title: Phospholipase A2 pathway association with macrophage-mediated polycarbonate-urethane biodegradation.
abstract: Activation of the phospholipase A2 (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 PLA2 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 PLA2 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 PLA2 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 PLA2 along with cytosolic PLA2. Understanding PCNU activation of intracellular pathways, such as PLA2, will allow the design of materials optimized for their intended use.
authors.affiliation: University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ont., K1Y 4W7, Canada.
authors.forename: Donna Lee M
authors.initials: DL
authors.lastname: Dinnes
authors.forename: J Paul
authors.initials: JP
authors.lastname: Santerre
authors.forename: Rosalind S
authors.initials: RS
authors.lastname: Labow
mesh_terms: D020341:Absorbable Implants; D016718:Arachidonic Acid / Q000096:biosynthesis* / Q000276:immunology; D001672:Biocompatible Materials / Q000009:adverse effects / Q000737:chemistry; D005549:Foreign-Body Reaction / Q000139:chemically induced* / Q000201:enzymology* / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008422:Materials Testing; D010587:Phagocytosis / Q000187:drug effects* / Q000276:immunology; D010741:Phospholipases A / Q000276:immunology / Q000378:metabolism*; D054467:Phospholipases A2; D011140:Polyurethanes / Q000009:adverse effects* / Q000737:chemistry; D020298:U937 Cells
chemical_list: D001672:Biocompatible Materials; D011140:Polyurethanes; D016718:Arachidonic Acid; D010741:Phospholipases A; D054467:Phospholipases A2