1
reduced CsA promoted EBV- B cell colony formation to 22.5 1.76. CsA induced EBV-B cell 3 H-thymidine uptake from control of 12, 481670 to 26,514 2732 (CPM/well). Vit.E at 40M reduced CsA promoted 3 H-thymidine uptake to 16,146 2088 (n6, P0.05). Conclusion: This observation provides evidence that CsA induced oxidative stress activates NFB and promotes EBV infected B cell transformation. These events could be blocked by antioxidant Vit.E. These findings add to the understanding of the mechanism of CsA promoted EBV related post-transplant lympho-proliferative disor- ders (PTLD). 436. EXOGENOUS INTERLEUKIN-6 ENHANCES LIVER RE- GENERATION AFTER MAJOR AND EXTREME LIVER RESECTION. X. Jin, T. A. Zimmers, E. A. Perez, L. G. Koniaris; University of Miami, Miami, FL. Objective: To determine the potential therapeutic benefits of exogenous administration of interleukin-6 (IL-6), hepatocyte growth factor (HGF) or the combination on the hepatic regenerative re- sponse in vivo. Methods: Mice were administered recombinant IL-6 alone (400ng/ul or 400ng/hr), HGF alone (400ng/ul or 400ng/hr) or the combination by osmotic mini-pump. Alternatively, mice were injected with cells over-expressing IL-6. Mice were subjected to no surgery, sham surgery, 70% or 90% hepatectomy. Results: Exoge- nous IL-6 by pump induced liver growth without fat or muscle wasting, resulting in high plasma IL-6 level (1471.6 149.4 pg/ml ) versus control (14.5 0.8pg/ml). IL-6 administration by either route increased both total and fractional liver mass and stimulated hepa- tocyte proliferation, as revealed by increased hepatic mitotic figures, BrdU incorporation and PCNA expression. In contrast, HGF alone did not increase liver mass or PCNA expression, while co- administration of HGF and IL-6 did not increase liver mass or PCNA expression over IL-6 alone. IL-6 also induced expression of the anti- apoptotic factors Bcl-2 and Bcl-xL. IL-6 accelerated liver regenera- tion and recovery of liver mass, with earlier hepatocyte entry into S phase and decreased expression of pro-apoptotic factors, including caspase-3 and cleaved PARP after 70% hepatectomy. IL-6 also im- proved survival and accelerated liver growth after 90% hepatectomy. Conclusions: Exogenous IL-6, but not HGF, can induce liver growth in non-injured livers. Furthermore, IL-6 administration can enhance the hepatic regenerative response by increasing hepatocyte prolifer- ation and reducing hepatocyte apoptosis. These findings suggest IL-6 therapy has the potential to enhance liver growth and regeneration in clinical settings. 437. ASSOCIATION OF PRETRANSPLANT PROINFLAMMA- TORY ADIPOKINES AND RENAL ALLOGRAFT OUT- COME - A PILOT STUDY REPORT OF PRETRANS- PLANT RETROPERITONEAL ADIPOSE TISSUE GENE EXPRESSION. Y. Lu 1 , W. Craig 2 , G. Espinal 2 , B. Hammock 3 , K. Schmelzer 3 , C. Troppmann 1 , J. McVicar 1 , T. Weaver 1 , R. Perez 1 ; 1 University of California Davis Medical Center, De- partment of Surgery, Sacramento, CA, 2 UC Davis, Depart- ments of Pediatrics and NPB, Davis, CA, 3 UC Davis, Depart- ment of Entomology and Analytical Biochemistry, Davis, CA. Introduction. It is clear that adipose tissue plays an important role in regulation of inflammation and immunity. The importance of immunomodulatory role of adipokines in transplantation has not been elucidated. In this pilot study, we investigated the hypothesis that the alteration of pre-transplant proinflammatory gene expres- sion in retroperitoneal adipose tissue increases the risk of acute allograft rejection and inflammation of renal transplant recipients. Methods. Samples of 63 consecutive kidney transplant recipients were included in the study. Pretransplant retroperitoneal adipose tissue was obtained during surgery for gene expression analysis by real-time RT-PCR. A panel of 18 genes involved in the inflammatory response and lipid metabolism were examined and correlated with allograft outcomes. Additionally, serum lipid metabolites (by HPLC) involved the in 3 major enzymatic pathways (cycloxygenase, lipoxy- genase and Soluble epoxide hydrolase were also assessed and corre- lated with allograft outcome. Results and Discussions. RT-PCR data were divided into 4 groups based on post-transplant patient biopsy results: non-rejection (NR, n30), acute rejection (AR, n4), acute tubular necrosis (ATN, n9) and chronic nephropathy (CN, n4). Expression of most of the inflammatory and lipid metabolism genes was higher in AR patients when compared to NR (p0.05) (Fig.1). Specifically, IL-6, TNF and CCL3/MIP1,LDL, CCL2/MCP1, Cyclooxygenase 2 (COX2), Lipoxygenase 5 (ALOX5), PPAR, and HMG-CoA reducatase expression were increased 1.1 to 1.5 fold (p0.05) in AR patients. Conversely, adipose expression of adiponec- tin and leptin were significantly decreased in AR patients when compared to NR (p0.01). Serum concentrations of ecosanoids PGF2, PGD2 (p0.01) and PGE2 (fig.2) were decreased in AR suggesting a possible protective role for cyclooxygenase. Serum lev- els of lipoxygenase and epoxide hydrolase metabolites were not sig- nificantly different between AR and NR groups. There were no sig- nificant correlations of age, gender, ethnicity, BMI, etiology of renal failure, and dialysis type and durations among study groups. Con- clusion. Expression of pretransplant proinflammatory and lipid me- tabolite genes were increased in retroperitoneal adipose tissue in AR patients. Further study has been focusing on adipose tissue gene expression and its role in transplant immune response. 438. HISTOPATHOLOGIC FINDINGS IN A MODIFIED HET- EROTOPIC FEMORAL HEART TRANSPLANTATION 320 ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS

