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P-selectin and ICAM-1-dependent adherence reactions: role in the genesis of postischemic no-reflow
S N Jerome1, M Doré, J C Paulson
1Department of Physiology, Louisiana State University Medical Center, School of Medicine in Shreveport 71130.
Insights
Blocking P-selectin and ICAM-1 with antibodies reduced postischemic no-reflow in canine muscles. Targeting functional epitopes on these molecules improved microvascular patency after ischemia-reperfusion injury.
Area of Science:
- Cardiovascular Research
- Immunology
- Skeletal Muscle Physiology
Background:
- Postischemic no-reflow is a critical complication following reperfusion injury.
- Endothelial cell adhesion molecules, P-selectin and ICAM-1, mediate leukocyte adhesion and contribute to microvascular dysfunction.
- Understanding the role of these molecules is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the efficacy of immunoneutralization of P-selectin and ICAM-1 in preventing postischemic capillary no-reflow.
- To determine if targeting specific functional epitopes on these adhesion molecules impacts microvascular patency.
Main Methods:
- Canine gracilis muscles were subjected to ischemia-reperfusion (I-R) injury.
- Microvascular patency was assessed using India ink perfusion and computerized video imaging.
- Monoclonal antibodies (MAbs) targeting P-selectin and ICAM-1 functional epitopes were administered.
Main Results:
- Ischemia-reperfusion significantly reduced capillary patency.
- Immunoneutralization of P-selectin with functional epitope-binding MAbs (MD6, PB1.3) significantly improved capillary perfusion.
- ICAM-1 immunoneutralization also increased the number of patent capillaries, though to a lesser extent than P-selectin MAbs.
- A P-selectin MAb binding a nonfunctional epitope did not improve perfusion.
Conclusions:
- P-selectin and ICAM-1 play significant roles in the development of the no-reflow phenomenon in postischemic skeletal muscle.
- Targeting functional epitopes of P-selectin and ICAM-1 with antibodies can attenuate postischemic microvascular dysfunction.
- These findings suggest potential therapeutic targets for managing reperfusion injury.
Abstract:
The aim of this study was to determine whether immunoneutralization of P-selectin or intercellular adhesion molecule-1 (ICAM-1) (endothelial cell adhesion molecules involved in leukocyte rolling and firm adhesion, respectively) would attenuate the development of postischemic capillary no-reflow. Microvascular patency was assessed in vascularly isolated canine gracilis muscles by perfusion with contrast media (India ink) at the end of the experimental protocol. Computerized video imaging was used to quantitate the number of ink-containing microvessels (< 10 microns diam) per muscle fiber in histological samples obtained from isolated canine gracilis muscles subjected to 4.5 h of continuous perfusion (nonischemic control), 4 h of ischemia and 30 min of reperfusion (I-R), I-R + P-selectin monoclonal antibodies (MAbs) (MD6 or PB1.3), and I-R + ICAM-1 MAbs (CL18/6C7 or R6.5). The efficacy of a P-selectin MAb (MD3) that binds to a nonfunctional epitope was also evaluated. I-R was associated with a marked reduction in the number of patent capillaries per fiber (3.1 +/- 0.2 vs. 1.1 +/- 0.2 patent capillaries/fiber for control and I-R, respectively). Immunoneutralization with MAbs directed against functional epitopes on P-selectin (MD6 or PB1.3) significantly improved capillary perfusion (2.3 +/- 0.3 and 3.6 +/- 0.6 patent capillaries/fiber, respectively). On the other hand, MAb MD3, which binds to nonfunctional epitopes on P-selectin, failed to limit the development of postischemic no-reflow (1.0 +/- 0.2 patent capillaries/fiber). Immunoneutralization of ICAM-1 with CL18/6C7 and R6.5 increased the number of patent capillaries per fiber to 1.8 +/- 0.1 and 2.5 +/- 0.3, respectively. These data indicate that P-selectin and ICAM-1-dependent adherence reactions play an important role in the development of the no-reflow phenomenon in postischemic skeletal muscle.