Inhibition of macrophages with gadolinium chloride alters intercellular adhesion molecule-1 expression in the liver during acute endotoxemia in rats

✍ Scribed by Nosheen Ahmad; Carol R. Gardner; Edward J. Yurkow; Debra L. Laskin

• Book ID: 102851215
• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 537 KB
• Volume: 29
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510290324

✦ Synopsis

Cell adhesion molecules are important for localized accumulation of phagocytes at sites of tissue damage. In the present studies, we analyzed the effects of blocking hepatic macrophages on expression of ␤ 2 integrins and intercellular adhesion molecule-1 (ICAM-1) adhesion molecules on liver cells during acute endotoxemia. Flow cytometric analysis revealed distinct subpopulations of macrophages from control animals that varied on the basis of their size and density. In contrast, hepatocytes and endothelial cells were relatively homogeneous. Treatment of rats with endotoxin (5 mg/kg, intravenously) resulted in a time-dependent increase in the percentage of small, dense macrophages and a progressive loss of larger, less-dense cells. In contrast, no major effects were observed on the physical properties of hepatocytes or endothelial cells. ICAM-1 was found to be constitutively expressed on endothelial cells and hepatocytes, as well as on macrophages. Induction of acute endotoxemia resulted in a time-dependent increase in ICAM-1 expression on hepatocytes, which was observed within 3 hours and reached a maximum after 24 hours. An increase in ICAM-1 expression was also observed on endothelial cells and on macrophages at 3 hours, followed by a decrease at 24 to 48 hours. Macrophages and endothelial cells also constitutively expressed ␤ 2 integrins. Induction of acute endotoxemia had no effect on ␤ 2 integrin expression by these cells. Pretreatment of rats with gadolinium chloride (GdCl 3 ), a macrophage inhibitor known to block endotoxin-induced liver injury, abrogated the effects of endotoxin on ICAM-1 expression by hepatocytes and macrophages. In contrast, ICAM-1 expression on endothelial cells increased. Interestingly, treatment of rats with GdCl 3 alone resulted in a marked increase in expression of ICAM-1 on endothelial cells and hepatocytes, and of ␤ 2 integrins on macrophages and endothelial cells. Taken together, these data suggest that ICAM-1 is involved in mediating macrophage adherence and accumulation in the liver during endotoxemia. Furthermore, macrophages appear to regulate expression of this cell adhesion molecule on parenchymal cells. (HEPATOLOGY 1999;29:728-736.) Tissue damage initiates an inflammatory response characterized by an accumulation of macrophages at the site of injury. These cells are primarily derived from blood monocytes. Cell adhesion molecules are a group of membraneassociated proteins present on leukocytes, endothelial cells, and parenchymal cells that facilitate monocyte adherence and emigration out of the blood and into the tissue. Expression of several different classes of cell adhesion molecules have been reported to be up-regulated on liver cells after exposure of animals to hepatotoxic doses of alcohol 1,2 or endotoxin, 3,4 following reperfusion injury, 5,6 and in humans with acute and chronic inflammatory liver diseases. [7][8][9] Increased quantities of soluble circulating adhesion molecules have also been detected in various models of liver injury. 2,7,8,10 These findings, together with the observation that liver injury is abrogated by administration of antibodies to certain cell adhesion molecules, [4][5][6]11 suggest that they play a role in hepatotoxicity associated with inflammation.

Endotoxin is a bacterially derived product known to induce liver injury at toxic doses. 12 We have previously demonstrated that acute endotoxemia is associated with an increase in the number of macrophages in the liver. 13,14 These cells are activated to release reactive oxygen and nitrogen intermediates that we speculate contribute to hepatotoxicity. [14][15][16][17] Intercellular adhesion molecule-1 (ICAM-1) is one important cell surface molecule that mediates antigenindependent contact between cells. ICAM-1 serves as a counter-receptor for the ␤ 2 integrins, LFA-1 and MAC-1. [18][19][20] Interleukin-1 (IL-1) and tumor necrosis factor ␣ have been reported to induce ICAM-1 and ␤ 2 integrin expression on responsive cell types. 3,11 These macrophage-derived cytokines are produced in increased quantities in the liver during endotoxemia. 21 These findings suggest that macrophages may contribute to the regulation of endotoxin-induced inflammation in the liver. To test this possibility, we used sensitive techniques in analytical cytometry to analyze the effects of blocking hepatic macrophages on expression of ICAM-1 and ␤ 2 integrins on liver cells during acute endotoxemia. We found increased ICAM-1 expression on both parenchymal and nonparenchymal liver cells from animals treated with endotoxin. Moreover, this response was abrogated in hepato-