Role of superoxide in hemorrhagic shock-induced P-selectin expression

Superoxide has been implicated in the regulation of endothelial cell adhesion molecule expression and the subsequent initiation of leukocyte-endothelial cell adhesion in different experimental models of inflammation. The objective of this study was to assess the contribution of oxygen radicals to P-selectin expression in a murine model of whole body ischemia-reperfusion, i.e., hemorrhage-resuscitation (H/R), with the use of different strategies that interfere with either the production (allopurinol, CD11/CD18-deficient or p47phox−/− mice) or accumulation [intravenous superoxide dismutase (SOD), mutant mice that overexpress SOD] of oxygen radicals. P-selectin expression was quantified in different regional vascular beds by use of the dual-radiolabeled monoclonal antibody technique. H/R elicited a significant increase in P-selectin expression in all vascular beds. This response was blunted in SOD transgenic mice and in wild-type mice receiving either intravenous SOD or the xanthine oxidase inhibitor allopurinol. Mice genetically deficient in either a subunit of NADPH oxidase or the leukocyte adhesion molecule CD11/CD18 also exhibited a reduced P-selectin expression. These results implicate superoxide, derived from both xanthine oxidase and NADPH oxidase, as mediators of the increased P-selectin expression observed in different regional vascular beds exposed to hemorrhage and retransfusion.

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Anti-inflammatory drugs and endothelial cell adhesion molecule expression in murine vascular beds

Gut ◽

10.1136/gut.44.2.186 ◽

1999 ◽

Vol 44 (2) ◽

pp. 186-195 ◽

Cited By ~ 29

Author(s):

N Mori ◽

Y Horie ◽

M E Gerritsen ◽

D C Anderson ◽

D N Granger

Keyword(s):

Cell Adhesion ◽

Endothelial Cell ◽

Adhesion Molecules ◽

Adhesion Molecule ◽

Distal Colon ◽

Intercellular Adhesion Molecule ◽

Aminosalicylic Acid ◽

Antibody Technique ◽

Vascular Beds ◽

Endothelial Cell Adhesion

BackgroundInflammatory bowel diseases (IBD) are characterised by an intense infiltration of leucocytes that is mediated by adhesion molecules expressed on the surface of activated endothelial cells.AimsTo determine whether drugs used in the treatment of IBD, specifically dexamethasone (DEX), 5-aminosalicylic acid (5-ASA), methotrexate (MTX), and 6-mercaptopurine (6-MP), alter the expression of endothelial cell adhesion molecules (ECAMs).MethodsThe expression of P-selectin, E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular CAM 1 (VCAM-1) in different vascular beds of C57Bl/6J mice was measured using the dual radiolabelled monoclonal antibody technique.ResultsLipopolysaccharide (LPS) elicited a profound increase in the expression of all ECAMs in the mesentery, small intestine, caecum, and distal colon. The LPS induced increase in CAM expression was not significantly affected by prior treatment with either MTX or 6-MP. However, pretreatment with either DEX or 5-ASA significantly attenuated LPS induced increases in expression of P- and E-selectin, and VCAM-1 in the majority of tissues evaluated. DEX also blunted the LPS induced increase in ICAM-1 expression in the caecum and distal colon. DEX, but not 5-ASA, largely abolished the rise in plasma tumour necrosis factor α elicited by LPS.ConclusionsThese findings suggest that DEX and 5-ASA may exert their beneficial therapeutic action in IBD, at least in part, by inhibiting the expression of ECAMs which mediate leucocyte adhesion and transmigration in the microvasculature.

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Enteric microflora contribute to constitutive ICAM-1 expression on vascular endothelial cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2000.279.1.g186 ◽

2000 ◽

Vol 279 (1) ◽

pp. G186-G191 ◽

Cited By ~ 31

Author(s):

Shunichiro Komatsu ◽

Rodney D. Berg ◽

Janice M. Russell ◽

Yuji Nimura ◽

D. Neil Granger

Keyword(s):

Cell Adhesion ◽

Endothelial Cell ◽

Adhesion Molecules ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Significant Proportion ◽

