Our results demonstrated that argatroban, a direct thrombin inhibitor, could suppress leukocyte–endothelial cell interactions in the postlaser rat retina. The mRNA expressions of P-selectin and ICAM-I were also suppressed significantly in the argatroban-treated retina. On the basis of these findings, we suggest that argatroban may attenuate blood–retinal barrier breakdown after retinal scatter laser photocoagulation, not only by inhibiting coagulation but also by inhibiting inflammatory reactions mediated by accumulated leukocytes and platelets.
We previously showed that inflammatory leukocyte–endothelial interactions were observed in both the photocoagulated and the nonphotocoagulated halves of rat retina and demonstrated a significant increase of vascular permeability in the nonphotocoagulated portions.
7 An investigation using the fluorophotometric technique developed by Taguchi et al.
24 has demonstrated that hydrogen peroxide diffused into the vitreous after retinal scatter photocoagulation. Hydrogen peroxide was found to induce upregulation of adhesion molecules on the vascular endothelium and subsequent leukocyte–endothelial interactions.
25 Accordingly, scatter photocoagulation may cause inflammatory leukocyte behavior, such as rolling and accumulation in the nonphotocoagulated retina through oxidative stress-induced upregulation of adhesion molecules on the vascular endothelium.
Recent evidence suggests that leukocytes and platelets play a critical role in disrupting the microvascular barrier in various organs.
26 27 28 These reports have suggested that leukocyte–endothelial contact, such as leukocyte adhesion on the vascular endothelium and subsequent leukocyte extravasation, may be responsible for increased microvascular permeability under inflammatory conditions. Using AO leukocyte fluorography, we have demonstrated in vivo that platelet depletion suppresses leukocyte rolling and subsequent accumulation in postischemic tissues.
26 Platelets adhering to vascular endothelium contribute to the recruitment of leukocytes through the expression of P-selectin on their surfaces and participate in leukocyte-dependent tissue injury.
26 Moreover, thrombin activates platelets and causes them to produce inflammatory mediators, such as serotonin, leukotrienes, thromboxane A2, monocyte chemotactic protein-3, and platelet-derived growth factor.
29 30 Some investigators have shown that anticoagulant therapy attenuates the inflammatory reactions, such as leukocyte–endothelial cell interactions, or fibrin formation.
12 13 14 15 We demonstrated previously that argatroban could also suppress leukocyte- and platelet–endothelial cell interactions in the postischemic rat retina and that the expression of mRNA of P-selectin and ICAM-I was suppressed significantly in the argatroban-treated retina.
15 We hypothesized that argatroban, a selective thrombin inhibitor, has a potential effect on the blood–retinal barrier breakdown by inhibition of the aggregation of platelets.
Wilson et al.
31 showed the gene expression in the mouse retina 3 days after argon laser photocoagulation, as determined by microarray analysis. In their study, both genes, P-selectin and ICAM-I, were not the upregulated ones. Conversely, our results showed mRNA upregulation of these adhesion molecules in the nonphotocoagulated portions of the retina. The time course of postlaser reaction may account for these conflicting results, as reported by Wilson et al. and us. In the acute phase, the mRNA expressions of these adhesion molecules were upregulated after scatter laser photocoagulation. Then, argatroban inhibited the mRNA expressions of these adhesion molecules. The suppressed leukocyte–endothelial cell interactions in the postlaser retina of argatroban-treated rats were associated with the suppressed expressions of these adhesion molecules.
In conclusion, we have demonstrated that argatroban can attenuate leukocyte–endothelial cell interactions and blood–retinal barrier breakdown in the nonphotocoagulated portions of the retina after partial scatter laser photocoagulation. These results suggest that argatroban attenuates the development of macular edema by inhibiting inflammatory reactions mediated by leukocytes and platelets. Argatroban may have a therapeutic effect on macular edema after photocoagulation.