Exogenous interleukin-6 enhances liver regeneration after major and extreme liver resection

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Page 1: Exogenous interleukin-6 enhances liver regeneration after major and extreme liver resection

reduced CsA promoted EBV- B cell colony formation to 22.5 �1.76.CsA induced EBV-B cell 3H-thymidine uptake from control of 12,481�670 to 26,514 �2732 (CPM/well). Vit.E at 40�M reduced CsApromoted 3H-thymidine uptake to 16,146 �2088 (n�6, P�0.05).Conclusion: This observation provides evidence that CsA inducedoxidative stress activates NF�B and promotes EBV infected B celltransformation. These events could be blocked by antioxidant Vit.E.These findings add to the understanding of the mechanism of CsApromoted EBV related post-transplant lympho-proliferative disor-ders (PTLD).

436. EXOGENOUS INTERLEUKIN-6 ENHANCES LIVER RE-GENERATION AFTER MAJOR AND EXTREME LIVERRESECTION. X. Jin, T. A. Zimmers, E. A. Perez,L. G. Koniaris; University of Miami, Miami, FL.

Objective: To determine the potential therapeutic benefits ofexogenous administration of interleukin-6 (IL-6), hepatocyte growthfactor (HGF) or the combination on the hepatic regenerative re-sponse in vivo. Methods: Mice were administered recombinant IL-6alone (400ng/ul or 400ng/hr), HGF alone (400ng/ul or 400ng/hr) orthe combination by osmotic mini-pump. Alternatively, mice wereinjected with cells over-expressing IL-6. Mice were subjected to nosurgery, sham surgery, 70% or 90% hepatectomy. Results: Exoge-nous IL-6 by pump induced liver growth without fat or musclewasting, resulting in high plasma IL-6 level (1471.6 � 149.4 pg/ml )versus control (14.5 � 0.8pg/ml). IL-6 administration by either routeincreased both total and fractional liver mass and stimulated hepa-tocyte proliferation, as revealed by increased hepatic mitotic figures,BrdU incorporation and PCNA expression. In contrast, HGF alonedid not increase liver mass or PCNA expression, while co-administration of HGF and IL-6 did not increase liver mass or PCNAexpression over IL-6 alone. IL-6 also induced expression of the anti-apoptotic factors Bcl-2 and Bcl-xL. IL-6 accelerated liver regenera-tion and recovery of liver mass, with earlier hepatocyte entry into Sphase and decreased expression of pro-apoptotic factors, includingcaspase-3 and cleaved PARP after 70% hepatectomy. IL-6 also im-proved survival and accelerated liver growth after 90% hepatectomy.Conclusions: Exogenous IL-6, but not HGF, can induce liver growthin non-injured livers. Furthermore, IL-6 administration can enhancethe hepatic regenerative response by increasing hepatocyte prolifer-ation and reducing hepatocyte apoptosis. These findings suggest IL-6therapy has the potential to enhance liver growth and regenerationin clinical settings.

