Therapeutical effect of ulinastatin on early lung injury in mice with primary blast injury

  Background   The disruption of the pulmonary membrane and the infiltration of polymorphonuclear neutrophil granulocytes across the basement membrane into the pulmonary tissue, resulting in excessive inflammatory response, is considered to be an essential step in the pathogenesis of primary lung injury and respiratory impairment. Ulinastatin, a serine protease inhibitor with broad anti-inflammatory activity, may play a therapeutical role in primary blast lung injury by inhibiting the functions of neutrophils.

  Objective   To investigate whether ulinastatin can protect early lung injury in mice with primary blast injury by inhibiting the effect of neutrophils.

  Methods   Totally 136 mice were randomly divided into control group (group C, n=16), blast injury group (group B, n=60) and ulinastatin group (group U, n=60). Moderate primary blast injury model was made in mice of group B and group U by polyblack aluminum high explosive. Ulinastatin solution (1×10⁴U/mL) was prepared, and group U was intraperitoneally injected with ulinastatin solution at the dosage of 5×10⁴ U/kg immediately after injury, 12h for each time. Mice in the group C, the group B and the group U were sacrificed at 6 h, 24 h and 48 h after injury for the determination of lung histopathology, lung tissue water content, levels of TNF-α, NF-κB, CXCL-1, NE, and MMP-9 in serum, NADPH oxidase (NAO) activity, and expression of NE and MMP-9 in lung tissue. And lung functions of mice in the group C along with mice in the group B, the group U at 48 h after injury were also measured.

  Results   Compared with the group C, obvious neutrophil infiltration was observed in the group B at 6 h after injury, and there were a large number of inflammatory cells infiltrated at 24 h and 48 h, with severe thickening of alveolar wall, stenosis of alveolar cavity and more tissue congestion. In group U, the infiltration of inflammatory cells reduced significantly at each time point, and the degree of alveolar swelling and congestion was also significantly decreased, compared with group B. The water content of lung tissue in group U was lower than that in group B at 6 h, 24 h and 48 h after injury. The contents of TNF-α, NF-κB, CXCL-1 in serum and the activity of NAO in the group U were significantly lower than those in the group B; the contents of NE and MMP-9 in serum and the expression of NE and MMP-9 in lung tissue in group U were significantly lower than those in group B, and the differences were more significant at 48 h after injury (P < 0.05). Compared with group B, the pulmonary functions of group U were improved at 48 h after injury, VTs and PIFs were significantly higher, while Fs, EF50s and Penhs were significantly lower (all P < 0.01).

  Conclusion   Early application of ulinastatin can inhibit the production of cytokines and the production of a variety of neutrophil-derived serine proteases, thus relieving excessive inflammatory response and preventing lung tissue progressive injury, which contributes to the improvement of lung histopathology and lung function in mice with primary blast lung injury.