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

Abstract

Background: Inflammatory 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.

Aims: To 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).

Methods: The 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.

Results: Lipopolysaccharide (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 alpha elicited by LPS.

Conclusions: These 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.

Figure 1

Effect of anti-inflammatory drugs on the expression of P-selectin in (A) mesentery, (B) small intestine, (C) caecum, and (D) distal colon. The numbers of animals in each experimental group was as follows: control, 5; LPS + control, 7; LPS + 5-ASA, 5; LPS + DEX, 5; LPS + MTX, 5; LPS + 6-MP, 5. *p<0.05 versus LPS + untreated.

Figure 2

Effect of anti-inflammatory drugs on the expression of E-selectin in (A) mesentery, (B) small intestine, (C) caecum, and (D) distal colon. The numbers of animals in each experimental group were as follows: control, 5; LPS + control, 7; LPS + 5-ASA, 5; LPS + DEX, 5; LPS + MTX, 5; LPS + 6-MP, 5. *p<0.05 versus LPS + untreated.

Figure 3

Effect of anti-inflammatory drugs on the expression of ICAM-1 in (A) mesentery, (B) small intestine, (C) caecum, and (D) distal colon. The numbers of animals in each experimental group were as follows: control, 5; LPS + control, 7; LPS + 5-ASA, 5; LPS + DEX, 5; LPS + MTX, 5; LPS + 6-MP, 5. *p<0.05 versus LPS + untreated.

Figure 4

Effect of anti-inflammatory drugs on the expression of VCAM-1 in (A) mesentery, (B) small intestine, (C) caecum, and (D) distal colon. The numbers of animals in each experimental group were as follows: control, 5; LPS + control, 7; LPS + 5-ASA, 5; LPS + DEX, 5; LPS + MTX, 5; LPS + 6-MP, 5. *p<0.05 versus LPS + untreated.

Figure 5

Effect of 5-ASA and DEX on plasma TNF-α concentrations in stimulated animals. The numbers of animals in each experimental group was as follows: control, 5; LPS + control, 5; LPS + 5-ASA, 5; LPS + DEX, 5. *p<0.05 versus LPS + untreated.