Experimental Study On The Role Of Neutrophil Elastase In Lung Injury Induced By Burn-blast Combined Injury In Rats

Objective:Burn-blast combined injury is a common injury in war and daily life, and the serious lung injury is one of the most common causes of death during early stage. The previous researches have shown that neutrophil elastase (NE) played an important role in progression of acute lung injury (ALI) models caused by multi-factors, but which role in lung injury induced by burn-blast combined injury is not clear yet. Sivelestat (ONO-5046·Na) is a specific NE inhibitor, which has shown a protective effect against lung injury on part of ALI animal models and clinical studies. This study was aimed to explore the role of NE, and the protective effect of sivelestat in lung injury induced by burn-blast combined injury in male Sprague Dawley rats.Methods:One hundred and sixty male SD rats were randomly divided into 3 groups:burn-blast combined injury (BB) group, sivelestat treatment (S) group and control (C) group. Animals in BB group and S group were inflicted with moderate blast injury caused by explosion source,5g 8701 compressed dynamite stick, 75cm away, left chest facing the explosive source, followed by exerting 25% TBSA full-thickness burn on back with 94℃water for 12s. Rats in C group were sham burned on back with 37℃water for 12s. During the first 24 hours post injury, animals in 3 groups received intraperitoneal injection of sodium lactate Ringer's solution (50mL-kg-1·12h-1). Animals in S group were intraperitoneally injected with sivelestat (75mg·kg-1·12h-1) from 30min through 7d post injury. At Oh (just C group),3h,6h,12h, Id,2d,3d,7d post-injury (8 rats in each point except 6 in C group), blood gas analysis were determined by portable blood gas analyzer, protein concentration, NE activity in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in lung tissue by colorimetric method, serum concentrations of tumor necrosis factor-a (TNF-a) and interleukin-8 (IL-8) by ELISA. Moreover, lung tissue wet/dry weight (W/D) ratio and pathology of lung tissue were also investigated.Results:In BB group, NE activity in BALF increased and peaked at 2d post injury (vs. C group, P<0.01). Arterial oxygen pressure (PaO2) decreased; protein concentration in BALF, MPO activity in lung tissue, lung tissue W/D ratio, serum concentrations of TNF-αand IL-8 increased (vs. C group P<0.01 or P<0.05, especially within 3d post injury). Pathological investigation of lung tissue showed neutrophil infiltration, progressive bleeding and pulmonary edema, which reached the most serious extent on 1d post injury, followed by gradually attenuation, but not restored until 7d post injury. Compared with animals in BB group, sivelestat treatment attenuated NE activity in BALF since 6h post injury (P< 0.01 or P< 0.05). PaO2 increased, while protein concentration in BALF, pulmonary W/D ratio, MPO activity and serum TNF-αand IL-8 concentrations in S group were lower than that in BB group (P<0.01 or P<0.05, especially within 3d post injury). Furthermore, except for PaO2, all the aforementioned parameters in S group were still higher than that in C group(P<0.01 or P<0.05). Histopathological analysis of lung tissue indicated that neutrophil infiltration and pulmonary edema changes in S group were slighter than that in BB group.Conclusions:Inhibition of NE activity with sivelestat exerts a protective effect in lung injury after burn-blast combined injury. Thus, NE may play an important role in the progression of lung injury induced by burn-blast combined injury. The mechanisms of NE in the lung injury may be by increased NE activity to induce increase of pulmonary vascular permeability, increase of neutrophil sequestration in lung tissue, increase of production of inflammatory mediators TNF-α, IL-8. The specific NE inhibitor, Sivelestat, has partial protective effects in lung injury induced by burn-blast combined injury.