Karen E. Todd

Interleukin-10 reduces the systemic inflammatory response in a murine model of intestinal ischemia/reperfusion

BACKGROUND Intestinal ischemia/reperfusion (I/R) is known to increase systemic cytokine levels, as well as to activate neutrophils in distant organs. This study was designed to investigate the effect of interleukin-10 (IL-10) on cytokine release, pulmonary neutrophil accumulation, and histologic changes in a murine model of I/R. METHODS Forty female Swiss-Webster mice were divided into four groups. Group 1 underwent 45 minutes of superior mesenteric artery occlusion followed by 3-hour reperfusion (I/R). Group 2 underwent laparotomy alone (Sham). Group 3 underwent I/R, but was treated with IL-10, 10,000 units IP every 2 hours, starting 1 hour before reperfusion (Pretreatment). Group 4 was treated with an equal dose of IL-10, starting 1 hour after reperfusion (Posttreatment). All animals were killed at 3 hours, standard assays were performed for serum cytokine levels, and lung myeloperoxidase activity and intestinal histology were scored. RESULTS Serum cytokines (TNF-alpha and IL-6), lung myeloperoxidase levels, and histologic score were significantly reduced when IL-10 was administered either before or after reperfusion. CONCLUSIONS IL-10 reduced the severity of local and systemic inflammation in a murine model of intestinal I/R when given before or after reperfusion injury. These observations suggest that IL-10 may exert its effect by blocking cytokine production and distant organ neutrophil accumulation.

Kupffer cell blockade reduces hepatic and systemic cytokine levels and lung injury in hemorrhagic pancreatitis in rats.

Severe acute pancreatitis (AP) is associated with both the local (pancreatic) release of cytokines and an elevation in their systemic plasma concentrations. This may lead to organ dysfunction and death of the patient. The aims of this study were to investigate the source(s) of systemic cytokine production during experimental AP. Forty-two rats were allocated to five groups (control, sham operation and saline injection, sham operation and gadolinium chloride injection, intraductal sodium-taurocholate infusion and saline injection, or intraductal sodium-taurocholate infusion and gadolinium chloride injection). Blood from the iliac artery, portal vein, and hepatic vein, along with tissue from the pancreas, liver, and lung, were collected. Serum levels of TNF&agr;, IL-1&bgr;, IL-6, and IL-10 were determined by enzyme-linked immunosorbent assay. Tissue mRNA for IL-1&bgr; and IL-10 was assessed by reverse-transcription polymerase chain reaction. In untreated animals with AP, the lowest serum cytokine levels were found in the portal vein. In the hepatic vein, the levels of TNF&agr;, IL-1&bgr;, and IL-6 were higher. The highest serum levels were detected in the systemic circulation. In the gadolinium chloride-treated group, there was no increase in hepatic or systemic cytokine levels and less lung injury was observed. Extrapancreatic cytokine production from both the liver and the lung contributed significantly to systemic levels of TNF&agr;, IL-1&bgr;, IL-6, and IL-10 in this experimental model of AP.

Resection of locally advanced pancreatic cancer after downstaging with continuous-infusion 5-fluorouracil, mitomycin-C, leucovorin, and dipyridamole.

Patients with locally advanced pancreatic adenocarcinoma who receive conventional therapy with radiation with S-fluorouracil(5-FU) have median survivals ranging from 8 to 12 months. Here we report our experience with a four-drug chemotherapeutic regimen that resulted in sufficient downstaging of tumor in some patients to justify surgical reexploration and resection. From April 1991 through April 1994,38 patients received 5-FU as a continuous infusion (200 mg/m2/day), calcium leucovorin weekly by imravenous bolus injection (30 mg/m2), mitomycin-C every 6 weeks (10 mg/m2 intravenously), and dipyridamole daily orally (75 mg) for locally advanced unresected pancreatic cancer. All of these patients were evaluable for response, toxicity, and survival. There were 14 partial responses and one complete response—a 39% response rate. The median survival for all patients was 15.5 months; the l-year survival rate from time of initial diagnosis was 70%. Six of 15 responding patients had sufficient tumor regression to meet clinical criteria for resectability and reexploration, four of whom underwent a curative resection. The median survival of these six patients was 28 months from the time of original diagnosis. The l-year survival was 83 %, with one patient still alive and free of disease at 53 months. We believe this unique experience from a single institution justifies a prospective multi-institutional trial to evaluate the efficacy of this approach iu a larger number of patients.

survival outcome among 54 intubated pediatric bone marrow transplant patients

Objectives: To assess the outcome of children who required endotracheal intubation after bone marrow transplantation and to determine whether prognostic indicators that might assist decision‐making regarding the institution of mechanical ventilation could be identified. Design: Retrospective chart review. Setting: Critical care, reverse isolation unit at a university hospital. Patients: Fifty‐four pediatric bone marrow transplant recipients who required endotracheal intubation. Interventions: None. Measurements and Main Results: The following variables were assessed for effect on survival: a) the presence of additional nonhematoporetic organ system failure; b) the duration of required ventilatory assistance; c) the etiology of respiratory failure; d) the presence of significant graft vs. host disease; and e) the underlying disease for which the transplant was done. Six of 54 intubated pediatric bone marrow transplant recipients were extubated and discharged from the hospital. No patient with a diagnosis of leukemia or with multiple organ system failure could be extubated or discharged from the hospital. The presence of pulmonary parenchymal disease indicated poor prognosis for survival. Conclusions: The decision to intubate a pediatric bone marrow transplant patient remains a difficult one. In this population, multiple organ system failure and primary pulmonary parenchymal disease were associated with a high mortality rate. These factors should be taken into account before and throughout the course of mechanical ventilation in this patient population. (Crit Care Med 1994; 22:171‐176)

