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Anesthetics impact the resolution of inflammation.

Chiang N, Schwab JM, Fredman G, Kasuga K, Gelman S, Serhan CN - PLoS ONE (2008)

Bottom Line: Lidocaine did not alter the levels of specific lipid mediators, including pro-inflammatory leukotriene B(4), prostaglandin E(2) and anti-inflammatory lipoxin A(4), in the cell-free peritoneal lavages.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).Isoflurane enhances whereas lidocaine impairs timely resolution of acute inflammation.

View Article: PubMed Central - PubMed

Affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.

ABSTRACT

Background: 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. 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 findings: Using 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 B(4), prostaglandin E(2) and anti-inflammatory lipoxin A(4), in the cell-free peritoneal lavages. Addition of a lipoxin A(4) 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) approximately 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 resolution (T(max)), while isoflurane shortened resolution interval (Ri).

Conclusions: Taken 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.

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Related in: MedlinePlus

Lidocaine alters leukocyte infiltration during acute inflammation and delays resolution.(A) Mice were injected with zymosan A in the absence or presence of lidocaine (0.008% or 0.08%) and peritoneal lavages were collected at indicated time points. Total leukocytes were enumerated by light microscopy, and PMN and mononuclear cells determined by differential leukocyte counting. Results are expressed as the mean±SEM from n = 3–4. *p<0.05, **p<0.01, ***p<0.001 when compared to mice treated with zymosan A alone at the same time points. (B) Mice were injected with lidocaine (0.08%) 15 min prior to injection of zymosan A. Peritoneal lavages were collected at 24 h, and total leukocytes enumerated. Results are expressed as mean±SEM from n = 3. *p<0.05, **p<0.01 when compared to mice treated with zymosan A alone.
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pone-0001879-g001: Lidocaine alters leukocyte infiltration during acute inflammation and delays resolution.(A) Mice were injected with zymosan A in the absence or presence of lidocaine (0.008% or 0.08%) and peritoneal lavages were collected at indicated time points. Total leukocytes were enumerated by light microscopy, and PMN and mononuclear cells determined by differential leukocyte counting. Results are expressed as the mean±SEM from n = 3–4. *p<0.05, **p<0.01, ***p<0.001 when compared to mice treated with zymosan A alone at the same time points. (B) Mice were injected with lidocaine (0.08%) 15 min prior to injection of zymosan A. Peritoneal lavages were collected at 24 h, and total leukocytes enumerated. Results are expressed as mean±SEM from n = 3. *p<0.05, **p<0.01 when compared to mice treated with zymosan A alone.

Mentions: We first determined whether lidocaine alters cellular infiltration in a self-limited spontaneously resolving murine peritonitis. For these analyses, we used our reported resolution map that was constructed using an unbiased systems approach that combined cell trafficking into inflammatory exudates and mass spectrometry-based proteomics and lipid mediator lipidomics of resolving exudates [8]. Here, a microbial stimulus, the yeast wall zymosan A, was administered intraperitoneally to initiate inflammation [15], together with lidocaine given concomitantly. Given the inflammation-resolution map as a background terrain, lidocaine was introduced in order to determine if it significantly changed the signature of resolution map and indices in zymosan-initiated peritonitis. Inflammatory exudates were collected at the indicated time intervals 4–72 h (Fig. 1A). Zymosan alone, as expected, stimulated an acute increase in the total leukocyte numbers (i.e. PMN and mononuclear cells) present in the peritoneal exudates during the initial phase of inflammation (4 h after zymosan, 11.8±0.4×106 leukocytes), with a maximal infiltration at 12 h (30.0±2.5×106 leukocytes), followed by a decline or resolution as monitored to 72 h. The time course of PMN infiltration followed a similar trend, peaking (17.5±2.5×106 PMN) at 12 h after zymosan challenge (Fig. 1A). An anesthetic dose of lidocaine, i.e. 0.08% (w/v) [16] administered with zymosan A significantly increased the number of total leukocytes by ∼49% within exudates at 4 h (p<0.05). The increase in exudate PMN was ∼58% (p<0.05). In the mice treated with both lidocaine and zymosan, the numbers of PMN continued to increase after 12 h and reached a maximum at 24 h. As a result, in the presence of lidocaine, the number of PMN in the exudate was significantly increased at this time point (∼60% increase, p<0.01). In contrast, the patterns of mononuclear cell infiltrates did not appear to be significantly altered by lidocaine treatment in this time course (4–72 h). Even doses as low as 0.008% (w/v) lidocaine, when given together with zymosan, led to a significant increase in the accumulation of PMN at 24 h (∼75% increase, p<0.001). Lidocaine alone without zymosan challenge did not alter peritoneal leukocyte numbers in this 4–24 h interval after administration (Fig. S1B). These results suggested that lidocaine might hamper PMN clearance during the normal spontaneous resolution phase of acute inflammation.


