Leukocyte Adhesion Molecules in the Liver and Plasma Cytokine Levels in Endotoxin-Induced Rat Liver Injury

Ohira, Hiromasa; Ueno, Takato; Torimura, T; Tanikawa, K; Kasukawa, Reiji

doi:10.3109/00365529509096349

Cited by 39 publications

(25 citation statements)

References 25 publications

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“…This time period is consistent with the kinetics of inflammatory cell accumulation in the liver after endotoxin administration. 39,40 Increases in ICAM-1 mRNA have previously been described in both parenchymal and nonparenchymal cells following endotoxin treatment of animals. 3 Our finding of increased ICAM-1 protein expression on these cells is novel and in accord with this report.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Macrophages With Gadolinium Chloride Alters Intercellular Adhesion Molecule–1 Expression in the Liver During Acute Endotoxemia in Rats

et al. 1999

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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 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. 7-9 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. 14-17 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] Inter...

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Section: Discussionmentioning

confidence: 99%

Inhibition of Macrophages With Gadolinium Chloride Alters Intercellular Adhesion Molecule–1 Expression in the Liver During Acute Endotoxemia in Rats

et al. 1999

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“…Concentrations of the primary PMN chemokines, IL-8 (humans, primates, rabbits, and sheep) and CINCs (rat), peak in blood by 2-3 h after LPS administration [175,180]. Sources of plasma CINCs in rat are not known, but these chemokines are produced in both the liver and lungs during endotoxemia [193][194][195][196].…”

Section: Intermediate Effectors (1-3 H)mentioning

confidence: 99%

“…By 1-2 h, the synthesis of secondary mediators elicited by TNF-␣ and LPS begin to appear in plasma and include pro-inflammatory interleukins (IL-1, IL-6) and chemokines such as IL-8 in humans [179] and cytokineinduced neutrophil chemoattractants (CINCs) and macrophage inflammatory proteins(MIPs) in rats [180]. In addition, antiinflammatory factors such as IL-10 and PGE 2 begin to appear by 2-3 h [181,182].…”

Section: Intermediate Effectors (1-3 H)mentioning

confidence: 99%

Neutrophil migration during endotoxemia

Wagner

Roth

1999

Journal of Leukocyte Biology

177

125

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Endotoxemia is marked by a global activation of inflammatory responses, which can lead to shock, multiple organ failure, and the suppression of immune and wound healing processes. Neutrophils (PMNs) play a central role in some of these responses by accumulating in tissues and releasing reactive oxygen species and proteases that injure host structures. This review focuses on altered PMN migratory responses that occur during endotoxemia and their consequences in the development of pulmonary infection. The inflammatory mediators that might be responsible for these altered responses are discussed. The oxidant potential of PMNs is increased after exposure to endotoxin both in vitro and during clinical and experimental endotoxemia. However, other functions such as chemotaxis and phagocytosis are often depressed in these same cells. Endotoxin exposure renders PMNs hyperadhesive to endothelium. The sum of these effects produces activated inflammatory cells that are incapable of leaving the vasculature. As such, the endotoxic PMN is more likely to promote tissue injury from within microvascular beds than to clear pathogens from extravascular sites. Moreover, the functional characteristics of endotoxic PMNs are similar to those observed during trauma, burn injury, sepsis, surgery, and other inflammatory conditions. Accordingly, several clinical conditions might have a common effector in the activated, yet migratorially dysfunctional, PMN. Direct effects of endotoxin on PMNs as well as effects of endogenous mediators released during endotoxemia are discussed. Understanding PMN behavior during endotoxemia may provide basic and critical insights that can be applied to a number of inflammatory scenarios. J. Leukoc. Biol. 66: 10-24; 1999.

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“…This step is mainly dependent on ICAM-1 [29] and ␤ 2 integrins [3] and may be mediated by formation of chemotactic chemokines such as IL-8 by hepatocytes [6,56,57]. After transmigration, neutrophils adhere to parenchymal cells [58]. This step also involves ␤ 2 integrins and ICAM-1 [59,60].…”

Section: Figmentioning

confidence: 99%

Increased P-selectin gene expression in the liver vasculature and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock

Essani¹,

Fisher²,

Simmons³

et al. 1998

Journal of Leukocyte Biology

132

158

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We studied the role of P-selectin, an adhesion molecule known to be important for neutrophil localization to sites of inflammation, in a model of inflammatory liver injury. Male C3Heb/ FeJ (ET-sensitive) mice treated with 700 mg/kg galactosamine and 100 g/kg Salmonella abortus equi endotoxin (Gal/ET), murine tumor necrosis factor ␣ (TNF-␣, 15 g/kg), or interleukin-1 (IL-1, 13-23 g/kg), showed increased P-selectin mRNA levels in the liver. In contrast, C3H/HeJ (ET-resistant) mice responded only to cytokines with P-selectin mRNA formation. Whereas no P-selectin expression was detectable in control livers, there was temporary staining of endothelium in large blood vessels but not in sinusoids between 3 and 5 h after ET, TNF-␣, or IL-1 treatment. Severe liver injury induced by Gal/ET at 7 h was not inhibited by an anti-P-selectin antibody in C3Heb/FeJ mice or in P-selectin-deficient animals. Sequestration of neutrophils in sinusoids, i.e. those neutrophils that have been identified as critical for the injury, was not affected by the antibody or in P-selectindeficient mice. However, the temporary margination in portal and post-sinusoidal venules was reduced by 75% in anti-P-selectin antibody-treated animals and by 51% in P-selectin-deficient mice. We conclude that hepatic P-selectin gene transcription in vivo involves cytokines. However, blocking P-selectin neither attenuated sinusoidal neutrophil sequestration nor prevented neutrophil-induced liver injury during endotoxin shock but attenuated neutrophil margination in larger vessels. Thus, our data demonstrate similarities and fundamental differences in the requirement for adhesion molecules to localize neutrophils in the liver vasculature compared to other organs during an inflammatory response.

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Leukocyte Adhesion Molecules in the Liver and Plasma Cytokine Levels in Endotoxin-Induced Rat Liver Injury

Abstract: These data suggest that PMN-SEC and PMN-hepatocyte interactions via leukocyte adhesion molecules, related to inflammatory cytokines such as TNF and IL-8, exist and play an important role in the pathogenesis of acute liver injury.

Cited by 39 publications

References 25 publications

Inhibition of Macrophages With Gadolinium Chloride Alters Intercellular Adhesion Molecule–1 Expression in the Liver During Acute Endotoxemia in Rats

Inhibition of Macrophages With Gadolinium Chloride Alters Intercellular Adhesion Molecule–1 Expression in the Liver During Acute Endotoxemia in Rats

Neutrophil migration during endotoxemia

Increased P-selectin gene expression in the liver vasculature and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock

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