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

Abstract

Aim: To clarify the contributions of ulinastatin to cellular immune responses in vivo, we examined the functional alterations of splenocytes and quantitatively evaluated the effects of ulinastatin on the splenocyte function during experimental severe acute pancreatitis. Methods: Severe acute pancreatitis was induced in rats by retrograde injection of 3% sodium deoxycholate. Thirty minutes after induction of pancreatitis, the rats were randomly assigned to four groups, receiving either saline or 50,000 U/kg of ulinastatin, respectively. Splenocytes were obtained aseptically and stimulated with concanavalin A for 24 h. Then the proliferative activity of cultured splenocytes was measured by using an MTT cellular proliferation assay, and the cytokine concentrations in the culture supernatants were measured by enzyme-linked immunosorbent assays. Results: Upon stimulation, the release of interleukin-2, interleukin-10, and interferon-γ was significantly decreased in the splenocytes from rats with pancreatitis as compared with those from sham operation and control groups. The splenocyte proliferation was also significantly suppressed in this group. In contrast, the proliferative as well as the cytokine-releasing capacities of the splenocytes from rats treated with ulinastatin were significantly increased as compared with those from rats with pancreatitis. Conclusions: The deficiencies in proliferation and cytokine release in response to antigen stimulation demonstrated an anergic state of splenocytes during severe acute pancreatitis. Treatment with ulinastatin contributed to the recovery of the immune function by improving proliferative responses and cytokine release of splenocytes. These data suggest that a protease-modulating therapy may be an effective strategy for the treatment of immunosuppression induced by severe acute pancreatitis.

Ulinastatin ameliorates tissue damage of severe acute pancreatitis through modulating regulatory T cells

“…Maciejewski et al [7] showed that ulinastatin administration increased the survival rate in experimental animals of AP. Furthermore, previous studies [6, 8] have shown that ulinastatin can inhibit the expression of tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), and increase the levels of IL-2 and IL-10. The studies on the mechanism of the anti-inflammatory effect of ulinastatin have mainly been focused on the roles of these cytokines.…”

Ulinastatin activates the renin–angiotensin system to ameliorate the pathophysiology of severe acute pancreatitis

“…However, the clinical outcome of anti‐proteolytic drug trials, and the mechanism of drug action deduced thereof, remains controversial . The potential of ulinastatin in treating pancreatitis has been demonstrated extensively in conditions such as post‐endoscopic retrograde cholangiopancreatography pancreatitis, experimental acute pancreatitis, and chronic pancreatitis . In addition to blocking proteases, there is growing evidence that ulinastatin might play a role in preventing progressive inflammation of the pancreas, irrespective of the associated cause …”

“…Previous in vivo studies have shown that ulinastatin can inhibit the expression of nuclear factor‐κB (NF‐κB), tumor necrosis factor‐α (TNF‐α), and interleukin‐6 (IL‐6), and increase the levels of IL‐2, IL‐10, and interferon‐γ . These cytokines play important roles in the initiation and amplification of inflammatory responses during pancreatitis.…”

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

“…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).…”