Effects of phorbol myristate acetate and sivelestat on the lung injury caused by fat embolism in isolated lungs.
BACKGROUND
Fat embolism syndrome (FES) associated with acute lung injury (ALI) is a clinical condition following long bone fracture. We have reported 14 victims due to ALI with FES. Our laboratory has developed an animal model that produced fat emboli (FE). The major purpose of this study was to test whether neutrophil activation with phorbol myristate acetate (PMA) and inhibition with sivelestat (SVT) exert protection on the lung.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Physical Education and Kinesiology, National Dong Hwa University, Hualien, Taiwan.
Chia-Chih
CC
Lin
Pei-Hsin
PH
Liu
Shang Jyh
SJ
Kao
Hsing I
HI
Chen
D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D004620:Embolism, Fat / Q000150:complications / Q000276:immunology / Q000503:physiopathology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000494:pharmacology*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects; D011655:Pulmonary Embolism / Q000150:complications / Q000276:immunology / Q000503:physiopathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D018836:Inflammation Mediators; D013449:Sulfonamides; C069195:sivelestat; D019272:Leukocyte Elastase; D013755:Tetradecanoylphorbol Acetate; D005998:Glycine