Effects of phorbol myristate acetate and sivelestat on the lung injury caused by fat embolism in isolated lungs

The lungs of Sprague-Dawley rats were isolated and perfused. FE was produced by addition of corn oil micelles into the lung perfusate. PMA and SVT were given simultaneously with FE. Parameters such as lung weight/body weight ratio, LW gain, exhaled nitric oxide (NO), protein concentration in bronchoalveolar lavage relating to ALI were measured. The neutrophil elastase (NE), myeloperoxidase, malondialdehyde and phopholipase A2 activity were determined. We also measured the nitrate/nitrite, methyl guanidine (MG), and cytokines. Pulmonary arterial pressure and microvascular permeability were assessed. Lung pathology was examined and scored. The inducible and endothelial NO synthase (iNOS and eNOS) were detected.FE caused ALI and increased biochemical factors. The challenge also resulted in pulmonary hypertension and increased microvascular permeability. The NE appeared to be the first to reach its peak at 1 hr, followed by other factors. Coadministration with PMA exacerbated the FE-induced changes, while SVT attenuated the effects of FE.The FE-induced lung changes were enhanced by PMA, while SVT had the opposite effect. Sivelestat, a neutrophil inhibitor may be a therapeutic choice for patients with acute respiratory distress syndrome (ARDS) following fat embolism.Fat embolism syndrome (FES) is a serious clinical problem in patients associated with long bone fracture [1-3]. Although the precise mechanisms of FES remain unclear, intravasation of fat or fatty acids from broken long bones and other sources is the primary cause leading to FES [3,4]. In two clinical investigations, we have reported a total of 14 cases who died of acute respiratory distress syndrome (ARDS) associated with FES [1,3]. The occurrence of ARDS following FES suggests that the lung is one of the target organs following intravasation of fat emboli [1-4].In order to elucidate the possible mediators involved in the ARDS associated with FES, we have developed an animal model that produces fat embolism