title: Inducible nitric oxide synthase inhibitors prolonged the survival of skin xenografts through selective down-regulation of pro-inflammatory cytokine and CC-chemokine expressions.
abstract: To elucidate the possible immunoregulatory role of nitric oxide (NO) in cellular xenograft rejection we performed rat-to-mouse skin xenotransplantation. The rat skin engrafted mice were treated with the inducible NO synthase (iNOS) inhibitors, aminoguanidine (AMG, 200 mg/kg) and NG-nitro-L-arginine methyl ester (L-NAME, 60 mg/kg) every other day until rejection. Skin xenograft survival was monitored and immune cell infiltration and intragraft cytokine and chemokine mRNA expressions were analyzed 7 days after grafting. Compared with the control mice, the AMG- and L-NAME treated mice showed delayed xenograft rejection by approximately 3 days (8.9 +/- 0.7 days vs. 11.7 +/- 1.2 and 12.0 +/- 0.9 days, respectively). Infiltrations of CD11b+, MOMA-2+ cells and neutrophils were significantly reduced in both AMG- and L-NAME treated graft but CD4+ and CD8+ cells were not. The expression of cytokines such as IL-1beta, IL-2, IL-6, IL-12 and IFN-gamma in AMG- and L-NAME treated grafts were significantly decreased (P<0.01), whereas IL-10, TNF-alpha and TGF-beta1 were unchanged or enhanced. Additionally, the expressions of CC-chemokines, such as RANTES and MIP-1alpha, were significantly reduced (P<0.01) whereas the expressions of CXC-chemokines, such as IP-10 and MIG, were unchanged. These results imply that prolonged rat-to-mouse skin xenograft survival by iNOS inhibitors may be due to the selective inhibition of pro-inflammatory cytokines and chemokines and suggest the possible regulatory role of NO in cytokine and chemokine expressions during xenotransplant rejection.
authors.affiliation: Transplantation Research Institute, Seoul National University Hospital, Seoul 110-744, South Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Donghee
authors.initials: D
authors.lastname: Kim
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Lee
authors.forename: Inho
authors.initials: I
authors.lastname: Choi
authors.forename: Chung-Gyu
authors.initials: CG
authors.lastname: Park
authors.forename: Kil Soo
authors.initials: KS
authors.lastname: Kim
authors.forename: Jongwon
authors.initials: J
authors.lastname: Ha
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Kim
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Yang
authors.forename: Yon Su
authors.initials: YS
authors.lastname: Kim
authors.forename: Jin Suk
authors.initials: JS
authors.lastname: Han
authors.forename: Suhnggwon
authors.initials: S
authors.lastname: Kim
authors.forename: Jung Sang
authors.initials: JS
authors.lastname: Lee
authors.forename: Curie
authors.initials: C
authors.lastname: Ahn
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002452:Cell Count; D019742:Chemokines, CC / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects*; D006146:Guanidines / Q000494:pharmacology; D007150:Immunohistochemistry; D008222:Lymphokines / Q000032:analysis / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D016038:Skin Transplantation; D014183:Transplantation, Heterologous
chemical_list: D039481:CD11b Antigen; D019742:Chemokines, CC; D016207:Cytokines; D004791:Enzyme Inhibitors; D006146:Guanidines; D008222:Lymphokines; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester