Influence of a Human Protease Inhibitor on Surgical Stress Induced Immunosuppression

Abstract

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.

Perioperative cimetidine administration promotes peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with gastrointestinal cancer: Results of a randomized controlled clinical trial

“…Previous studies demonstrated that T helper cells decreased and T suppressor cells increased significantly as early as 1 day after surgery [22][23][24] . Many subsequent studies also confirmed that surgery for patients with lung cancer [25] , esophageal cancer [26] , gastric cancer [27,28] and colorectal cancer [29,30] induced immediate severe immunosuppression. For cancer patients, an important function adversely affected by this immunosuppression is the anti-tumor response itself.…”

Protective Effects of Ulinastatin on Proliferation and Cytokine Release of Splenocytes from Rats with Severe Acute Pancreatitis

“…Conclusions: The deficiencies in proliferation and cytokine release in response to antigen stimulation demon-ity of inflammatory proteases, including trypsin, plasmin, etc., and to limit the enhanced production of inflammatory cytokines [10,11] . Ulinastatin has been reported [12] to significantly reduce the severity of immunosuppression induced by surgical stress. However, so far, there are few studies in which the effects of ulinastatin on the suppressed cellular immunity during severe acute pancreatitis were evaluated.…”

Ulinastatin promotes T lymphocyte apoptosis in rats with severe acute pancreatitis via mitochondrial pathways

“…Clinical and basic research studies have shown the value of UTI. A clinical study by Sato et al (2002) found that UTI has a corrective effect on immune deficiency-caused surgical stress (Sato et al, 2002); UTI can enhance immune function and improve the immune imbalance in sepsis cases through increasing the ratio of inducer T lymphocytes. In 2009, Huang et al (2009) initiated UTI immunotherapy and revealed that UTI therapy can noticeably improve the quality of life of sepsis patients.…”

“…The immune indices in patients, including T lymphocyte counts, T lymphocyte function, and cytokine pro-duction, in the perioperative period were recovered to different extents after the application of UTIs. Consequently, it has been suggested that the UTI improves immune function (Sato et al, 2002;Ma et al, 2006).…”