Molecular Medicine

, Volume 18, Issue 12, pp 1481–1490 | Cite as

Dysfunction of Inflammation-Resolving Pathways Is Associated with Exaggerated Postoperative Cognitive Decline in a Rat Model of the Metabolic Syndrome

  • Xiao Su
  • Xiaomei Feng
  • Niccolo Terrando
  • Yan Yan
  • Ajay Chawla
  • Lauren G Koch
  • Steven L Britton
  • Michael A Matthay
  • Mervyn Maze
Research Article


The cholinergic antiinflammatory pathway (CAP), which terminates in the spleen, attenuates postoperative cognitive decline (PCD) in rodents. Surgical patients with metabolic syndrome exhibit exaggerated and persistent PCD 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 A4 (LXA4), another inflammation-resolving pathway in LCR, 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 PCD (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 Mφ). Under lipopolysaccharide (LPS) stimulation, tumor necrosis factor (TNF)-α 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-α production could not be inhibited by an α7 nicotinic acetylcholine receptor agonist, whereas inhibition by the β2 adrenergic agonist, salmeterol, was significantly less (−35%) than that obtained in HCR rats. Compared to HCR, sham and surgery LCR rats had reduced β2 adrenergic receptor-expressing T lymphocytes (59%, 44%), Tregs (47%, 54%) and M2 Mφ (45%, 39%); surgical LCR rats’ hippocampal M2 Mφ) 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 PCD.



The LCR-HCR rat model system was funded by the National Center for Research Resources grant R24 RR017718 (to LG Koch and SL Britton) and is currently supported by the Office of Research Infrastructure Programs/OD grant ROD012098A (to LG Koch and SL Britton) from the National Institutes of Health. SL Britton was also supported by National Institutes of Health grant RO1 DK077200. We acknowledge the expert care of the rat colony provided by Molly Kalahar and Lori Gilligan. The LCR and HCR model can be made available for collaborative study (contact or This work was also supported by Parker B Francis Fellowship (X Su), the Knowledge Innovation Program of the CAS (Y114P11209, X Su), the National Natural Science Foundation of China (81270139, X Su), and funds from the Department of Anesthesia, University of California San Francisco.


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Authors and Affiliations

  • Xiao Su
    • 1
    • 2
  • Xiaomei Feng
    • 1
    • 3
  • Niccolo Terrando
    • 1
  • Yan Yan
    • 1
  • Ajay Chawla
    • 4
  • Lauren G Koch
    • 5
  • Steven L Britton
    • 5
  • Michael A Matthay
    • 4
  • Mervyn Maze
    • 1
  1. 1.Department of Anesthesia and Perioperative CareUniversity of CaliforniaSan FranciscoUSA
  2. 2.Unit of Respiratory Infection and Histopathology, Institut Pasteur of ShanghaiChinese Academy of SciencesShanghaiChina
  3. 3.Department of Anesthesiology, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiChina
  4. 4.Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoUSA
  5. 5.Department of AnesthesiologyUniversity of Michigan Medical SchoolAnn ArborUSA

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