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ObjectiveTo compare the effects of 35% hepatic cryoablation with a similar degree of radiofrequency ablation (RFA) on lung inflammation, nuclear factor B (NF-B) activation, and production of NF-B dependent cytokines. Summary Background DataMultisystem injury, including acute lung injury, is a severe complication associated with hepatic cryoablation of 30% to 35% or more of liver parenchyma, but this complication has not been reported with RFA. MethodsSprague-Dawley rats underwent 35% hepatic cryoablation or RFA and were killed at 1, 2, and 6 hours. Liver and lung tissue were freeze-clamped for measurement of NF-B activation, which was detected by electrophoretic mobility shift assay. Serum concentrations of tumor necrosis factor ␣ and macrophage inflammatory protein 2 were measured by enzyme-linked immunosorbent assay. Histologic studies of pulmonary tissue and electron microscopy of ablated liver tissue were compared among treatment groups. ResultsHistologic lung sections after cryoablation showed multiple foci of perivenular inflammation, with activated lymphocytes, foamy macrophages, and neutrophils. In animals undergoing RFA, inflammatory foci were not present. NF-B activation was detected at 1 hour in both liver and lung tissue samples of animals undergoing cryoablation but not after RFA, and serum cytokine levels were significantly elevated in cryoablation versus RFA animals. Electron microscopy of cryoablationtreated liver tissue demonstrated disruption of the hepatocyte plasma membrane with extension of intact hepatocyte organelles into the space of Disse; RFA-treated liver tissue demonstrated coagulative destruction of hepatocyte organelles within an intact plasma membrane. To determine the stimulus for systemic inflammation, rats treated with cryoablation had either immediate resection of the ablated segment or delayed resection after a 15-minute thawing interval. Immediate resection of the cryoablated liver tissue prevented NF-B activation and lung injury; however, pulmonary inflammatory changes were present when as little as a 15-minute thaw interval preceded hepatic resection. ConclusionsHepatic cryoablation, but not RFA, induces NF-B activation in the nonablated liver and lung and is associated with acute lung injury. Lung inflammation is associated with the thawing phase of cryoablation and may be related to soluble mediator(s) released from the cryoablated tissue. These findings correlate the clinical observation of an increased incidence of multisystem injury, including adult respiratory distress syndrome (ARDS), after cryoablation but not RFA.

Pulmonary thromboembolism (PEm) is a serious and life threatening disease and the most common cause of acute pulmonary vascular occlusion. Even following successful treatment of PEm, many patients experience long-term disability due to diminished heart and lung function. Considerable damage to the lungs presumably occurs due to reperfusion injury following anti-occlusive treatments for PEm and the resulting chronic inflammatory state in the lung vasculature. We have used a rat model of irreversible PEm to ask whether pulmonary vascular occlusion in the absence of reperfusion is itself sufficient to induce an inflammatory response in lungs. By adjusting the severity of the vascular occlusion, we were able to generate hypertensive and nonhypertensive PEm, and then examine lung tissue for expression of CXC and C-C chemokine genes and bronchoalveolar lavage (BAL) fluid for the presence of chemokine proteins. Hypertensive and nonhypertensive PEm resulted in increased expression of both CXC and C-C chemokines genes in lung tissues. Hypertensive PEm was also associated with a 50–100-fold increase in protein content in lung BAL fluid, which included the CXC chemokines cytokine-induced neutrophil chemoattractant and macrophage-inflammatory protein 2. The presence of chemokines in BALs was reflected by a potent neutrophil chemotactic activity in in vitro chemotaxis assays. Abs to cytokine-induced neutrophil chemoattractant blocked the in vitro neutrophil chemotactic activity of BAL by 44%. Our results indicate that the ischemia and hypertension associated with PEm are sufficient to induce expression of proinflammatory mediators such as chemokines, and establish a proinflammatory environment in the ischemic lung even before reperfusion.

The mean Amicus CD34+ cell collection efficiency was better (p<0.05) than that of the CS-3000 Plus collection. Short-term engraftment was durable. The PBPCs collected with the Amicus separator are safe and effective for use for autologous transplant patients requiring PBPC rescue from high-dose myeloablative chemotherapy.

2002.-Our objective was to test the effect of inhibition of thromboxane synthase versus inhibition of cyclooxygenase (COX)-1/2 on pulmonary gas exchange and heart function during simulated pulmonary embolism (PE) in the rat. PE was induced in rats via intrajugular injection of polystyrene microspheres (25 m). Rats were randomized to one of three posttreatments: 1) placebo (saline), 2) thromboxane synthase inhibition (furegrelate sodium), or 3) COX-1/2 inhibition (ketorolac tromethamine). Control rats received no PE. Compared with controls, placebo rats had increased thromboxane B2 (TxB2) in bronchoalveolar lavage fluid and increased urinary dinor TxB2. Furegrelate and ketorolac treatments reduced TxB2 and dinor TxB2 to control levels or lower. Both treatments significantly decreased the alveolar dead space fraction, but neither treatment altered arterial oxygenation compared with placebo. Ketorolac increased in vivo mean arterial pressure and ex vivo left ventricular pressure (LVP) and right ventricular pressure (RVP). Furegrelate improved RVP but not LVP. Experimental PE increased lung and systemic production of TxB 2. Inhibition at the COX-1/2 enzyme was equally as effective as inhibition of thromboxane synthase at reducing alveolar dead space and improving heart function after PE. thromboembolism/treatment; cyclooxygenase; thromboxane; leukotriene; ketorolac; heart failure; Langendorff; animal model PULMONARY EMBOLISM (PE) continues to be a major cause of morbidity and mortality in the United States. In one large autopsy-based study, massive PE was the second leading cause of sudden death in adults aged Ͻ65 yr (4). The primary treatment strategy for massive PE is the recanalization of occluded pulmonary vasculature by fibrinolytic agents (11), catheter fragmentation (32), or surgical removal of clot (16). However, up to one-half of patients with massive PE have contraindications to fibrinolysis (15), and few hospitals have facilities for invasive treatment of PE. Even under optimal conditions (e.g., immediate bolus infusion of a fibrinolytic agent), these interventions require Ͼ2 h to effect a significant reduction in pulmonary vascular resistance (20). PE may also cause pulmonary vasoconstriction through the liberation of vasoconstrictive agents, including PGF 2␣ and thromboxane (Tx) A 2 and B 2 (10). PE can cause hypoxemia and increased pulmonary arterial pressure in previously healthy patients (19). Both hypoxemia and increased shear forces in the pulmonary vascular bed have been found to increase expression of the cyclooxygenase (COX)-2 gene (3). In humans with PE, blood concentrations of thromboxane have been found to be elevated for up to 7 days after onset of symptoms (10). Both the mechanical vascular occlusion and release of vasoconstrictive agents from massive PE appear to produce a synergistic effect that causes acute pulmonary hypertension, worsened gas exchange, impaired right ventricular (RV) function that can culminate in acute cor pulmonale, circulatory shock, and even death (26,30,39).In the ...

These data show that hepatic cryosurgery results in systemic inflammation with activation of NF-kappa B and increased production of NF-kappa B-dependent cytokines. Our data suggest that lung injury and death in this animal model is mediated by an exaggerated inflammatory response to cryosurgery.

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