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

Activation of the phospholipase A(sub 2) (PLA2) pathway is a key cell signaling event in the inflammatory response. The PLA2 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 PLA2 and polycarbonate-based polyurethane (PCNU) biodegradation, and the effect that material surface had on PLA(sub 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. PLA2 inhibiting agents resulted in significantly decreased PCNU biodegradation (p < 0.05). Moreover, when activation of PLA(sub 2) was assessed ((super 3)H-AA release), significantly more (super 3)H-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(sub 2) inhibitors. The pattern of inhibition of U937 cell-mediated biodegradation and (super 3)H-AA release that was modulated by PCNU surface differences, suggests a role for secretory PLA(sub 2) along with cytosolic PLA(sub 2). Understanding PCNU activation of intracellular pathways, such as PLA(sub 2), will allow the design of materials optimized for their intended use.