Hepatocyte injury by activated neutrophils in vitro is mediated by proteases.

OBJECTIVE: This study determined the mechanism used by neutrophils (PMNs) to induce hepatocellular injury. SUMMARY BACKGROUND DATA: Neutrophils have been shown to be potent mediators of cell and tissue injury and have been hypothesized to contribute to the hepatic injury that occurs after trauma and infection. Oxygen radical scavengers protect the liver in vivo from inflammatory injury and it has been suggested that PMNs are the source of these toxic oxygen radicals. The specific mechanism used by PMNs to produce hepatocellular damage, however, has not been determined. METHODS: Neutrophils were cultured in vitro with hepatocytes (HCs) and stimulated with phorbol 12-myristate 13-acetate (PMA) to induce HC injury in the presence of oxygen radical scavengers and protease inhibitors. RESULTS: PMA induced a PMN-mediated HC injury that was dependent on the number of PMNs present and the concentration of PMA. Protease inhibitors reduced the extent of HC injury, while oxygen radical scavengers had no effect. Hydrogen peroxide, directly applied, was able to injure HCs, but only at concentrations greater than those that could be produced by PMA-stimulated PMNs. CONCLUSIONS: PMNs are cytotoxic to cultured HCs, predominantly due to the release of proteolytic enzymes, while HCs appear relatively resistant to oxidative injury. Involvement of neutrophil toxic oxygen radicals in hepatic damage in vivo may require impairment of HC antioxidant defenses or may involve injury to nonparenchymal liver cells with secondary effects on HCs.     

Effect of FR167653 on pancreatic ischemia-reperfusion injury in dogs

BACKGROUND: The role of inflammatory cytokines is still unclear in ischemia-reperfusion injury of the pancreas. We investigated the effect of FR167653 (FR), a newly developed compound that is a potent suppressor of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha on ischemia-reperfusion injury of the isolated pancreatic tail in dogs. METHODS: The tail of the pancreas was subjected to ischemia for 90 minutes. During occlusion of the vascular inflow, the head of the pancreas was removed. A control group (n = 14) and an FR treatment group (n = 11) were evaluated for survival rate, tissue blood flow, arterial oxygen pressure (Pao(2)), serum amylase and lipase levels, glucose and insulin, liver enzymes, creatinine, IL-1beta mRNA in the peripheral blood, and histopathology. RESULTS: Six of the 14 control animals and 2 of the 11 FR-treated animals died. The FR treatment group showed lower amylase (P=.037) and lipase (P =.030) levels, lower IL-1beta mRNA expression (P =.033), and less pancreatic tissue damage (P =.041) than did the control group, but there was no remarkable change in endocrine function (P =.422). Pao(2) during the acute phase in the FR treatment group was maintained (P=.009), but pulmonary tissue was damaged. Results of biochemical and histologic examinations of the liver and kidneys were unremarkable. CONCLUSIONS: FR ameliorates ischemia-reperfusion injury of the pancreas and reduces the production of inflammatory cytokines that may contribute to secondary damage to distant organs.     

Experimental observations on spinal cord injury produced by electrifying the vessels of the cord in dogs

To make the ischemic effect on spinal cord clear, different vessels of the cord of 38 dogs, in 5 groups, were electrically cauterized individually or in combination. The animals in each group were sacrificed in due time periods, and the pathology of corresponding segment of each cord was observed grossly and under electron as well as light microscopes. The findings were described in this paper. As a consequence, the dogs in each group manifested paraplegia varying in degrees. However, dogs with the anterior cord artery and unilateral radicular artery, or both the anterior and posterior cord arteries cauterized developed irreversible, complete paraplegia. Cauterization of the anterior cord artery, or the posterior cord artery and unilateral radicular artery, or the radicular artery on both sides, gave rise to reversible, incomplete paraplegia. Anatomy of vessels of the spinal cord of other 9 dogs were dissected and studied. Their presence and distribution were cited and referred to the discussion about the effect of ischemia induced by electrifying them individually or in combination.     

Intestinal atresia in fetal dogs produced by localized ligation of mesenteric vessels.

