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Insight into the mechanism by which metoclopramide improves immune functions after trauma-hemorrhage
M W Knöferl1, M K Angele, A Ayala
1Department of Surgery, Center for Surgical Research, Brown University School of Medicine and Rhode Island Hospital, Providence, Rhode Island 02903, USA.
Abstract:
Although studies have shown that prolactin (Prl) and metoclopramide (Mcp) administration restores the depressed cell-mediated immune functions after hemorrhage, the underlying mechanism responsible for the immunostimulatory effects of Mcp remains unknown. We hypothesized that Mcp improves immune responses by upregulating the secretion of Prl. To test this hypothesis, male C3H/HeN mice were subjected to sham operation or laparotomy (i.e., soft tissue trauma) and hemorrhagic shock (Hem; 35 +/- 5 mmHg for 90 min) and then resuscitated. Plasma Prl levels were determined 30 min after Mcp (1 microgram/g body wt sc at end of Hem) or vehicle (Veh) treatment in sham and Hem mice. The results indicate that plasma Prl levels increased significantly in Mcp-treated mice (sham-Veh 249.9 +/- 5.3, Hem-Veh 229.9 +/- 7.6, Hem-Mcp 596.9 +/- 73.1 ng/ml, one-way ANOVA, P < 0.05 vs. Veh). To determine whether Mcp produces its salutary effects directly or indirectly via increased Prl secretion, splenocyte proliferation and splenocyte interleukin (IL)-2 and IL-3 release from untreated sham or Hem mice were determined in the presence of increasing concentrations of mouse Prl or Mcp. The addition of Mcp had no effect on splenocyte immune functions in vitro. However, the addition of Prl restored the hemorrhage-induced depressed splenocyte proliferation as well as splenocyte IL-2 and IL-3 release in vitro in a dose-dependent manner. Thus the beneficial effects of Mcp on immune functions after Hem appear to be mediated by Prl. Because Mcp increases plasma levels of the immunoenhancing hormone Prl, this agent should be considered a useful adjunct for the treatment of immunodepression in trauma victims.
Insights
Metoclopramide (Mcp) administration boosts immune function after hemorrhage by increasing prolactin (Prl) levels. This study confirms Prl mediates Mcp
Area of Science:
- Immunology
- Endocrinology
- Trauma Research
Background:
- Hemorrhage and trauma significantly depress cell-mediated immune functions.
- Prolactin (Prl) and metoclopramide (Mcp) have shown potential in restoring immune function post-hemorrhage.
- The precise mechanism by which Mcp exerts its immunostimulatory effects remains unclear.
Purpose of the Study:
- To investigate the hypothesis that Mcp enhances immune responses by upregulating Prl secretion.
- To determine if Mcp's beneficial effects on immune function after hemorrhage are mediated directly or indirectly through Prl.
Main Methods:
- Male C3H/HeN mice underwent sham operation or hemorrhagic shock (HS) followed by resuscitation.
- Plasma Prl levels were measured after Mcp or vehicle administration.
- Splenocyte proliferation and cytokine (IL-2, IL-3) release were assessed in vitro with varying concentrations of Prl or Mcp.
Main Results:
- Mcp treatment significantly increased plasma Prl levels in both sham and HS mice.
- In vitro, Mcp alone did not affect splenocyte immune functions.
- Prl administration dose-dependently restored hemorrhage-induced suppression of splenocyte proliferation and IL-2/IL-3 release.
Conclusions:
- The immunostimulatory effects of Mcp following hemorrhage are mediated by increased Prl secretion.
- Mcp's ability to elevate Prl levels suggests its utility as an adjunct therapy for trauma-induced immunodepression.
- Further research into Prl's role in trauma recovery is warranted.