Influence of a Human Protease Inhibitor on Surgical Stress Induced ImmunosuppressionSato N.a · Endo S.b · Kimura Y.a · Ikeda K.a · Aoki K.a · Iwaya T.a · Akiyama Y.a · Noda Y.a · Saito K.a
Departments of aSurgery I and bCritical Care Medicine, Iwate Medical University School of Medicine, Morioka, Japan
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Background/Aim: Postoperative tissue injury and immunosuppression can occur after major surgery. In this study, we explore the potential benefits of administering a protease inhibitor to treat immunosuppression caused by surgical stress. Methods: Sixteen patients with esophageal cancer were preoperatively allocated at random into two equal groups. A urinary trypsin inhibitor, ulinastatin (UTI), was intravenously administered to the treatment (UTI) group at a dose of 150,000 U every 12 h from the start of surgery until postoperative day 5, whereas the control group received a placebo. One unit of UTI was defined as the amount of UTI necessary to inhibit the activity of 2 µg of bovine pancreatic trypsin by 50%. We measured the plasma levels of polymorphonuclear neutrophil elastase, interleukin 8, circulating T lymphocyte subsets, and mitogenic activity and in vitro production of tumor necrosis factor alpha in lipopolysaccharide-stimulated whole blood. Results: The postoperative serum value of polymorphonuclear neutrophil elastase was significantly lower in the UTI group, but the interleukin 8 concentrations did not significantly vary between the two groups. On the other hand, the severity of the postoperative immunosuppression was reduced in the UTI group, and immune functions, such as the numbers of T lymphocytes, the mitogenic activity of lymphocytes, and the level of tumor necrosis factor alpha production in whole blood, recovered significantly earlier in the UTI group. Conclusion: These data suggest that a protease-modulating therapy may be a new strategy for the treatment of surgical stress induced immune dysfunction.
© 2002 S. Karger AG, Basel
J.R. Siewert, K. Emmanuilidis
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The goal of the study was to demonstrate the therapeutic potential of ulinastatin (human trypsin/protease inhibitor) for postoperative immunosuppression in patients following one-time resection of esophageal carcinoma.
It was shown that there was no significant difference in interleukin 8 levels within the time investigated. The polymorphonuclear neutrophil elastase showed a significantly lower value only on the 1st and 3rd days postoperatively in patients who had been treated with the inhibitor. The number of circulating T cells reached a nadir on the 3rd postoperative day in the control group. In contrast, the postoperative T cell count in the ulinastatin-treated patients was significantly higher and for the most part constant. The T cell proliferation potential was also significantly higher on the 1st postoperative day in the protease-treated patients. The tumor necrosis factor alpha production in the lipopolysaccharide-stimulated whole-blood assay was lower postoperatively in both groups, but showed a rapid recovery in the treatment group.
The results of this study are basically interesting, and it is now known that protease inhibitors modulate the immune system. The mechanism of immunological regulation, however, is still unclear. The lower elastase level in peripheral blood is an anticipated reaction to ulinastatin administration and has no further significance for the postoperatively changed immunological situation.
The results concerning circulating T cells and their proliferation capacity are interesting. Here, there are two points to be considered. With a lower T cell count, the proliferation capacity in relation to the whole-cell count is naturally lower and could also be observed in the control group. In addition, the T cell function with respect to their immune response to cytokines was not adequately investigated. A lower number of total T cells does not necessarily correlate with a worsened overall function. For function tests, the authors use tumor necrosis factor alpha and interleukin 10. It would have been interesting to see the results of further T cell function analyses.
From a clinical standpoint, the patient collective is very homogeneous. Overall, the number of patients is too small to assess the clinical relevance of the study. It would be interesting to investigate the difference in the incidence of and mortality from postoperative sepsis in a larger number of esophageal resection patients by comparing those treated with the protease inhibitor versus a control group.
Overall, the study is very interesting, and we still have much to learn about its contents. The most important laboratory data refer to the T cell function test and the postoperative tumor necrosis factor alpha levels resulting therefrom. Besides an attempt to clarify the mechanism of action of protease inhibitors, this study should be extended further. With a larger patient collective, the outcomes of postoperative sepsis and mortality would be of great interest.
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