Rolipram inhibits leukocyte‐endothelial cell interactions in vivo through P‐ and E‐selectin downregulation

Abstract

1 Rolipram, a selective phosphodiesterase (PDE) type 4 inhibitor, was used to characterize leukocyte recruitment mechanisms in models of acute and subacute in¯ammation. Intravital microscopy within the rat mesenteric microcirculation was employed. 2 Mesentery superfusion with PAF (0.1 mM) induced a signi®cant increase in leukocyte rolling¯ux, adhesion and emigration at 60 min. Rolipram pretreatment, markedly inhibited these parameters by 100, 95 and 95% respectively. 3 Similar eects were observed when the mesentery was superfused with LPS (1 mg ml 71) for the same time period and these leukocyte parameters were nearly abrogated by rolipram pretreatment. 4 LPS exposure of the mesentery for 4 h caused a greater increase in leukocyte rolling¯ux, adhesion and emigration which were inhibited by rolipram administration by 51, 71 and 81% respectively. 5 Immunohistochemistry revealed a signi®cant increase in P-selectin expression after 60 min superfusion with PAF which was attenuated by rolipram. 6 LPS exposure of the mesentery for 4 h caused a signi®cant increase in P-and E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. Rolipram pretreatment down-regulated both P-and E-selectin expression but had no eect on ICAM-1 and VCAM-1 expression. 7 Signi®cant increases in plasma cyclic AMP levels were detected at 4.5 h after rolipram administration. 8 In conclusion, we have demonstrated that rolipram is a potent in vivo inhibitor of leukocyteendothelial cell interactions. The eects observed are mediated through endothelial P-and E-selectin downregulation. Therefore, selective PDE-4 inhibitors may be useful in the control of dierent in¯ammatory disorders.

Rolipram Attenuates Bile Duct Ligation–Induced Liver Injury in Rats: A Potential Pathogenic Role of PDE4

“…The bile duct ligation surgery was performed on 8-weekold Sprague-Dawley rats (Harlan, Indianapolis, IN), as described previously (Song et al, 2011), and assigned to three study groups (eight per group): 1) BDL, 2) BDL1rolipram (5 mg/kg body weight three times a week), and 3) BDL1dimethylsulfoxide (DMSO) serving as a vehicle control). Rolipram dose was chosen based on our preliminary studies and published work (Sanz et al, 2002;Odashima et al, 2005;Videla et al, 2006). Rolipram and DMSO were given intraperitoneally throughout the study period.…”

Direct evidence of leukocyte adhesion in arterioles by angiotensin II

“…When the experiment using intravital microscopy was completed, the portion exposed to saline or to Ang II for 4 hours was then isolated and further fixed in 4% paraformaldehyde for 90 minutes at 4°C, as previously described. 30 After fixation, the tissue was dehydrated using graded acetone washes at 4°C and embedded in paraffin wax, and 4-m-thick sections were cut.…”

“…Immunohistochemical localization of P-selectin, E-selectin, ICAM-1, and VCAM-1 was accomplished using a modified avidin and biotin immunoperoxidase technique, as previously described by Sanz et al 30 After different previous procedures, tissue sections were incubated with the antirat-P-selectin mAb (RMP-1), antirat-E-selectin mAb (RME-1), antirat- Thirty arterioles and venules were examined in each group for each CAM investigated, and the percentage of positive-staining vessels was determined. Positive staining was defined as an arteriole or a venule displaying brown reaction product.…”

Compound Danshen injection improves endotoxin-induced microcirculatory disturbance in rat mesentery

“…Furthermore, it is demonstrated that LPS stimulation evokes an increase in the expression of adhesion molecules, including L-selectin [7] and CD11b/CD18 in leukocytes, E-selectin and intercellular adhesion molecule 1 (ICAM-1) in endothelial cells [7][8][9][10][11][12][13] . In addition, LPS stimulation can cause the release of proinflammatory mediators and vasoactive substances, such Abstract AIM: To investigate the effect of compound Danshen injection on lipopolysaccharide (LPS)-induced rat mesenteric microcirculatory dysfunctions and the underlying possible mechanism by an inverted intravital microscope and high-speed video camera system.…”