which are primarily mediated through the nitric oxide (NO) signaling pathway[22,23,24,25]. We evaluated the role of VEGF in FE-induced ARDS and its possible mechanisms
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