title: Effect of phorbol esters on the macrophage-mediated biodegradation of polyurethanes via protein kinase C activation and other pathways.
abstract: It was previously found that re-seeding monocyte-derived macrophages (MDM) on polycarbonate-based polyurethanes (PCNUs) in the presence of the protein kinase C (PKC) activator phorbol myristate acetate (PMA) inhibited MDM-mediated degradation of PCNUs synthesized with 1,6-hexane diisocyanate (HDI), as well as esterase activity and monocyte-specific esterase (MSE) protein. However, no effect on the degradation of a 4,4'-methylene bisphenyl (MDI)-derived PCNU (MDI321) occurred. This finding suggested that oxidation, a process linked to the PKC pathway, was not activated in the same manner for all PCNUs. In the current study MDM were re-seeded onto the above PCNU surfaces with PMA, PKC-inactive 4alphaPMA and the PKC inhibitor bisindolylmaleimide I hydrochloride (BIM) for 48 h before assaying for PCNU degradation, esterase activity, MSE protein, DNA, cell viability and cell morphology. 4alphaPMA did not alter MDM-mediated HDI PCNU degradation but MDI321 degradation increased in this condition. BIM alone had no effect on any parameter; however, when BIM and PMA were added together, the PMA inhibition of biodegradation, esterase activity and MSE protein was partially reversed for MDM on HDI PCNUs only. Adding PMA to MDM on HDI PCNUs increased intercellular connections, whereas 4alphaPMA or BIM+PMA increased cell size. Although this study demonstrated a role for oxidation via a PKC-activated pathway in MDM-mediated PCNU degradation, phorbol esters appear to also activate non-PKC pathways that have roles in biodegradation. Moreover, the sensitivity to material surface chemistry in the MDM response to each PCNU dictates a multi-factorial degradative process involving alternate material specific oxidative and hydrolytic mechanisms.
authors.affiliation: University of Ottawa Heart Institute, Ottawa, ON, Canada K1Y 4W7.
authors.forename: Joanne Eileen
authors.initials: JE
authors.lastname: McBane
authors.forename: J P
authors.initials: JP
authors.lastname: Santerre
authors.forename: Rosalind
authors.initials: R
authors.lastname: Labow
mesh_terms: D001672:Biocompatible Materials / Q000378:metabolism; D018929:Cell Culture Techniques; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D004950:Esterases / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D008301:Maleimides / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology; D010703:Phorbol Esters / Q000494:pharmacology*; D011140:Polyurethanes / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013499:Surface Properties
chemical_list: D001672:Biocompatible Materials; D007211:Indoles; D008301:Maleimides; D010703:Phorbol Esters; D011140:Polyurethanes; D011493:Protein Kinase C; D004950:Esterases; C413962:monocyte-specific esterase; C070515:bisindolylmaleimide I