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Recombinant soluble P-selectin glycoprotein ligand 1 moderates local and remote injuries following experimental
C Kyriakides1, J Favuzza, Y Wang
1Department of Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Background:
A central role for the polymorphonuclear leucocyte (PMN) in skeletal muscle ischaemia-reperfusion has been demonstrated by the observation that PMN depletion reduced local and remote pulmonary vascular permeability. This study investigated the role of recombinant soluble P-selectin glycoprotein ligand-immunoglobulin fusion protein (rPSGL-Ig), a P- and E-selectin antagonist, in moderating injury.
Methods:
Mice underwent 2 h of hindlimb ischaemia and 3 h of reperfusion. Muscle and lung vascular permeability index (PI) was assessed by extravasation of (125)I-radiolabelled albumin. Lung myelo peroxidase (MPO) activity was also measured.
Results:
In mice treated with rPSGL-Ig 1 mg/kg before reperfusion (n = 12) muscle PI was reduced by 40 per cent, whereas it was moderated by 20 per cent in animals treated 30 min after reperfusion (n = 15). Lung PI in mice treated with rPSGL-Ig before (n = 12) and 30 min after (n = 15) reperfusion was reduced by over 99 and 98 per cent respectively. Lung MPO activity in mice treated with rPSGL-Ig before (n = 10) and 30 min after (n = 12) reperfusion was reduced by 68 and 58 per cent respectively. Treatment with rPSGL-Ig 1 h after reperfusion, or with m20ek.Fc 1 mg/kg (n = 9; negative control for rPSGL-Ig which is inactive for selectin binding) before reperfusion failed significantly to moderate local or remote organ injury.
Conclusion:
Selectin blockade moderated local skeletal muscle and remote lung injury following hindlimb ischaemia--reperfusion. Significantly, delayed antiselectin therapy also decreased injury.
Insights
Selectin blockade with rPSGL-Ig reduced skeletal muscle and lung injury after hindlimb ischemia-reperfusion. Delayed treatment also effectively decreased organ damage, highlighting selectin
Area of Science:
- Biomedical research
- Vascular biology
- Inflammation and injury
Background:
- Polymorphonuclear leukocytes (PMNs) play a key role in skeletal muscle ischemia-reperfusion injury.
- PMN depletion reduces local and remote pulmonary vascular permeability.
- Recombinant soluble P-selectin glycoprotein ligand-immunoglobulin fusion protein (rPSGL-Ig) is a P- and E-selectin antagonist.
Purpose of the Study:
- To investigate the role of rPSGL-Ig in moderating skeletal muscle and lung injury following hindlimb ischemia-reperfusion.
- To evaluate the efficacy of both immediate and delayed administration of rPSGL-Ig.
Main Methods:
- Mice underwent 2 hours of hindlimb ischemia and 3 hours of reperfusion.
- Vascular permeability index (PI) in muscle and lung was assessed using extravasated (125)I-radiolabeled albumin.
- Lung myeloperoxidase (MPO) activity was measured as an indicator of neutrophil infiltration.
Main Results:
- rPSGL-Ig treatment before reperfusion reduced muscle PI by 40% and lung PI by over 99%.
- Delayed treatment (30 min post-reperfusion) with rPSGL-Ig reduced muscle PI by 20% and lung PI by 98%.
- Lung MPO activity was significantly reduced by rPSGL-Ig, with greater reduction when administered before reperfusion (68%) compared to delayed treatment (58%).
- Treatment 1 hour after reperfusion or with a control agent (m20ek.Fc) did not significantly moderate injury.
Conclusions:
- Selectin blockade effectively moderated both local skeletal muscle and remote lung injury following hindlimb ischemia-reperfusion.
- Delayed administration of antiselectin therapy also demonstrated significant efficacy in decreasing organ injury.