Hepatic Kupffer cell blockade reduces mortality of acute hemorrhagic pancreatitis in mice

Inflammatory cytokines derived from the liver may cause distant organ failure and death m severe pancreatms To minmize hver cytokme release, we studied the effects of Kupffer cell blockade on the mortality rate and severity of mflammatlon m a model of that disease Thirty nuce were dlvlded mto three groups Group 1 received gadohmum chloride (1 mg/l00 g mtravenously), which blocks Kupffer cell acuvlty, and regular food Groups 2 and 3 were fed a chohne-deficient, etionine-supplemented diet and developed severe pancreatitls Group 2 (control) received intravenous sahne solution, and group 3 recewed gadohmum chlonde Animals were lulled at 72 hours Serum levels of tumor necrosis factor-a and mterlenkm-1p, mterleukmd, and mterlenkm-10 were determined by enzyme-hnked lmmunosorbent assay Lung neutrophll mfiltration was assessed by myeloperoxldase assay Pancreatic mflammauon was scored m a blinded manner In a separate experiment, mortahty rates were determmed m saline- and gadohnmm-treated animals (n = 100) Gadohmium reduced the levels of all the cytokmes and lung myeloperoxldase (P <0 0.5) Gadolmium also reduced the mortality rate (52% vs 86%,P<0 001) However, the degree of pancreatic mflammaaon was unchanged by gadohnmm treatment These data support the hypothesis that mortality m severe pancreauus may m part be related to the secondary release of hepauc cytokmes.

Endoscopic measurement of pancreatic tissue perfusion in patients with chronic pancreatitis and control patients

BACKGROUND Pancreatic blood flow is diminished in experimental models of acute and chronic pancreatitis. We attempted to develop a safe and reliable technique for its measurement in patients and to examine blood flow in patients with chronic pancreatitis and in control subjects. METHOD Pancreatic blood flow was measured using the hydrogen gas clearance technique and an endoscopically placed platinum ductal electrode. Pancreatic blood flow was measured in 12 patients with chronic pancreatitis diagnosed clinically and radiographically, and in 11 control patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) for non-pancreatic pathology. RESULTS Patients with chronic pancreatitis had a significantly lower pancreatic blood flow compared with control patients (51.5 versus 91.7 mL/min/100 gm, p < 0.01). With secretin stimulation pancreatic blood flow increased in two control patients, whereas this notable rise was not seen in three patients with chronic pancreatitis. CONCLUSIONS Measurement of pancreatic blood flow with an endoscopically placed electrode is relatively safe and simple to perform. The scarring and vascular fibrosis associated histologically with chronic pancreatitis is reflected in lower pancreatic blood flow.

An ETa/ETb endothelin antagonist ameliorates systemic inflammation in a murine model of acute hemorrhagic pancreatitis

BACKGROUND Endothelin peptides are polykines with strong vasoconstrictor properties. We have previously shown that endothelin antagonism (PD145065) reduces the local severity of acute pancreatitis. We now investigated the effect of endothelin antagonism on systemic inflammation in a model of acute hemorrhagic pancreatitis. METHODS Forty-two mice were divided into four groups. Group 1 was fed standard food plus PD145065 every 8 hours. Group 2 was fed a choline-deficient ethionine (CDE) supplemented diet and given saline every 8 hours. Group 3 was fed a CDE diet and treated with PD145065 every 8 hours from initiation of diet. Group 4 was fed a CDE diet and given PD145065 from 48 hours after initiation of diet. Animals were killed at 70 hours. Serum was collected. Pancreata and lung tissue were harvested. RESULTS Histology score, serum amylase level, lung myeloperoxidase, and interleukin (IL)-10 were all significantly reduced in both treatment groups (groups 3 and 4) (p < 0.05). IL-6 levels were reduced in group 3 only (p < 0.05). The mortality rate did not differ among any of the groups. CONCLUSIONS Endothelin antagonism decreased the severity of acute pancreatitis and reduced markers of systemic inflammation. Late treatment at 48 hours failed to prevent the rise in IL-6. Mortality rates were unaffected by treatment.

Intragastric Alcohol Causes Endothelin Release from Feline Pancreas

The mechanism by which alcohol causes pancreaticdamage is still largely unknown. One importantcontributory factor may be the endothelins, potentvasoconstricting endothelialderived peptides. The aim of this study was to examine in vivo endothelinrelease from the pancreatic vascular endothelium afteralcohol ingestion. In anesthetized cats immunoreactiveendothelin was measured in serum after instillation of alcohol into the stomach (20 ml, 40%). Afterintragastric alcohol, a rise in endothelin was seen inpancreatic venous effluent (to a mean of 24.5 ±7.7 pg/ml at 60 min). Control serum from the femoral artery exhibited no rise in endothelin (2.11± 1.2 pg/ml). Pancreatic blood flow wassignificantly decreased in a further group to 93% basalafter intravenous infusion of 0.1 nmol/kg ET-1 and to61% after infusion of 1 nmol/kg ET-1. Portal serum levelsof endothelin were 105 pg/ml and 15 pg/ml, respectively,immediately following bolus infusion and decreased tonormal levels within 120 sec. We conclude that the serum endothelin rise after intragastricethanol may be a major factor behind the drop inpancreatic blood flow.

The surgical approach to severe acute pancreatitis

The indications for surgery in severe acute pancreatitis include circumstances in which the diagnosis is uncertain, persistent biliary pancreatitis, infected pancreatic necrosis, and some patients with pancreatic abscess. The controversy surrounding surgical treatment for sterile pancreatic necrosis, and situations in which the disease persists in spite of intensive medical management are also addressed. Surgical principles and the merits of open versus closed drainage are reviewed.