Transgenic Mice With Increased Copper/Zinc–Superoxide Dismutase Activity Are Resistant to Hepatic Leukostasis and Capillary No-Reflow After Gut Ischemia/Reperfusion

From the Departments of Molecular and Cellular Physiology (Y.H., S.C.F., D.N.G.) and Medicine (R.W.), Center of Excellence in Arthritis and Rheumatology, Louisiana State University Medical Center, Shreveport; Webb-Waring Institute, University of Colorado, Denver (J.M.M.); and the Departments of Pediatrics and Biochemistry and Biophysics, University of California, San Francisco (C.J.E.).

Correspondence to D. Neil Granger, PhD, Department of Physiology, LSU Medical Center, 1501 Kings Highway, Shreveport, LA 71130-3932. E-mail dgrang{at}lsumc.edu

Abstract—The objectives of this study were to (1) determine whether transgenic (Tg) mice overexpressing copper/zinc–superoxide dismutase (CuZn-SOD) are protected from the deleterious effects of gut ischemia/reperfusion (I/R) and (2) compare the effectiveness of Tg SOD overexpression in attenuating I/R injury to intravascularly administered CuZn-SOD or manganese (Mn)-SOD. The accumulation of fluorescently labeled leukocytes and number of nonperfused sinusoids were monitored by intravital microscopy in livers of wild-type mice (C57BL/6), CuZn-SOD Tg mice, and wild-type mice receiving either CuZn-SOD or Mn-SOD. All parameters were measured for 1 hour after release of the occluded (for 15 minutes) superior mesenteric artery. Gut I/R in wild-type mice led to an increased number of stationary leukocytes, while reducing the number of perfused sinusoids (capillary no-reflow). All of these responses were significantly blunted in CuZn-SOD Tg mice, with a corresponding attenuation of liver enzyme release into plasma. Exogenously administered SOD had little or no effect on gut I/R-induced leukostasis or capillary no-reflow in the liver. These observations suggest a role for superoxide in gut I/R-induced leukostasis and hypoxic stress in the liver. Furthermore, the findings suggest that cellular localization of SOD activity is an important determinant of the protective actions of this enzyme in experimental models of I/R injury.

Key Words: leukocyte adhesion • tissue hypoxia • hepatocellular injury • inflammation • oxygen free radical

This article has been cited by other articles:

				S. M. Davidson and M. R. Duchen Endothelial Mitochondria: Contributing to Vascular Function and Disease Circ. Res., April 27, 2007; 100(8): 1128 - 1141. [Abstract] [Full Text] [PDF]

				H. Van Remmen, Y. Ikeno, M. Hamilton, M. Pahlavani, N. Wolf, S. R. Thorpe, N. L. Alderson, J. W. Baynes, C. J. Epstein, T.-T. Huang, et al. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging Physiol Genomics, December 16, 2003; 16(1): 29 - 37. [Abstract] [Full Text] [PDF]

				M. C. Montalto, M. L. Hart, J. E. Jordan, K. Wada, and G. L. Stahl Role for complement in mediating intestinal nitric oxide synthase-2 and superoxide dismutase expression Am J Physiol Gastrointest Liver Physiol, June 9, 2003; 285(1): G197 - G206. [Abstract] [Full Text] [PDF]

				W. H. Cerwinka, D. Cooper, C. F. Krieglstein, C. R. Ross, J. M. McCord, and D. N. Granger Superoxide mediates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H535 - H541. [Abstract] [Full Text] [PDF]

				R. Yang, D. J. Gallo, J. J. Baust, T. Uchiyama, S. K. Watkins, R. L. Delude, and M. P. Fink Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock Am J Physiol Gastrointest Liver Physiol, July 1, 2002; 283(1): G212 - G221. [Abstract] [Full Text] [PDF]

				F. M. Akgur, M. F. Brown, G. B. Zibari, J. C. McDonald, C. J. Epstein, C. R. Ross, and D. N. Granger Role of superoxide in hemorrhagic shock-induced P-selectin expression Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H791 - H797. [Abstract] [Full Text] [PDF]

				T. Yoshida, N. Maulik, R. M. Engelman, Y.-S. Ho, and D. K. Das Targeted Disruption of the Mouse Sod I Gene Makes the Hearts Vulnerable to Ischemic Reperfusion Injury Circ. Res., February 18, 2000; 86(3): 264 - 269. [Abstract] [Full Text] [PDF]

				D. Salvemini, Z. Wang, J. L. Zweier, A. Samouilov, H. Macarthur, T. P. Misko, M. G. Currie, S. Cuzzocrea, J. A. Sikorski, and D. P. Riley A Nonpeptidyl Mimic of Superoxide Dismutase with Therapeutic Activity in Rats Science, October 8, 1999; 286(5438): 304 - 306. [Abstract] [Full Text]