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P Boros

Publications and source records attributed to P Boros.

At least 19 recordsLinked to original sources
PubMed2006

New cellular and molecular immune pathways in ischemia/reperfusion injury.

Ischemia/reperfusion injury (IRI) is a multi-factorial antigen-independent inflammatory condition that profoundly affects both early and long-term function of the allograft as suggested by both clinical and experimental data. In recent years, the acute phase of IRI has been increasingly viewed as part of the innate immune response. Identification of novel molecular pathways and new insights into the mechanisms of known mediators of IRI have established links among innate immunity, adaptive immune responses and organ regeneration, and thus long-term graft function. This review approaches these novel aspects of IRI in the context of solid organ transplantation, presenting data on new observations with kidney, liver and heart allografts.

Animals↗
PubMed2001

Intrahepatic expression and release of vascular endothelial growth factor following orthotopic liver transplantation in the rat.

BACKGROUND: Morphological and functional changes to sinusoidal endothelial cells mediated by soluble factors released from activated Kupffer cells, including cytokines, are considered pivotal events in ischemia/reperfusion injury (IRI) to liver grafts. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific cytokine with potent pro-inflammatory and mitogenic effects. We investigated the possible role of VEGF in IRI to liver grafts using a syngeneic rat orthotopic liver transplantation model. METHODS: Transplantation was performed in Lewis rats using livers preserved for various periods of time (24-48 hr) in University of Wisconsin solution at 4 degrees C. Systemic VEGF levels were measured by enzyme-linked immunosorbent assay (ELISA). Intrahepatic VEGF expression was analyzed by Northern blotting and in situ hybridization. The effects of anti-VEGF neutralizing antibody treatment on the extent of IRI were assessed by measuring liver function tests, lipid peroxidation, and metalloproteinase activity. RESULTS/CONCLUSION: VEGF is expressed and released in a biphasic pattern during the early postoperative period after liver transplantation. Anti-VEGF antibody treatment, administered during reperfusion, decreased the degree of damage, suggesting that VEGF may have a role in IRI to liver grafts.

Animals↗
PubMed2001

Graft function and survival depend primarily on host factors in compromised recipient models of orthotopic liver transplantation in the rat.

BACKGROUND: Experimental models of liver transplantation use normal recipients, although most patients undergoing liver transplantation suffer from acute or chronic liver failure. This study was designed to analyze the outcome of orthotopic liver transplantation in compromised rat hosts. METHODS: Recipient animals were either rats with D-galactosamine-induced acute or rats with chronic liver failure secondary to common bile duct ligation. Liver damage was evaluated by monitoring enzymes, bilirubin, ammonia levels, prothrombin, thrombin time, and cytokines. In vivo function of hepatocytes and sinusoidal endothelial cells were evaluated by indocyanine green and hyaluronic acid uptake. Transplantation was performed in normal, acute, and chronic liver failure rats at different time points using either freshly harvested or cold-preserved syngeneic livers. RESULTS: Survival with fresh grafts decreased significantly when transplants were performed 48 hr after the induction of acute liver failure. No rats with acute liver failure survived transplantation with grafts stored for 12 or 24 hr although in chronic failure survival was more 80%. Survival of acute liver failure rats receiving 6 hr preserved grafts was 16.6% compared with 83.3% observed with fresh grafts transplanted at the same time point after D-galactosamine injection. Elevated tumor necrosis factor-alpha and interleukin-1beta levels as well as impaired sinusoidal endothelial cell function were detected in acute liver failure rats with 6 h preserved grafts. CONCLUSION: These results suggest that preoperative status and different host factors have a significant effect on outcome and graft function after liver transplantation in rats.

Animals↗
PubMed2001

Combination of electroporation and DNA/dendrimer complexes enhances gene transfer into murine cardiac transplants.

Electroporation is a new gene delivery method to increase gene transfer and expression in vivo. Starburst polyamidoamine dendrimers have been demonstrated to augment gene expression in vitro and in vivo. We hypothesized that the combination of electroporation and dendrimer could enhance the gene transfer and gene expression in cardiac transplants. After immersion in DNA/dendrimer complexes or intracoronary transfer of DNA/dendrimer complexes, both nonvascularized and vascularized syngeneic cardiac grafts, respectively, were subjected to serial electrical pulses before transplantation. beta-Galactosidase reporter gene expression in the graft was determined by X-Gal staining. Gene expression was enhanced 10- to 45-fold in grafts immersed in DNA/dendrimer complexes, or after intracoronary transfer of DNA/dendrimer complexes, and subjected to 20 square wave 25-ms pulses with a strength of 200 V/cm. The combination of electroporation and DNA/dendrimer complexes may provide a novel approach to enhance gene transfer and gene expression ex vivo.

Animals↗
PubMed2001

Recurrence of hepatitis C after liver transplantation is associated with increased systemic IL-10 levels.

BACKGROUND: Recurrence of hepatitis C after liver transplantation is an almost universal occurrence. T-cell derived cytokines have an important role in the development of liver damage associated with chronic hepatitis C, their post-transplant levels, however, have not been correlated with histologic recurrence of the disease. AIMS: We sought to analyze levels of TNF-alpha, soluble IL-2 receptor, IL-4 and IL-10 at 1 month, 6 months and 1 year after transplantation in 27 patients undergoing transplantation for hepatitis C related end-stage liver disease. METHODS: HCV RNA levels were monitored by a branched-chain DNA signal amplification assay. Diagnosis of recurrent hepatitis was based on 1-year protocol biopsies and on biopsies performed for liver enzyme elevations. RESULTS: Recurrent hepatitis C was detected in 52% (n=14) of the 27 patients. HCV RNA levels rose over time in all patients regardless of histologic recurrence. TNF-alpha, and IL-4 levels, although elevated, did not show specific patterns over time or in correlation with recurrence. Similarly, the early elevation followed by a gradual decrease over the first year in the amount of soluble IL-2 receptor was not related to histologic recurrence. We observed a significant increase in circulating IL-10 levels over the first year in patients with biopsy-proven recurrence, while patients with no signs of histologic recurrence displayed increased, but steady levels. CONCLUSIONS: These results suggest that while these cytokines are associated with post-transplant recurrence of hepatitis C, their production may be altered by additional factors.

Hepatitis C↗
PubMed2000

Expression of GMP-140 (P-selectin) correlates with graft viability in cold-preserved rat livers.

BACKGROUND: Ischemia/reperfusion injury is an inflammatory process involving cytokine release, Kupffer cell activation, and sinusoidal endothelial cell activation. GMP-140 is synthesized by endothelial cells. METHODS: We analyzed by Western blotting the expression of GMP-140 in a syngeneic rat liver transplantation model using grafts preserved for different periods of time. RESULTS: Compared with prereperfusion samples, expression did not change significantly in freshly harvested and 4-hr preserved livers. In grafts preserved for 24 hr (100% survival), GMP-140 levels increased dramatically at 1 hr, then returned to baseline at 24 hr after transplantation. Forty-eight hour preserved grafts (0% survival) showed a decreasing expression. To identify possible mediators, the effects of tumor necrosis factor-alpha and interleukin-1beta on GMP-140 expression in primary sinusoidal endothelial cells were analyzed. These cytokines increased both the percentage of stained cells as well as their mean staining fluorescence. CONCLUSIONS: The absence of increase in 48-hr grafts suggests that GMP-140 may distinguish viable from nonviable livers.

Animals↗
PubMed2000

DNA/dendrimer complexes mediate gene transfer into murine cardiac transplants ex vivo.

Starburst polyamidoamine dendrimers are synthetic polymers with unique structural and physical characteristics suitable for DNA gene transfer. Our previous studies demonstrated that Starburst dendrimers augment plasmid-mediated gene transfer efficiency in a nonvascularized, cardiac transplantation model. In this study, the fifth generation of ethylenediamine core dendrimer was investigated for its ability to enhance gene transfer and expression in a clinically relevant murine vascularized heart transplantation model. The plasmid pMP6A-beta-gal, encoding beta-galactosidase (beta-Gal), was incubated with dendrimers to form complexes. The complexes were perfused via the coronary arteries during donor graft harvesting, and reporter gene expression was determined by quantitative evaluation of X-Gal staining. The grafts infused with pMP6A-beta-gal/dendrimer complexes showed beta-Gal expression in myocytes from 7 to 14 days. A number of variables for transfer of the DNA/dendrimer complexes were tested, including DNA:dendrimer charge ratios, concentrations of DNA and dendrimer, preservation solutions, ischemic time, and enhancement of vascular permeability by serotonin, papaverine, and VEGF administration. The results showed that DNA/dendrimer complexes containing 20 microg of DNA and 260 microg of dendrimer (1:20 charge ratio) in a total volume of 200 microl resulted in highest gene expression in the grafts. The results also showed that prolonged incubation (cold ischemic time) to 2 h and pretreatment with serotonin further enhanced gene expression.

