Effect of linezolid on cytokine production capacity and plasma endotoxin levels in response to lipopolysaccharide stimulation of whole blood

Takahashi, Goro; Sato, Nobuhiro; Yaegashi, Yasunori; Kojika, Masahiro; Matsumoto, Naoya; Kikkawa, Tomohiro; Shozushima, Tatsuyori; Akitomi, Shinji; Aoki, Katsumi; Ito, Naoko; Hoshikawa, Koichi; Suzuki, Yasushi; Inoue, Yasuhiro; Wakabayashi, Go; Endo, Shunsuke

doi:10.1007/s10156-009-0012-5

Cited by 21 publications

(14 citation statements)

References 19 publications

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“…Some studies have shown that linezolid reduces the level of lipopolysaccharide-induced production of inflammatory cytokines in whole blood (5)(6)(7). Additionally, in the previous studies with methicillin-sensitive S. aureus and MRSA, linezolid has been shown to have an inhibitory effect on the pathogeninduced production of inflammatory cytokines (2-4).…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory Effect of Linezolid on Methicillin-Resistant Staphylococcus aureus Supernatant-Induced MUC5AC Overexpression in Human Airway Epithelial Cells

Kaku

Yanagihara

Morinaga

et al. 2014

Antimicrob Agents Chemother

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bLinezolid is the first member of the oxazolidinones and is active against drug-resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA). Additionally, linezolid shows an immunomodulatory effect, such as inhibition of inflammatory cytokine production. In this study, we examined the effect of linezolid on MRSA-induced MUC5AC overexpression in airway epithelial cells. In this study, an MRSA supernatant was used to avoid the direct effect of linezolid on MRSA. MUC5AC protein production was significantly increased with a 40-fold dilution of MRSA supernatant. At the mRNA level, MUC5AC gene expression was significantly increased 6 and 9 h after stimulation. In an inhibition study, linezolid significantly reduced MRSA-induced MUC5AC protein and mRNA overexpression at concentrations of 5 and 20 g/ml, which were the same as the trough and peak concentrations in human epithelial lining fluid. In an analysis of cell signaling, among the mitogen-activated protein kinase inhibitors, only the extracellular signal-regulated protein kinase 1/2 (ERK1/2) inhibitor reduced the MUC5AC protein production to the same level as that of the control; on Western blot analysis, only ERK1/2 was phosphorylated by the MRSA supernatant. In addition, the ERK1/2 phosphorylation was inhibited by linezolid. MUC5AC and MUC5B are the major barrier that traps inhaled microbial organisms, particulates, and foreign irritants. However, in patients with chronic respiratory diseases, pathogen-induced MUC5AC overexpression causes many problems, and control of the overexpression is important. Thus, this study revealed that linezolid showed a direct immunomodulatory effect in airway epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Immunomodulatory Effect of Linezolid on Methicillin-Resistant Staphylococcus aureus Supernatant-Induced MUC5AC Overexpression in Human Airway Epithelial Cells

Kaku

Yanagihara

Morinaga

et al. 2014

Antimicrob Agents Chemother

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“…15) In their study, SIADH-induced hyponatremia occurred following linezolid treatment for more than 3 weeks, and the hyponatremia resolved after the cessation of linezolid. However, recent in vitro 24,25) and in vivo 26) studies demonstrated that linezolid had anti-inflammatory effects, in addition to its antimicrobial effects. In those studies, linezolid reduced the production of cytokines from peripheral blood cells stimulated with lipopolysaccharide.…”

Section: Discussionmentioning

confidence: 99%

“…In those studies, linezolid reduced the production of cytokines from peripheral blood cells stimulated with lipopolysaccharide. 24,25) Matsumoto et al demonstrated that linezolid treatment resulted in a significant and concentration-dependent suppression of paw edema induced by carrageenan. 26) Hence, it is unlikely that linezolid-related hyponatremia is associated with SIADH induced by inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

A Retrospective Analysis of Risk Factors for Linezolid-Associated Hyponatremia in Japanese Patients

Tanaka

Suzuki

Takumi

et al. 2016

Biological & Pharmaceutical Bulletin

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Linezolid is an oxazolidinone antibiotic against Gram-positive bacteria. Although thrombocytopenia is a major adverse effect of linezolid, hyponatremia also often develops after linezolid administration. This study examined the frequency of hyponatremia that developed during linezolid treatment and identified its risk factors. In this retrospective, single-center, observational cohort study, 61 hospitalized patients treated with linezolid between January 2013 and January 2015 were analyzed. Hyponatremia was defined as a sodium level of ≤134 mEq/L for the duration of linezolid treatment. Its risk factors were identified via a logistic regression analysis. Hyponatremia occurred in 11 (18.0%) patients, and it was severe in a case (a sodium level of ≤128 mEq/L). Univariate and multiple logistic regression analyses identified the plasma C-reactive protein (CRP) level before the initial administration of linezolid and the concomitant use of a potassium-sparing diuretic as the independent variables associated with the development of hyponatremia. The odds ratios were 1.081 (95% confidence interval [CI]; 1.008-1.158) (p 0.028) and 11.017 (95% CI; 1.869-64.939) (p 0.008), respectively. Before linezolid treatment, the CRP levels of the hyponatremia group were significantly higher than those of the no-hyponatremia group (p<0.001). The frequency of hyponatremia development was significantly higher in the patients who received both the potassium-sparing diuretic and linezolid ( p 0.016). These results suggest that the plasma sodium levels of patients with severe inflammation who are treated with linezolid and those of linezolid-treated patients co-administered a potassium-sparing diuretic should be continuously monitored.

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“…These reports describe the immunomodulatory effects of LZD on bacteria. On the other hand, Garcia-Roca et al and Takahashi et al demonstrated reduced cytokine synthesis from peripheral blood cells induced by LPS stimulation, also using in vitro experimental models (8,28). These studies examined immunomodulatory effects of LZD in the host.…”

Section: Figmentioning

confidence: 99%

Virulence-Suppressing Effects of Linezolid on Methicillin-Resistant Staphylococcus aureus: Possible Contribution to Early Defervescence

Yoshizawa

Tateda

Saga

et al. 2012

Antimicrob Agents Chemother

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bIn the present study, immunomodulatory effects of linezolid (LZD) on methicillin-resistance Staphylococcus aureus (MRSA) infections were evaluated. We have retrospectively reviewed treatment effects of LZD on 52 patients with severe MRSA infections. Sixty-four percent of the febrile patients demonstrated significant defervescence within 3 days, despite the presence of positive culture results. We speculated that this finding might be due to early anti-inflammatory effects of LZD, and to investigate this further we initiated in vivo experiments using mice MRSA pneumonia models. Mice were treated with either LZD or vancomycin (VCM) immediately after intranasal administration of MRSA. Bacterial numbers and levels of inflammatory cytokines in the lungs were determined. Although the bacterial burden in the lungs was not apparently different between the two groups, LZD but not VCM treatment significantly reduced induction of inflammatory cytokines in the lungs (P < 0.05). To evaluate whether this anti-inflammatory response was due to suppression of virulence factor expression, filter-sterilized supernatants of MRSA incubated in broth overnight with sub-MICs of LZD were subcutaneously administered to mice. To clarify whether LZD possesses direct host-modulating activity, cytokine responses to the supernatants were examined in mice pretreated with LZD. Interestingly, MRSA solutions prepared in the presence of sub-MICs of LZD revealed significant suppression of interleukin 6 (IL-6) in a dose-dependent manner (P < 0.05), but pretreatment of mice with LZD revealed no changes in cytokines. These findings suggest that sub-MICs of LZD might suppress virulence factors of MRSA, which may be associated with a reduction in endogenous pyrogens. These data may explain at least in part early defervescence observed in LZD-treated individuals. L inezoid (LZD) (Zyvox; Pfizer, Japan) is the first available agent in a new class of antimocrobials called oxazolidinones and was approved in Japan in 2006 for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections, such as sepsis, skin and soft tissue infections, surgical site infections, and pneumonia. It has a unique mechanism of action, which is inhibition of bacterial protein synthesis at the initiation step of protein biosynthesis (24), resulting in good efficacy in treating Gram-positive bacterial infections.Recently, several classes of antimicrobial agents, such as macrolides and quinolones, are reported to possess certain immunomodulatory effects (6,7,11,16,22,29). In particular, protein synthesis-suppressing antibiotics, such as clindamycin and macrolides, can induce a general inhibition of virulence factor expression, such as alpha-toxin (14,17,21,23,32). Although several investigators have reported immunomodulatory activity of LZD (4,5,8,9), the precise mechanism and its contribution to the clinical course are poorly understood.After approval of LZD for MRSA infections, administration of LZD has been used generally to treat patients with severe MRSA infections. ...

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Effect of linezolid on cytokine production capacity and plasma endotoxin levels in response to lipopolysaccharide stimulation of whole blood

Cited by 21 publications

References 19 publications

Immunomodulatory Effect of Linezolid on Methicillin-Resistant Staphylococcus aureus Supernatant-Induced MUC5AC Overexpression in Human Airway Epithelial Cells

Immunomodulatory Effect of Linezolid on Methicillin-Resistant Staphylococcus aureus Supernatant-Induced MUC5AC Overexpression in Human Airway Epithelial Cells

A Retrospective Analysis of Risk Factors for Linezolid-Associated Hyponatremia in Japanese Patients

Virulence-Suppressing Effects of Linezolid on Methicillin-Resistant Staphylococcus aureus: Possible Contribution to Early Defervescence

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