Anesthetics Impact the Resolution of Inflammation

Nan Chiang,Gabrielle Fredman,Kie Kasuga,Simon Gelman,Jan M Schwab,Charles N Serhan,Marie Csete

doi:10.1371/journal.pone.0001879

Nan Chiang, Gabrielle Fredman + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0001879

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Journal: PloS one	Publication Date: Apr 2, 2008
Citations: 150	License type: CC BY 4.0

Affiliation: Brigham and Women's Hospital, Harvard University

Abstract

BackgroundLocal and volatile anesthetics are widely used for surgery. It is not known whether anesthetics impinge on the orchestrated events in spontaneous resolution of acute inflammation. Here we investigated whether a commonly used local anesthetic (lidocaine) and a widely used inhaled anesthetic (isoflurane) impact the active process of resolution of inflammation.Methods and FindingsUsing murine peritonitis induced by zymosan and a systems approach, we report that lidocaine delayed and blocked key events in resolution of inflammation. Lidocaine inhibited both PMN apoptosis and macrophage uptake of apoptotic PMN, events that contributed to impaired PMN removal from exudates and thereby delayed the onset of resolution of acute inflammation and return to homeostasis. Lidocaine did not alter the levels of specific lipid mediators, including pro-inflammatory leukotriene B4, prostaglandin E2 and anti-inflammatory lipoxin A4, in the cell-free peritoneal lavages. Addition of a lipoxin A4 stable analog, partially rescued lidocaine-delayed resolution of inflammation. To identify protein components underlying lidocaine's actions in resolution, systematic proteomics was carried out using nanospray-liquid chromatography-tandem mass spectrometry. Lidocaine selectively up-regulated pro-inflammatory proteins including S100A8/9 and CRAMP/LL-37, and down-regulated anti-inflammatory and some pro-resolution peptides and proteins including IL-4, IL-13, TGF-â and Galectin-1. In contrast, the volatile anesthetic isoflurane promoted resolution in this system, diminishing the amplitude of PMN infiltration and shortening the resolution interval (Ri) ∼50%. In addition, isoflurane down-regulated a panel of pro-inflammatory chemokines and cytokines, as well as proteins known to be active in cell migration and chemotaxis (i.e., CRAMP and cofilin-1). The distinct impact of lidocaine and isoflurane on selective molecules may underlie their opposite actions in resolution of inflammation, namely lidocaine delayed the onset of resoluion (Tmax), while isoflurane shortened resolution interval (Ri).ConclusionsTaken together, both local and volatile anesthetics impact endogenous resolution program(s), altering specific resolution indices and selective cellular/molecular components in inflammation-resolution. Isoflurane enhances whereas lidocaine impairs timely resolution of acute inflammation.

Highlights

Resolution of acute inflammation was widely held to be a passive event [1]
To characterize resolution of inflammation in cellular and molecular terms, we established a resolution map and defined the main quantitative indices (Fig. S1A) [8]. These indices chart and take into account (i) the magnitude of PMN tissue infiltration; (ii) the time interval when numbers of PMN reach Ymax within exudates (Tmax); (iii) duration: the time point (T50) when PMN numbers reduce to 50% of Ymax (R50); and (iv) the resolution interval (Ri): the time interval from the maximum PMN point (Ymax) to the 50% reduction point (R50) [i.e. T50-Tmax]. Using this set of resolution indices, we demonstrated that endogenous mediators such as resolvins and protectins accelerate resolution as evidenced by initiating the resolution of inflammation at earlier times (QTmax and T50) and/or shortening the resolution interval (QRi) [8,9]
Local anesthetic lidocaine impairs resolution We first determined whether lidocaine alters cellular infiltration in a self-limited spontaneously resolving murine peritonitis

Summary

Introduction

Resolution of acute inflammation was widely held to be a passive event [1]. It is clear that tissue resolution or its return from an inflammatory and/or disease state is an active process involving novel mediators [2,3]. Resolution agonists, in comparison, are antiinflammatories, but act by different mechanisms than the classic ones [recently reviewed in ref 5]. Local and volatile anesthetics are widely used for surgery. It is not known whether anesthetics impinge on the orchestrated events in spontaneous resolution of acute inflammation. We investigated whether a commonly used local anesthetic (lidocaine) and a widely used inhaled anesthetic (isoflurane) impact the active process of resolution of inflammation

Methods

Results

Discussion

Conclusion