Anesthetics impact the resolution of inflammation.

Chiang N, Schwab JM, Fredman G, Kasuga K, Gelman S, Serhan CN - PLoS ONE (2008)

Lidocaine alters leukocyte infiltration during acute inflammation and delays resolution.(A) Mice were injected with zymosan A in the absence or presence of lidocaine (0.008% or 0.08%) and peritoneal lavages were collected at indicated time points. Total leukocytes were enumerated by light microscopy, and PMN and mononuclear cells determined by differential leukocyte counting. Results are expressed as the mean±SEM from n = 3–4. *p<0.05, **p<0.01, ***p<0.001 when compared to mice treated with zymosan A alone at the same time points. (B) Mice were injected with lidocaine (0.08%) 15 min prior to injection of zymosan A. Peritoneal lavages were collected at 24 h, and total leukocytes enumerated. Results are expressed as mean±SEM from n = 3. *p<0.05, **p<0.01 when compared to mice treated with zymosan A alone.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2268966&req=5

pone-0001879-g001: Lidocaine alters leukocyte infiltration during acute inflammation and delays resolution.(A) Mice were injected with zymosan A in the absence or presence of lidocaine (0.008% or 0.08%) and peritoneal lavages were collected at indicated time points. Total leukocytes were enumerated by light microscopy, and PMN and mononuclear cells determined by differential leukocyte counting. Results are expressed as the mean±SEM from n = 3–4. *p<0.05, **p<0.01, ***p<0.001 when compared to mice treated with zymosan A alone at the same time points. (B) Mice were injected with lidocaine (0.08%) 15 min prior to injection of zymosan A. Peritoneal lavages were collected at 24 h, and total leukocytes enumerated. Results are expressed as mean±SEM from n = 3. *p<0.05, **p<0.01 when compared to mice treated with zymosan A alone.
Mentions: We first determined whether lidocaine alters cellular infiltration in a self-limited spontaneously resolving murine peritonitis. For these analyses, we used our reported resolution map that was constructed using an unbiased systems approach that combined cell trafficking into inflammatory exudates and mass spectrometry-based proteomics and lipid mediator lipidomics of resolving exudates [8]. Here, a microbial stimulus, the yeast wall zymosan A, was administered intraperitoneally to initiate inflammation [15], together with lidocaine given concomitantly. Given the inflammation-resolution map as a background terrain, lidocaine was introduced in order to determine if it significantly changed the signature of resolution map and indices in zymosan-initiated peritonitis. Inflammatory exudates were collected at the indicated time intervals 4–72 h (Fig. 1A). Zymosan alone, as expected, stimulated an acute increase in the total leukocyte numbers (i.e. PMN and mononuclear cells) present in the peritoneal exudates during the initial phase of inflammation (4 h after zymosan, 11.8±0.4×106 leukocytes), with a maximal infiltration at 12 h (30.0±2.5×106 leukocytes), followed by a decline or resolution as monitored to 72 h. The time course of PMN infiltration followed a similar trend, peaking (17.5±2.5×106 PMN) at 12 h after zymosan challenge (Fig. 1A). An anesthetic dose of lidocaine, i.e. 0.08% (w/v) [16] administered with zymosan A significantly increased the number of total leukocytes by ∼49% within exudates at 4 h (p<0.05). The increase in exudate PMN was ∼58% (p<0.05). In the mice treated with both lidocaine and zymosan, the numbers of PMN continued to increase after 12 h and reached a maximum at 24 h. As a result, in the presence of lidocaine, the number of PMN in the exudate was significantly increased at this time point (∼60% increase, p<0.01). In contrast, the patterns of mononuclear cell infiltrates did not appear to be significantly altered by lidocaine treatment in this time course (4–72 h). Even doses as low as 0.008% (w/v) lidocaine, when given together with zymosan, led to a significant increase in the accumulation of PMN at 24 h (∼75% increase, p<0.001). Lidocaine alone without zymosan challenge did not alter peritoneal leukocyte numbers in this 4–24 h interval after administration (Fig. S1B). These results suggested that lidocaine might hamper PMN clearance during the normal spontaneous resolution phase of acute inflammation.

Bottom Line: Lidocaine did not alter the levels of specific lipid mediators, including pro-inflammatory leukotriene B(4), prostaglandin E(2) and anti-inflammatory lipoxin A(4), in the cell-free peritoneal lavages.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).Isoflurane enhances whereas lidocaine impairs timely resolution of acute inflammation.

View Article: PubMed Central - PubMed

Affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.

ABSTRACT

Background: 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. 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 findings: Using 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 B(4), prostaglandin E(2) and anti-inflammatory lipoxin A(4), in the cell-free peritoneal lavages. Addition of a lipoxin A(4) 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) approximately 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 resolution (T(max)), while isoflurane shortened resolution interval (Ri).

Conclusions: Taken 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.

Show MeSH
Related in: MedlinePlus