Phospholipase A 2 pathway association with macrophage-mediated polycarbonate-urethane biodegradation

Abstract

Activation of the phospholipase A 2 (PLA 2) pathway is a key cell signaling event in the inflammatory response. The PLA 2 family consists of a group of enzymes that hydrolyze membrane phospholipids, resulting in the liberation of arachidonic acid (AA), a precursor to pro-inflammatory molecules. Given the well-documented activating role of biomaterials in the inflammatory response to medical implants, the present study investigated the link between PLA 2 and polycarbonate-based polyurethane (PCNU) biodegradation, and the effect that material surface had on PLA 2 activation in the U937 cell line. PCNUs were synthesized with poly(1,6-hexyl 1,2-ethyl carbonate)diol, 1,4-butanediol and one of two diisocyanates (hexane 1,6-diisocyanate or 4,4′-methylene bisphenyl diisocyanate) in varying stoichiometries and incubated with adherent U937 cells. PLA 2 inhibiting agents resulted in significantly decreased PCNU biodegradation ( p < 0.05 ). Moreover, when activation of PLA 2 was assessed ( 3H-AA release), significantly more 3H-AA was released from PCNU-adherent U937 cells than polystyrene-adherent U937 cells ( p < 0.05 ) which was significantly decreased in the presence of PLA 2 inhibitors. The pattern of inhibition of U937 cell-mediated biodegradation and 3H-AA release that was modulated by PCNU surface differences, suggests a role for secretory PLA 2 along with cytosolic PLA 2. Understanding PCNU activation of intracellular pathways, such as PLA 2, will allow the design of materials optimized for their intended use.