Phospholipase A2 pathway association with macrophage-mediated polycarbonate-urethane biodegradation.
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.
Dinnes
Donna Lee M
DL
University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ont., K1Y 4W7, Canada.
Santerre
J Paul
JP
Labow
Rosalind S
RS
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
D001672:Biocompatible Materials; D011140:Polyurethanes; D016718:Arachidonic Acid; D010741:Phospholipases A; D054467:Phospholipases A2