437. ASSOCIATION OF PRETRANSPLANT PROINFLAMMA-TORY ADIPOKINES AND RENAL ALLOGRAFT OUT-COME - A PILOT STUDY REPORT OF PRETRANS-PLANT RETROPERITONEAL ADIPOSE TISSUE GENEEXPRESSION. Y. Lu1, W. Craig2, G. Espinal2, B. Hammock3,K. Schmelzer3, C. Troppmann1, J. McVicar1, T. Weaver1,R. Perez1; 1University of California Davis Medical Center, De-partment of Surgery, Sacramento, CA, 2UC Davis, Depart-ments of Pediatrics and NPB, Davis, CA, 3UC Davis, Depart-ment of Entomology and Analytical Biochemistry, Davis, CA.

Introduction. It is clear that adipose tissue plays an importantrole in regulation of inflammation and immunity. The importance ofimmunomodulatory role of adipokines in transplantation has notbeen elucidated. In this pilot study, we investigated the hypothesisthat the alteration of pre-transplant proinflammatory gene expres-sion in retroperitoneal adipose tissue increases the risk of acuteallograft rejection and inflammation of renal transplant recipients.Methods. Samples of 63 consecutive kidney transplant recipientswere included in the study. Pretransplant retroperitoneal adiposetissue was obtained during surgery for gene expression analysis byreal-time RT-PCR. A panel of 18 genes involved in the inflammatoryresponse and lipid metabolism were examined and correlated with

allograft outcomes. Additionally, serum lipid metabolites (by HPLC)involved the in 3 major enzymatic pathways (cycloxygenase, lipoxy-genase and Soluble epoxide hydrolase were also assessed and corre-lated with allograft outcome. Results and Discussions. RT-PCRdata were divided into 4 groups based on post-transplant patientbiopsy results: non-rejection (NR, n�30), acute rejection (AR, n�4),acute tubular necrosis (ATN, n�9) and chronic nephropathy (CN,n�4). Expression of most of the inflammatory and lipid metabolismgenes was higher in AR patients when compared to NR (p�0.05)(Fig.1). Specifically, IL-6, TNF� and CCL3/MIP1,LDL, CCL2/MCP1,Cyclooxygenase 2 (COX2), Lipoxygenase 5 (ALOX5), PPAR�, andHMG-CoA reducatase expression were increased 1.1 to 1.5 fold(p�0.05) in AR patients. Conversely, adipose expression of adiponec-tin and leptin were significantly decreased in AR patients whencompared to NR (p�0.01). Serum concentrations of ecosanoidsPGF2�, PGD2 (p�0.01) and PGE2 (fig.2) were decreased in ARsuggesting a possible protective role for cyclooxygenase. Serum lev-els of lipoxygenase and epoxide hydrolase metabolites were not sig-nificantly different between AR and NR groups. There were no sig-nificant correlations of age, gender, ethnicity, BMI, etiology of renalfailure, and dialysis type and durations among study groups. Con-clusion. Expression of pretransplant proinflammatory and lipid me-tabolite genes were increased in retroperitoneal adipose tissue in ARpatients. Further study has been focusing on adipose tissue geneexpression and its role in transplant immune response.

438. HISTOPATHOLOGIC FINDINGS IN A MODIFIED HET-EROTOPIC FEMORAL HEART TRANSPLANTATION

320 ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS