Endothelial nitric oxide synthase protects transplanted mouse livers against storage/reperfusion injury: Role of vasodilatory and innate immunity pathways.
Endothelial nitric oxide synthase (eNOS) plays a role in microcirculatory and immunomodulatory responses after warm ischemia/reperfusion. We hypothesized that eNOS is essential to maintain microcirculation, attenuate macrophage infiltration and decrease graft injury after liver transplantation. Liver transplantation was performed after 18 hours of cold storage in University of Wisconsin (UW) solution from wildtype and eNOS-deficient (B6.129P2-Nos3(tm/Unc)/J) donor mice into wildtype mice. Serum ALT, necrosis by histology, apoptosis by TUNEL, and macrophage infiltration by immunostaining against F4/80 antigen were determined 2 to 8 hours after implantation. Hepatic microcirculation was investigated after 4 hours by intravital confocal microscopy following injection of fluorescein-labeled erythrocytes. After sham operation, livers of wildtype and eNOS-deficient mice were not different in ALT, necrosis, apoptosis, macrophage infiltration, and microcirculation. After transplantation, ALT increased >3 times more after transplantation of eNOS-deficient livers than wildtype livers. Necrosis was >4 times greater, and TUNEL and F4/80 immunostaining in nonnecrotic areas were 2 and 1.5 times greater in eNOS-deficient donor livers, respectively. Compared with wildtype and eNOS sham-operated mice, sinusoidal blood flow velocity increased 1.6-fold after wildtype transplantation, but sinusoidal diameter was not changed. After transplantation of eNOS-deficient livers, blood flow velocity and sinusoidal diameter decreased compared with transplanted wildtype livers. These results indicate that donor eNOS attenuates storage/reperfusion injury after mouse liver transplantation. Protection is associated with improved microcirculation and decreased macrophage infiltration. Thus, eNOS-dependent graft protection may involve both vasodilatory and innate immunity pathways.
Theruvath
T P
TP
Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Zhong
Z
Z
Currin
R T
RT
Ramshesh
V K
VK
Lemasters
J J
JJ
D000818:Animals; D007113:Immunity, Innate; D008102:Liver Circulation; D016031:Liver Transplantation / Q000276:immunology / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009926:Organ Preservation; D015427:Reperfusion Injury / Q000276:immunology / Q000517:prevention & control*; D014664:Vasodilation / Q000276:immunology*
D052250:Nitric Oxide Synthase Type III