期刊
MOLECULAR MEDICINE
卷 18, 期 12, 页码 1481-1490出版社
SPRINGER
DOI: 10.2119/molmed.2012.00351
关键词
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资金
- National Center for Research Resources grant [R24 RR017718]
- Office of Research Infrastructure Programs/OD grant from the National Institutes of Health [ROD012098A]
- National Institutes of Health grant [RO1 DK077200]
- Parker B Francis Fellowship
- Knowledge Innovation Program of the CAS [Y114P11209]
- National Natural Science Foundation of China [81270139]
- Department of Anesthesia, University of California San Francisco
The cholinergic antiinflammatory pathway (CAP), which terminates in the spleen, attenuates postoperative cognitive decline (POD) in rodents. Surgical patients with metabolic syndrome exhibit exaggerated and persistent POD that is reproduced in postoperative rats selectively bred for easy fatigability and that contain all features of metabolic syndrome (low-capacity runners (LCRs)). We compared the CAP and lipoxin A(4) (LXA(4)), another inflammation-resolving pathway in LOP, with its counterpart high-capacity runner (HCR) rats. Isoflurane-anesthetized LCR and HCR rats either underwent aseptic trauma involving tibial fracture (surgery) or not (sham). At postoperative d 3 (POD3), compared with HCR, LCR rats exhibited significantly exaggerated POD (trace fear conditioning freezing time 43% versus 57%). Separate cohorts were killed at POD3 to collect plasma for LXA4 and to isolate splenic mononuclear cells (MNCs) to analyze CAP signaling, regulatory T cells (Tregs) and M2 macrophages (M2 M phi). Under lipopolysaccharide (LPS) stimulation, tumor necrosis factor (TNF)-alpha produced by splenic MNCs was 117% higher in LCR sham and 52% higher in LCR surgery compared with HCR sham and surgery rats; LPS-stimulated TNF-alpha production could not be inhibited by an alpha 7 nicotinic acetylcholine receptor agonist, whereas inhibition by the beta 2 adrenergic agonist, salmeterol, was significantly less (-35%) than that obtained in HCR rats. Compared to HCR, sham and surgery HCR rats had reduced beta(2) adrenergic receptor-expressing T lymphocytes (59%, 44%), Tregs (47%, 54%) and M2 M phi (45%, 39%); surgical LOP rats' hippocampal M2 M phi was 66% reduced, and plasma LXA4 was decreased by 120%. Rats with the metabolic syndrome have ineffective inflammation-resolving mechanisms that represent plausible reasons for the exaggerated and persistent POD.
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