Increased intestinal permeability in rats with graft versus host disease.

BACKGROUND/AIMS: The study of graft versus host disease of the intestine has significant clinical relevance and may also be a model for other immune mediated intestinal diseases. There presently is no simple non-invasive test that can be used to evaluate graft versus host disease induced intestinal injury in humans or animal models. This study tested the hypothesis that graft versus host disease leads to an increase in host bowel permeability as assessed by the relative urinary excretion of orally administered lactulose and rhamnose. METHODS: The urinary excretion ratio of orally administered lactulose and rhamnose was determined daily for two weeks in (Lewis x Brown-Norway) F1 rats with graft versus host disease caused by either the transplantation of parental (Lewis) small bowel or the intraperitoneal injection of parental (Lewis) splenic lymphocytes. RESULTS: Significant twofold to fourfold increases in the lactulose to rhamnose ratio were seen in both small bowel transplant and splenic lymphocyte transfer animals suffering from graft versus host disease during the second postoperative week. This effect occurred sooner in small bowel transplant than in splenic lymphocyte transfer animals (postoperative day 7 versus 11, respectively). The signs of graft versus host disease, including splenomegaly and altered intestinal mucosal architecture, as well as the increased lactulose to rhamnose ratio were significantly attenuated in small bowel transplant animals treated with cyclosporine A (10 mg/kg/day). CONCLUSIONS: Graft versus host disease is associated with an increase in the lactulose to rhamnose clearance ratio reflecting an increase in host bowel permeability. This increase, along with the signs of systemic graft versus host disease, can be significantly ameliorated by cyclosporine A. The lactulose to rhamnose clearance ratio is a non-invasive technique that can be used to assess the intestinal effects of graft versus host disease and the associated increase in intestinal permeability.

Awake epidural anesthesia is associated with improved natural killer cell cytotoxicity and a reduced stress response.

BACKGROUND: Laparotomy under general anesthesia is associated with depressed natural killer cell cytotoxicity (NKCC) and compromised clearance of tumor cells. We tested the hypothesis that awake epidural anesthesia (AEA) improves NKCC compared to conventional general endotracheal anesthesia (GEA). PATIENTS AND METHODS: Preoperative, perioperative, and postoperative (day 3) NKCC, plasma epinephrine, norepinephrine, cortisol levels, and 24-hour urinary cortisol levels were measured in 20 patients undergoing open colectomy under either AEA or GEA. RESULTS: Preoperative and postoperative measurements were not significantly different in the two groups. Patients receiving GEA had a significant reduction in NKCC from 36% +/- 4% preoperatively to 22% +/- 4% perioperatively (P = 0.02). Patients receiving AEA had no significant change in NKCC. Perioperative plasma epinephrine and cortisol levels were higher with GEA than AEA. The perioperative 24-hour urinary cortisol excretion values were significantly higher in the group receiving GEA, suggesting a greater stress hormone response in this group compared to AEA patients. CONCLUSIONS: Compared to GEA, AEA appears to preserve perioperative NKCC. This effect may be related to an attenuated stress hormone response associated with AEA. Cancer patients may have improved killing of embolized tumor cells during surgery performed under AEA.

Graft-versus-host disease after small bowel transplantation is associated with host colonic injury.

The present studies were undertaken to evaluate the histologic effects of graft-versus-host disease on the host colon after small bowel transplantation. Graft-versus-host disease was produced in six Lewis x Brown Norway F1 rats by performing vascularized, out-of-continuity small bowel transplants from parental Lewis donors. Host proximal and distal colon were sampled 14 days after operation when signs of graft-versus-host disease, including weight loss and splenomegaly, were present. Tissue was assessed histologically by blinded observer and compared to eight sham-operated controls. Three histologic features were noted to be statistically increased in diseased animals: (1) mucin loss; (2) crypt abscesses; and (3) large lymphoid aggregates in the mucosa and submucosa. These features were more commonly noted in the distal rather than the proximal colon. Another group of five grafted animals treated with cyclosporine A (10 mg/kg/day intramuscularly) still lost weight but did not display overt signs of graft-versus-host disease and had normal-sized spleens. There was normal mucin content and no evidence of crypt abscesses in these treated animals, although large lymphoid aggregates were present. It is concluded that mucin loss, crypt abscesses, and large lymphoid aggregates are characteristics of graft-versus-host disease-induced colonic injury in this model and that these changes are most evident in the distal colon. Cyclosporine A therapy does not completely reverse the histological changes of colonic graft-versus-host disease. This model may be useful in studying the mechanisms by which immune mediated colitides preferentially affect the distal colon.

Glutamine does not increase ammonia in systemically drained small bowel transplants.

Glutamine (Gln) enhances small bowel function and ameliorates acute injury, but its metabolism generates portal ammonia (NH4), which normally is detoxified by the liver. Its beneficial use in small bowel transplantation (SBTx) therefore, may be offset by hyperammonemia, since such grafts may be systemically drained. We tested the hypothesis that oral glutamine supplementation increases plasma NH4 in rats with systemically drained SBTx. Lewis rats with isologous SBTx had plasma NH4 and Gln assayed during isonitrogenous, isocaloric Gln dietary supplementation and were compared to controls. Plasma NH4 levels were higher in the SBTx group during all dietary manipulations, consistent with previous studies. A Gln-deficient diet (0%) caused plasma Gln levels to fall in both experimental and control animals, but had no consistent effect on NH4 levels. With Gln supplementation (12.5 and 25% of total protein) Gln levels returned to baseline but again, plasma NH4 levels did not significantly change. We conclude that oral glutamine supplementation given in an isonitrogenous manner does not increase ammonia beyond that which is usually seen in animals with systemically drained SBTx. This suggests that Gln-enriched diets are not specifically contraindicated in patients with systemically drained SBTx and may be beneficial.