Animals↗
PubMed2000

Cytokine profiles in early rejection following OKT3 treatment in liver transplant patients.

OKT3 , a murine monoclonal antibody specific to the human CD3 complex, induces immunosuppression by depletion of T cells. Administration of OKT3 results in significant release of proinflammatory cytokines, such as TNFalpha and IL1beta. Liver recipients who experience rejection within 3 weeks after transplantation with OKT3 prophylaxis recover their T cells by postoperative day 10 despite complete initial clearance. We sought to analyze the role of proinflammatory and Th-1 cytokines in T cell recovery and rejection after liver transplantation with OKT3 prophylaxis. In plasma samples from 32 patients, we measured TNFalpha, IL1beta and IL6 (before transplant and on postoperative days 1, 2 and 3) and IL2, IFNgamma, sIL2R and slCAM (postoperative days 5, 7 and 10) and examined possible correlations with T-cell recovery and occurrence of rejection within 3 weeks. TNFalpha, IL1beta, and IL6 did not correlate with T-cell recovery. In patients who rejected, IL2 and IFNgamma on postoperative days 5 and 7 correlated with degree of T-cell recovery by day 10; a significant rise in sIL2R over time also correlated with T-cell recovery in this group. Our results emphasize the role of Th-1 cytokines in rejection following OKT3 induction and suggest that markers of T cell activation may predict risk.

Animals↗
PubMed2000

Th1/Th2 cytokines and ICAM-1 levels post-liver transplant do not predict early rejection.

Th1 derived cytokines IFN-gamma and IL-2, Th2 cytokine IL-4, and ICAM-1 have been implicated in liver allograft rejection. In order to determine whether monitoring of cytokine profiles during the first days post-liver transplant can predict early rejection we measured IFN-gg, IL-2, sIL-2 receptor, IL-4 and ICAM-1 in 22 patients, in plasma samples obtained within 4 h after liver perfusion (baseline) and between postoperative days (POD) 3-6. ICAM-1 and sIL-2R levels at POD 3-6 were significantly higher than at baseline but did not differ in presence or absence of rejection. Mean percentage increase of ICAM-1 levels was significantly lower in patients with Muromonab-C3 Orthoclone OKT3 (J.C. Health Care) (OKT3) whereas percentage increase of sIL-2R levels was higher in OKT3-treated patients. IFN-gamma levels at POD 3-6 increased from baseline while IL-4 levels were unchanged. Levels of IFN-gamma, IL-4 and their ratios did not correlate with rejection or immunosuppressive therapy. Thus, Th1/Th2 cytokine monitoring during the first week post-transplant does not predict early rejection and immunosuppressive therapy is the predominant factor affecting ICAM and sIL-2R levels after liver transplantation.

Female↗
PubMed2000

Serum hepatitis C virus RNA levels and histologic findings in liver allografts with early recurrent hepatitis C.

BACKGROUND: Histopathologic features of early recurrent hepatitis C after orthotopic liver transplantation (OLTx) may be modified by immunosuppressive therapy or complicated by other conditions. Hepatitis C virus (HCV) RNA level usually increases after OLTx, but its correlation to histologic findings is not clear. OBJECTIVE: To evaluate the histologic findings of early recurrent hepatitis C in liver allografts and its correlation to serum HCV RNA level. METHODS: We studied 14 patients who underwent OLTx for chronic HCV infection. Thirty liver biopsy specimens and HCV RNA levels of 22 corresponding plasma samples obtained during the first 6 months following OLTx were analyzed. The control group (9 patients, 25 biopsy specimens) was chosen at random from patients with chronic liver disease other than HCV who were undergoing OLTx, and all tested negative for HCV RNA by polymerase chain reaction after OLTx. RESULTS: Statistically significant pathological features of early recurrent HCV infection were the number of acidophilic bodies, piecemeal necrosis, lymphocyte predominance in the portal tracts, and fibrous septum. These findings and histologic activity index scores increased with time after OLTx. The HCV RNA levels determined by branched DNA assay showed no significant correlation with histologic features. However, patients with higher histologic activity index scores tended to have higher RNA levels. CONCLUSIONS: Liver biopsy specimens are helpful for the diagnosis or confirmation of early recurrent hepatitis C in liver allografts, but serial biopsy specimens are sometimes required for definite diagnosis. The HCV RNA levels are usually higher in patients who display signs of more severe liver damage.

Biopsy↗
PubMed2000

[Respiratory response to inspiratory resistive load changes in patients with obstructive sleep apnea syndrome].

Patients with OSA have many episodes of increased airway resistance because of repeated collapses of upper airways during night. The aim of this work was to evaluate respiratory response during chemical stimulation without and with added inspiratory resistive load (10 cmH2O/L/sec). The studies were performed during quiet breathing with air and during hypercapnic and hypoxic rebreathing tests without and with inspiratory resistive loading in 23 obese (BMI = 34.4 +/- 4.3 kg/m2) patients with OSA and in 10 healthy subjects with similar weight (BMI = 32.4 +/- 4.3 kg/m2). The measurements of respiratory responses (ventilation, mouth occlusion pressure) were performed with the use of computerized equipment. During quiet breathing in response to added load an increase of P0.1 in controls and in OSA patients was observed. During hypercapnic stimulation the ventilatory response with additional load decreased in patients as well as in controls. The slope of mouth occlusion pressure response increased significantly in controls (from 4.40 to 6.83 cmH2O/kPa, p < 0.001) and slightly weaker in OSA patients (from 4.21 to 5.43 cmH2O/kPa, p < 0.05). Although the difference between the slopes was not significant, we found that the absolute increase of P0.1 measured at point 8 kPa of PEtCO2 during loaded breathing was significantly smaller in OSA patients in comparison to controls. (2.1 vs. 10.3 cm H2O; p < 0.001). During hypoxic stimulation occlusion pressure responses were similar in both examined groups. In conclusion we postulate that OSA patients have impaired respiratory compensation of additional inspiratory load, what was demonstrated during hypercapnic rebreathing test.

Adult↗
PubMed1999

Correlation between von Willebrand factor levels and early graft function in clinical liver transplantation.

Cold preservation/reperfusion leads to sinusoidal endothelial cell (SEC) activation and damage in nearly every liver transplantation; the extent of these changes influences early graft function. Upon reperfusion, activated SEC show increased expression of adhesion molecules, including von Willebrand factor (vWF) which is released into the circulation. This study was designed to evaluate the levels of vWF measured in the caval effluent and correlate these findings with known markers of SEC damage and early graft function. Data were obtained from 35 patients undergoing orthotopic liver transplantation (LTx). Two samples were taken from each patient for measurement of vWF: a) from the portal vein immediately prior to reperfusion; and b) from the first 50 ml of the caval effluent. Commercial assays were used to measure vWF, as well as hyaluronic acid (HA), thrombomodulin (TM), IL-1 beta, IL-6, IL-8 and TNF-alpha. Patients were divided into two groups based on early graft function. Poor early graft function (PEGF) was defined as a peak aspartate transaminase (AST) or alanine transaminase (ALT) level > 2500 U/L during the first three postoperative days (POD) and a prothrombin time (PT) > 16 s on POD 2 (n = 8). The remaining 27 patients had good early graft function (GEGF). In patients with GEGF, vWF levels dropped significantly between the two time points. This change was not observed in those with PEGF. A positive linear correlation was observed in the PEGF group between vWF and HA and IL-6. The different pattern of change in vWF between the two groups, as well as the positive correlation between HA, IL-6 and vWF in PEGF, suggest that vWF may be a useful marker of early graft function.

Adult↗
PubMed1998

Differential in vivo recovery of sinusoidal endothelial cells, hepatocytes, and Kupffer cells after cold preservation and liver transplantation in rats.

BACKGROUND: The injury resulting from cold preservation/reperfusion primarily affects sinusoidal endothelial cells, while hepatocytes are thought to be less vulnerable; morphological changes and increased cytokine release suggest that Kupffer cells are activated. We evaluated the extent of functional damage to the different cell types in the liver after cold preservation and transplantation. Additionally, we analyzed in vivo the patterns of functional recovery of all three cell types over the first week after transplantation in Lewis rats. METHODS: We evaluated the in vivo uptake of hyaluronic acid, indocyanine green, and radio-labeled sulphur colloid to assess the function of sinusoidal endothelial cells, hepatocytes, and Kupffer cells, respectively. Measurements were performed immediately after transplantation using syngeneic grafts preserved in University of Wisconsin solution for different periods. Functional recovery was monitored in animals receiving grafts preserved for 24 hr over the first postoperative week. RESULTS: We found that hepatocyte were less affected compared with the profoundly damaged endothelial cells. The phagocytic ability of Kupffer cells was, however, also seriously compromised, which suggests a selective down-regulation. Functional recovery occurs in a differential manner during the first postoperative week starting with hepatocytes followed by sinusoidal endothelial cells. Phagocytic function further deteriorates after transplantation before showing improvement. CONCLUSIONS: In viable liver grafts, all cell types recover from preservation/reperfusion injury by the end of the first week after transplantation. The differential time courses of the recovery suggest that successful sinusoidal endothelial cell recovery may depend upon prior hepatocyte regeneration and may involve a paracrine interaction, via cytokines and growth factors.

