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Zinc Protects against Tumor Necrosis Factor-Induced Disruption of Porcine Endothelial Cell Monolayer Integrity^1,2,

Bernhard Hennig^*,,,3, Yin Wang^*,,, Santhini Ramasamy^* and Craig J. McClain^**,,,

^* Department of Nutrition and Food Science, University of Kentucky and Lexington Veterans' Administration Medical Center, Lexington, KY 40506 ^** Department of Medicine, University of Kentucky and Lexington Veterans' Administration Medical Center, Lexington, KY 40506 Graduate Center for Toxicology, University of Kentucky and Lexington Veterans' Administration Medical Center, Lexington, KY 40506 Graduate Faculty of Nutrition, University of Kentucky and Lexington Veterans' Administration Medical Center, Lexington, KY 40506

Some nutrients influence the metabolic response of cytokines such as tumor necrosis factor. Inadequate levels of the essential trace element zinc may play a role in tumor necrosis factor-induced disruption of the vascular endothelial barrier function. To test this hypothesis, endothelial cells cultured on polycarbonate filters or culture plates were exposed to six different treatments for 3 d: medium 199 enriched with 5% fetal bovine serum (control), control + two levels of supplemental zinc (7.7 and 12.3 µmol/L medium), tumor necrosis factor (5 x 10⁵ U/L) and tumor necrosis factor + the two levels of Zn as noted previously. Endothelial barrier function, expressed as albumin transfer across cultured endothelial monolayers, was not affected by Zn enrichment alone. Tumor necrosis factor treatment significantly increased albumin transfer compared with control cultures. The lower concentration of Zn partially and the higher concentration totally prevented the tumor necrosis factor-induced increase in albumin transfer. The increase in cytosolic release of [³H]adenine (marker of cell injury) induced by tumor necrosis factor was prevented by added Zn. Tumor necrosis factor treatment significantly decreased angiotensin-converting enzyme activity, and tumor necrosis factor also decreased activities of two other membrane-bound enzymes, total ATPase and Ca²⁺-ATPase. These activities all were restored by Zn enrichment. Tumor necrosis factor treatment caused a decrease in cellular Zn concentration, which was prevented when the culture media were enriched with Zn. These data suggest that an important relationship exists between Zn status and tumor necrosis factor-induced endothelial cell dysfunction.

KEY WORDS: • tumor necrosis factor • cell injury • endothelial cell integrity • zinc • zinc supplementation

¹ Supported in part by grants 1PO1 HL36552 from the National Institutes of Health, Veterans' Administration and the General Clinical Research Center MO1 RR 02602-08, University of Kentucky, grants from the National Live Stock and Meat Board, National Dairy Council, and the Kentucky Agricultural Experiment Station (article no. 92-9-146).

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

³ To whom correspondence should be addressed.

Manuscript received 10 November 1992. Revision accepted 5 February 1993.

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