The
selectin family of cellular adhesion molecules plays an important role in the cellular infiltration and molecular signaling associated with
ischemia/reperfusion (I/R).
Selectins are essential in the recruitment and infiltration of leukocytes to sites of
inflammation, and consequently,
selectin blockade represents an important area of current research in the potential alleviation of the cell-mediated injury associated with I/R. Previously, treatments targeted at only a single
selectin have proven ineffective, due to compensation by uninhibited
cell-adhesion molecules. However, pan-
selectin antagonists - those inhibitors capable of blocking the actions of all three
selectins - have demonstrated great potential in blocking the initial events in the leukocyte-endothelium adhesion cascade. A number of
therapeutics have been developed, with the most promising results demonstrated by a class of non-
oligosaccharide, small-molecule
selectin antagonists. TB-1269 and
OC-229 are two of the most promising of inhibitors in this class - they are capable of binding all three
selectins, they have been demonstrated to reduce neutrophil infiltration following
ischemia/reperfusion, and they have been associated with reduced tissue damage in experimental animal models of
ischemia/reperfusion involving the liver, the heart, the kidneys, and the whole body. Furthermore,
TBC-1269 has recently undergone successful phase I and phase IIa clinical trials for
asthma and
psoriasis. Though the timing of
selectin inhibition is essential in attenuating leukocyte infiltration and cell-mediated injury, the transient blockade of
selectin function, in a well-controlled setting, could be an extremely beneficial intervention in
ischemia/reperfusion injury.