Circulation. 2002;105:685-690
Published online before print December 31, 2001, doi: 10.1161/hc0602.103617
Published online before print December 31, 2001, doi: 10.1161/hc0602.103617
(Circulation. 2002;105:685.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Inflammatory Response After Open Heart Surgery
Release of Heat-Shock Protein 70 and Signaling Through Toll-Like Receptor-4
From the Faculty of Medicine (B.D., E.L., T.H.F., T.E., A.S.), Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway; the Department of Cardiothoracic Surgery (A.W., O.F.M.S.), St Elisabeth Heart Centre, University Hospital of Trondheim, Norway; the Department of Medicine (A.W.), Section for Hematology, University Hospital of Trondheim, Norway; and the School of Medicine (N.Q.), Shock and Trauma Research Center, University of Missouri, Kansas City.
Correspondence to Dr Brit Dybdahl, Faculty of Medicine, Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Medisinsk Teknisk Forskningssenter, N-7489 Trondheim, Norway. E-mail brit.dybdahl{at}medisin.ntnu.no
Background— Coronary artery bypass grafting with the use of cardiopulmonary bypass is known to mediate an inflammatory response. The stress-inducible heat-shock protein (HSP) 70 has been detected in myocardial cells after CABG, and toll-like receptors (TLRs) are suggested as putative signaling receptors for the HSPs, mediating synthesis of inflammatory cytokines. The main aims of our study were to explore the release of HSP70 and the regulation of monocyte TLR-2 and TLR-4 expression after CABG.
Methods and Results— Twenty patients referred for elective CABG were included in this study. Using immunoassays, we detected HSP70 in plasma after CABG, with peak concentration immediately after surgery. Interleukin-6 in plasma reached peak concentration 5 hours after surgery. Monocyte CD14, TLR-2, and TLR-4 expression, as analyzed by flow cytometry, was initially downregulated. On day 1, CD14 expression normalized, whereas TLR-2 and TLR-4 expression was upregulated. TLR-4 was significantly upregulated even on postoperative day 2. Additional experiments revealed that peritoneal macrophages from control (C3H/HeN) mice responded to HSP70 with release of tumor necrosis factor, whereas macrophages from mutated TLR-4 (C3H/HeJ) mice were unresponsive. In vitro, human adherent monocytes responded to recombinant HSP70 with interleukin-6 and tumor necrosis factor release. CD14 and TLR-4 monoclonal antibodies inhibited the cytokine response.
Conclusions— In this study, we observed an immediate release of HSP70 into the circulation and a modulation of monocyte TLR-2 and TLR-4 expression after CABG. TLR-4 and CD14 appear to be involved in an HSP70-mediated activation of innate immunity.
Key Words: heat-shock proteins • toll-like receptors • inflammation • cardiopulmonary bypass • angina
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