Antibody Technique ◽

Germ Free ◽

Vascular Beds ◽

Endothelial Cell Adhesion

Quantitative estimates of endothelial cell adhesion molecule expression have revealed that some adhesion molecules [e.g., intercellular adhesion molecule-1 (ICAM-1)] are abundantly expressed in different vascular beds under normal conditions. The objective of this study was to determine whether the enteric microflora contribute to the constitutive expression of ICAM-1 and other endothelial cell adhesion molecules in the gastrointestinal tract and other regional vascular beds. The dual radiolabeled monoclonal antibody technique was used to measure endothelial expression of ICAM-1, ICAM-2, vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in conventional, germ-free mice and germ-free mice receiving the cecal contents of conventional mice to reestablish the enteric microflora (total association). Constitutive ICAM-1 expression was significantly lower in the splanchnic organs (pancreas, stomach, small and large intestine, mesentery, and liver), kidneys, skeletal muscle, and skin of germ-free mice compared with their conventional counterparts. These differences were abolished after total association of germ-free mice with the indigenous gastrointestinal flora. The expression of ICAM-2, VCAM-1, and E-selectin in the various tissues studied did not differ between conventional and germ-free mice. These findings indicate that the indigenous gastrointestinal microflora are responsible for a significant proportion of the basal ICAM-1 expression detected in both intestinal and extraintestinal tissues.

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Heme oxygenase modulates selectin expression in different regional vascular beds

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.278.5.h1613 ◽

2000 ◽

Vol 278 (5) ◽

pp. H1613-H1617 ◽

Cited By ~ 100

Author(s):

Tushar J. Vachharajani ◽

Jack Work ◽

Andrew C. Issekutz ◽

D. Neil Granger

Keyword(s):

Cell Adhesion ◽

Endothelial Cell ◽

Inflammatory Response ◽

Heme Oxygenase ◽

Protoporphyrin Ix ◽

Zinc Protoporphyrin ◽

Antibody Technique ◽

Endothelial Cell Adhesion Molecules ◽

Vascular Beds ◽

Endothelial Cell Adhesion

Heme oxygenase (HO) catalyzes the degradation of heme to biliverdin, iron, and CO. The inducible isoform (HO-1) has been implicated as a modulator of the inflammatory response. HO-1 activity can be induced by hemin and inhibited with zinc protoporphyrin IX (ZnPP). Using these reagents, we assessed the possibility that HO-1 modulates the inflammatory response by altering the expression of endothelial cell adhesion molecules. Endotoxin (lipopolysaccharide, LPS)-induced expression of P- and E-selectin expression was quantified in different vascular beds of the rat using the dual radiolabeled monoclonal antibody technique. Pretreatment with hemin attenuated, whereas ZnPP treatment exacerbated, the increased selectin expression normally elicited by LPS. Biliverdin, at an equimolar dosage, was as effective as hemin in attenuating LPS-induced selectin expression in the lung, kidneys, liver, and intestines. These findings indicate that the anti-inflammatory properties of HO-1 may be related to an inhibitory action of P- and E-selectin expression in the vasculature. Biliverdin (or its metabolite, bilirubin), rather than CO, may account for this action of HO-1 on endothelial cell adhesion molecule expression.

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Quantification of murine endothelial cell adhesion molecules in solid tumors

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.3.h1156 ◽

1999 ◽

Vol 277 (3) ◽

pp. H1156-H1166 ◽

Cited By ~ 4

Author(s):

Robert R. Langley ◽

Janice Russell ◽

Michael J. Eppihimer ◽

Steven J. Alexander ◽

Mary Gerritsen ◽

...

Keyword(s):

Cell Adhesion ◽

Endothelial Cell ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Tumor Bearing ◽

Tnf Α ◽

Endothelial Cell Adhesion Molecules ◽

Vascular Beds ◽

Cell Adhesion Molecule 1 ◽

Endothelial Cell Adhesion

Coordinated adhesive interactions between lymphocyte receptors and endothelial cell adhesion molecules (CAMs) are a prerequisite for effector cell entry into tumor stroma. Whereas the diminished leukocyte-endothelial cell interactions observed in tumor microvessels have been attributed to a reduced expression of endothelial CAMs, there is no quantitative data bearing on this issue. The dual-radiolabeled monoclonal antibody technique was used to quantify constitutive and tumor necrosis factor (TNF)-α-induced expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), ICAM-2, P-selectin, E-selectin, and platelet-endothelial cell adhesion molecule 1 (PECAM-1) in different vascular beds of normal (C57Bl/6) and RM-1 tumor-bearing mice. When corrected for endothelial surface area, the constitutive expression of selectins in tumor vessels was higher than that observed in other vascular beds. Both constitutive and induced expression of endothelial CAMs in peripheral vascular beds did not differ between normal and tumor-bearing mice. Within the tumor, the magnitude of the upregulation of P-selectin, ICAM-1, and VCAM-1 after TNF-α was similar to that within other vascular beds. E-selectin expression in tumors was refractory to TNF-α, whereas PECAM-1 and ICAM-2 expression were significantly reduced. Our findings suggest that the presence of a solid tumor does not influence endothelial CAM expression in other vascular beds and that the higher density of selectins in nonstimulated tumor vessels may promote the recruitment of rolling leukocytes in this tissue.

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