The Effect of Fucoidin on the Remote Pulmonary Injury in a Two-Hit Trauma Model in Mice

Abstract

Background: Neutrophil recruitment into microvascular circuits is known to be initiated by selectin-mediated endothelial adherence. The effect of fucoidin (a natural sulfated polymer of L-fucose and this potent selectin ligand) on the selectin-dependent neutrophil migration within pulmonary and hepatic capillaries was studied in a two-hit trauma model in mice.

Methods and Results: Infrarenal ischemia (4 h) followed by reperfusion (4 h) and subsequent cecal ligation and puncture (CLP) resulted in pulmonary capillary leakage at 48 h as evidenced by an increased alveolar/plasma protein ratio (0.21 vs. 0.03 in control; p < 0.05) and also led to pulmonary neutrophil accumulation as assessed by the myeloperoxidase (MPO) content in homogenized lung tissue (0.29 U/min vs. 0.21 U/min in control; p > 0.05). A significant (p < 0.05) increase in interleukin-(IL-)6 (30.1 pg/ml) and IL-10 (44.9 pg/ml) was noted in the two-hit model. Ischemia/reperfusion (I/R) injury alone resulted in the same pattern of injury but to a lesser extent, whereas CLP alone did only lead to a significant increase in IL-6 and IL-10. The effect of fucoidin was diverse and depended on the type of injury. In the two-hit model, fucoidin, infused at a dosage of 2.5 mg/kg at the time of reperfusion, significantly reduced pulmonary leakage but seemed to deteriorate neutrophil accumulation as reflected by a slight MPO increase (p > 0.05). Also both cytokines, IL-6 (318.8 pg/ml) and IL-10 (106.1 pg/ml), significantly (p < 0.05) increased under these circumstances. In the protocol of each single injury (I/R or CLP), fucoidin significantly (p < 0.05) reduced the protein ratio, diminished IL-6 and IL-10 serum levels (p < 0.05 only for IL-6 in the I/R protocol), but again slightly raised (p > 0.05) lung and liver MPO. In all histological sections of either experimental protocol, fucoidin revealed less neutrophil accumulation and less interstitial edema formation.

Conclusion: Based on our data, we would conclude that fucoidin attenuates selectin-mediated neutrophil adherence leading to capillary leakage, although neutrophil recruitment seems not to be influenced. For clinical perspectives, it could be relevant that the selectin-dependent pathway of neutrophil adherence can be blocked by sulfated L-fucose.