Experimental ileal atresia and stenosis were produced by a localized ligation of the mesenteric vessels in fetuses from 13 pregnant mongrel dogs having gestational ages of 45-55 days. The intestinal infarct in the fetus was characterized by an aseptic coagulation necrosis selectively limited to the mucosa and submucosa, and also by intense hyperemia and minimal cellular reaction in the adjacent tissue. Eleven days after the devascularization, type 2 intestinal atresia, in which there is a long cord between the blunt ends microscopically similar to that seen in humans.     

Esophageal varices produced in dogs

In attempts to produce esophageal varices in dogs, we designed a procedure based on the concept of hyperdynamic flow. The first stage operation involved the achievement of an arteriovenous shunt between the left renal artery and the proximal splenic vein, in concert with the distal splenic venous-left renal venous shunt. About one month after the initial operation, sixteen of the twenty-eight dogs had tolerated the manipulations. Both shunts proved to be functioning well in six of sixteen survivors, in which an ameroid constrictor was placed around the splenic vein just proximal to the confluence of the left gastric vein. Again one month later, in five of these six, esophageal varices were evidenced, both endoscopically and histologically. Arterialization of left gastric vein concomitant with the distal splenorenal shunt, gave rise to a hyperdynamic state in the upper stomach and resulting in reproducible esophageal varices.     

Esophageal varices produced in dogs

In attempts to produce esophageal varices in dogs, we designed a procedure based on the concept of hyperdynamic flow. The first stage operation involved the achievement of an arteriovenous shunt between the left renal artery and the proximal splenic vein, in concert with the distal splenic venous-left renal venous shunt. About one month after the initial operation, sixteen of the twenty-eight dogs had tolerated the manipulations. Both shunts proved to be functioning well in six of sixteen survivors, in which an ameroid constrictor was placed around the splenic vein just proximal to the confluence of the left gastric vein. Again one month later, in five of these six, esophageal varices were evidenced, both endoscopically and histologically. Arterialization of left gastric vein concomitant with the distal splenorenal shunt, gave rise to a hyperdynamic state in the upper stomach and resulting in reproducible esophageal varices.     

Lung injury in patients following thoracotomy.

BACKGROUND--Postoperative lung injury is a recognised complication of thoracotomy for which there are few data regarding incidence and outcome. METHODS--In a case controlled study the notes of all adult patients who developed acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) following thoracotomy between 1991 and 1994 were examined and classified according to the guidelines of the American Thoracic Society/European Respiratory Society for ALI/ARDS. The predictive value of a routine preoperative assessment and duration of anaesthesia in determining those patients most likely to develop ALI/ARDS was assessed. RESULTS--Between 1991 and 1994 231 lobectomies, 103 pneumonectomies, and 135 wedge resections and segmentectomies were performed. The overall incidence of lung injury was 5.1%; 17 patients developed ARDS (two survived) and seven developed ALI (five survived). There was no significant difference compared with case matched controls in preoperative spirometric values, arterial oxygen tension (PaO2), or duration of anaesthesia. None of these parameters was useful in predicting those patients most likely to develop lung injury. CONCLUSION--Lung injury after thoracotomy is associated with a high mortality. Conventional parameters for preoperative assessment do not predict those patients most likely to develop ALI/ARDS in these circumstances.     

Cyanoacrylate sealing of pancreatic biopsy sites in dogs.

The ability of ethyl cyanocrylate monomer adhesive in preventing leaks following pancreatic surgery dogs was evaluated. Seventeen of 18 dogs in the control group had evidence of pancreatic leak following biopsy. There was no evidence of leak in 17 of 18 dogs on which the adhesive was used to seal the cut surface of the pancreas. Similar successful use of ethyl cyanoacrylate in patients would provide a safe method of taking a specimen from a mass for biopsy in the pancreas.     

Intrabiliary pressure changes produced by inhalational anesthetics in dogs]

The common bile duct pressure was studied in dogs under inhalation of 1.0 MAC and 2.0 MAC of halothane, enflurane, isoflurane or sevoflurane. A double lumen catheter was inserted into the common bile duct through the cholecystic duct for the measurement of intraductal pressure in the choledochoduodenal junction. The intra-bile-ductal pressure (IBP) was measured with constant rate infusion methods every 10 minutes for one hour. After obtaining control IBP measurements, 44 dogs received randomly either 1.0 MAC (n = 6 in each group) or 2.0 MAC (n = 5 in each group) of each four inhalational anesthetics, through a non-rebreathing system. The decreases in IBP produced by 1.0 MAC concentrations of four inhalation anesthetics were not statistically significant although there was a decline from control measurements obtained for each group. The elevations of IBP following 2.0 MAC halothane, isoflurane or sevoflurane were significantly depressed and were 38.3 +/- 21.2, 67.5 +/- 23.8, 63.7 +/- 23.7 (%, mean +/- SD) of the control levels, respectively. However, 2.0 MAC enflurane produced no significant decrease in IBP.     