Alanine Transaminase↗
PubMed1998

Hyperosmolarity associated with diabetes insipidus alters hepatocyte structure and function but not survival after orthotopic liver transplantation in rats.

BACKGROUND: This study was designed to evaluate the effect of donor hyperosmolarity secondary to diabetes insipidus, an almost universal occurrence among brain-dead patients, on hepatic function. METHODS: In vitro (isolated liver perfusion) and in vivo (hyaluronic acid and indocyanine green uptake, arterial ketone body ratio, orthotopic liver transplantation) experiments were conducted using Brattleboro rats, with hereditary hypothalamic diabetes insipidus, and Sprague-Dawley rats, with normal pituitary function. ATP content and recovery after cold preservation were measured during the perfusion. RESULTS: Cold-preserved livers from hyperosmolar rats were observed to have elevated hepatic enzyme release and decreased bile production compared with normosmolar controls. Moreover, in these livers, the recovery of ATP after cold preservation was completely absent. Transmission electron microscopy of liver biopsies collected from hyperosmolar rats demonstrated profound ultrastructural changes, particularly in the mitochondria, that were not evident in the biopsies from normosmolar rats. All the experimental groups demonstrated similar hyaluronic acid uptake, whereas indocyanine green uptake was markedly impaired in the hyperosmolar group, suggesting that hepatocyte and not sinusoidal endothelial cell function is adversely affected by hyperosmolarity. The arterial ketone body ratio was profoundly compromised by chronic and, to an even greater degree, by acute hyperosmolarity. Survival after transplantation using hyperosmolar donors was not affected in this study. CONCLUSIONS: These results are an important step toward understanding the mechanism whereby brain death, a complicated pathophysiologic phenomenon, adversely affects the hepatic allograft.

Adenosine Triphosphate↗
PubMed1998

The efficacy of prophylactic interferon alfa-2b in preventing recurrent hepatitis C after liver transplantation.

Clinical recurrence of hepatitis C after liver transplantation can lead to cirrhosis, liver failure, and death. In patients undergoing liver transplantation for hepatitis C, we assessed the efficacy of interferon alfa-2b (IFN) in preventing recurrent hepatitis. We randomized 86 patients to either an IFN group (3 MU three times a week starting within 2 weeks after transplantation and continued for 1 year) or a control (no IFN) group. Recurrence, the primary end point, was diagnosed on biopsy performed at 1 year or for abnormal biochemistries. HCV RNA levels were measured by branched-chain DNA (bcDNA) assay and arbitrarily defined as low, moderate, or high (< 10 x 10(5), 10-100 x 10(5), or > 100 x 10(5) Eq/mL, respectively). Data on 30 IFN patients and 41 no-IFN patients who survived > or = 3 months were reviewed. Mean follow-up was 669 +/- 228 days for IFN patients and 594 +/- 254 days for no-IFN patients. IFN patients were less likely to develop recurrent hepatitis (8 IFN vs. 22 no-IFN patients, P = .017, log rank analysis). IFN and 1-month HCV RNA level were independent predictors of recurrence. IFN reduced the risk of recurrence by a factor of 0.4 (P = .04, Cox proportional hazards model); HCV RNA level > 100 x 10(5) Eq/mL at 1 month after transplantation increased the risk by a factor of 3.1 (P = .01). Low, moderate, and high viral levels at 1 and 3 months were associated with significantly different rates of recurrence in IFN patients (P = .05 at 1 month and P = .003 at 3 months) but not in untreated patients (P = .28 at 1 month and P = .25 at 3 months). In patients with two or more rejections, the risk of recurrence was increased by a factor of 2.17 (P = .05). On 47 1-year biopsies (24 IFN; 23 no IFN), piecemeal necrosis was more common in untreated patients (P < .02). One- and 2-year patient survival, respectively, was 96% and 96% with IFN and 91.2% and 87.2% without (P = NS). Prophylactic IFN reduced the incidence of recurrent hepatitis after transplant. Although IFN was most effective in patients with low HCV RNA levels, we also noted an effect in patients with moderate levels. IFN did not prevent viremia, suggesting that it may work through alternative mechanisms.

Adult↗