Lung procurement by low-potassium dextran and the effect on preservation injury. Munich Lung Transplant Group.

BACKGROUND: This clinical study was performed to evaluate the effect of low-potassium dextran (LPD) solution on organ function in human lung transplantation. METHODS: A total of 80 patients were included in this study. Donor lungs were flushed with Euro-Collins (EC) solution in 48 cases or LPD (Perfadex) in 32 cases. Subsequently, single- (EC: n = 31; LPD: n = 15) or double-lung transplantations (EC: n = 17; LPD: n = 17) were performed. The evaluation parameters of transplant function were the reperfusion injury score (grade I to V); the alveolar/arterial oxygen ratio; the duration of respirator therapy; and the length of intensive care treatment and survival. RESULTS: Incidence and severity of reperfusion injury score were more severe in the EC group (31 of 48: grade I: n = 13; II: n = 8; III: n = 5; IV: n = 2; V: n = 3; LPD group: 17 of 32 patients; grade I: n = 12; II: n = 1; III: n = 3; IV: n = 0 grade V: n = 0), leading to death in three patients. In the LPD group, despite of the use of cardiopulmonary bypass, alveolar/arterial oxygen ratio values were significantly (P = 0.009) better during the early postoperative phase. Thirty-day mortality was 12% in the EC group and 6% in the LPD group. The one-year survival rate was 79% after the use of LPD (vs. EC: 62%). CONCLUSIONS: Graft preservation using LPD leads to better immediate and intermediate graft function after pulmonary transplantation and also results in better long-term survival.     

Cognitive deficits following traumatic brain injury produced by controlled cortical impact.

Traumatic brain injury produces significant cognitive deficits in humans. This experiment used a controlled cortical impact model of experimental brain injury to examine the effects of brain injury on spatial learning and memory using the Morris water maze task. Rats (n = 8) were injured at a moderate level of cortical impact injury (6 m/sec, 1.5-2.0 mm deformation). Eight additional rats served as a sham-injured control group. Morris water maze performance was assessed on days 11-15 and 30-34 following injury. Results revealed that brain-injured rats exhibited significant deficits (p less than 0.05) in maze performance at both testing intervals. Since the Morris water maze task is particularly sensitive to hippocampal dysfunction, the results of the present experiment support the hypothesis that the hippocampus is preferentially vulnerable to damage following traumatic brain injury. These results demonstrate that controlled cortical impact brain injury produces enduring cognitive deficits analogous to those observed after human brain injury.     

Surgical imperatives in pancreatic transplantation in dogs

The authors report their experience of segmental pancreatic autotransplantation in dogs. The most reliable model seems to be: segmental heterotopic pancreas transplantation with bladder diversion of the exocrine secretion and spleno-splenic arterio-venous fistula allowing monitoring of the exocrine secretion and a reduction in the thrombosis rate.     

Experimental spinal cord injury produced by axial tension

Fifty cats underwent spine distraction with forces applied until the evoked potential (EP) amplitude was reduced 50 or 95%. Neurologic status and EPs were monitored for up to 6 weeks. Fifty percent reduction occurred at (x) = 4.2-kg distraction/kg body weight (BW); 95% at 7.4 kg distraction/kg BW: differences were significant (p less than .05). The 50% group showed quadriparesis at 24 hours (Tarlov 1), improving by 4 weeks (x = 3). Ninety-five percent-group animals were quadriplegic initially, progressing to Tarlov 2.2. Residual EP changes occurred, particularly in the 95% group. Early histologic changes included central necrosis and neuronal chromatolysis. Later, axon disruption was observed, with cystic degeneration and gliosis at 4-6 weeks. Tissue damage correlated with ultimate neurologic status. Correlations between latency changes and early neurologic status, and between amplitude and histology were observed. The axial tension model may be of value in the study of spinal cord injury mechanisms.