Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects

Čulić, Ognjen; Eraković, Vesna; Čepelak, Ivana; Barišić, Karmela; Brajša, Karmen; Ferenčić, Željko; Galović, Ružica; Glojnarić, Ines; Manojlović, Zoran; Munić, Vesna; Novak-Mirčetić, Renata; Pavičić-Beljak, Verica; Sučić, Mirna; Veljača, Marija; Žanić‐Grubišić, Tihana; Parnham, Michael J.

doi:10.1016/s0014-2999(02)02042-3

Cited by 196 publications

(83 citation statements)

References 59 publications

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“…In contrast, the fluoroquinolones appear to have a more global immunosuppressive effect (8), including significant impairment of gamma interferon (45), and this may contribute to the results observed in this and other studies (1, 4, 11, 16, 21, 31-33, 42, 43). Besides suppressing the release of tumor necrosis factor and other cytokines in response to bacterial stimuli, the macrolides block or downregulate the production of reactive oxygen species, modulate neutrophil function, increase mucociliary clearance, and interfere with biofilm formation and flagellin expression by bacteria (6,7,23,37). Macrolides also reduce the adherence of pneumococci, the major cause of CAP, to respiratory epithelial cells (26).…”

Section: Discussionmentioning

confidence: 99%

Comparison of β-Lactam and Macrolide Combination Therapy versus Fluoroquinolone Monotherapy in Hospitalized Veterans Affairs Patients with Community-Acquired Pneumonia

Lodise

Kwa

Cosler

et al. 2007

Antimicrob Agents Chemother

104

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Section: Discussionmentioning

confidence: 99%

Comparison of β-Lactam and Macrolide Combination Therapy versus Fluoroquinolone Monotherapy in Hospitalized Veterans Affairs Patients with Community-Acquired Pneumonia

Lodise

Kwa

Cosler

et al. 2007

Antimicrob Agents Chemother

104

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“…This suggestion is strengthened by findings that the number of apoptotic granulocytes in blood of healthy volunteers was significantly increased after 3-day dosing with azithromycin (500 mg/day p.o.) (Culić et al, 2002). Moreover, macrolides decreased neutrophil survival in vitro through inhibition of GM-CSF release from activated human airway epithelial cells (Yamasawa et al, 2004).…”

Section: Azithromycin and Clarithromycin In Pulmonary Neutrophiliamentioning

confidence: 99%

Azithromycin and Clarithromycin Inhibit Lipopolysaccharide-Induced Murine Pulmonary Neutrophilia Mainly through Effects on Macrophage-Derived Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-1β

Bosnar¹,

Bošnjak²,

Čužić³

et al. 2009

J Pharmacol Exp Ther

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Macrolide antibiotics possess immunomodulatory/anti-inflammatory properties. These properties are considered fundamental for the efficacy of macrolide antibiotics in the treatment of chronic inflammatory diseases like diffuse panbronchiolitis and cystic fibrosis. However, the molecular mechanisms and cellular targets of anti-inflammatory/immunomodulatory macrolide activity are still not fully understood. To describe anti-inflammatory effects of macrolides in more detail and to identify potential biomarkers of their activity, we have investigated the influence of azithromycin and clarithromycin on the inflammatory cascade leading to neutrophil infiltration into lungs after intranasal lipopolysaccharide challenge in mice. Azithromycin and clarithromycin pretreatment reduced total cell and neutrophil numbers in bronchoalveolar lavage fluid and myeloperoxidase concentration in lung tissue. In addition, concentrations of several inflammatory mediators, including CCL2, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-1␤ (IL-1␤), tumor necrosis factor ␣, and sE-selectin in lung homogenates were decreased after macrolide treatment. Inhibition of cytokine production observed in vivo was also corroborated in vitro in lipopolysaccharide-stimulated monocytes/ macrophages, but not in an epithelial cell line. In summary, results presented in this article confirm that macrolides can suppress neutrophil-dominated pulmonary inflammation and suggest that the effect is mediated through inhibition of GM-CSF and IL-1␤ production by alveolar macrophages. Besides GM-CSF and IL-1␤, CCL2 and sE-selectin are also identified as potential biomarkers of macrolide anti-inflammatory activity in the lungs.Macrolide antibiotics (macrolides) are a well established class of antimicrobial agents characterized by the presence of a highly substituted macrocyclic lactone ring. Erythromycin, a natural product isolated from Saccharopolyspora erythraea, was the first macrolide to be introduced to clinical use over 50 years ago. Afterward, several semisynthetic derivatives of erythromycin, like clarithromycin (6-O-methylerythromycin A) and azithromycin (9-deoxy-9a-aza-9a-methyl-

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“…The macrolide azithromycin has clinical efficacy in this situation [17][18][19][20] but since it accumulates dramatically in phagocytic cells [21] and has been reported to affect the respiratory burst in vitro and in vivo [22,23], we excluded patients taking this antibiotic from our study. We have found no significant differences in receptor or particle-induced oxidative burst activity (assessed by cytochrome C reduction, and both luminol-and lucigenin-dependent chemiluminescence (lum-DCL and luc-DCL)) between CF and control neutrophils, and no detectable expression of CFTR protein in the normal (non-CF) human neutrophil.…”

mentioning

confidence: 99%

Cystic fibrosis neutrophils have normal intrinsic reactive oxygen species generation

McKeon¹,

Cadwallader²,

Idris³

et al. 2009

Eur Respir J

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Previous studies have identified abnormalities in the oxidative responses of the neutrophil in cystic fibrosis (CF), but it is unclear whether such changes relate to loss of membrane cystic fibrosis transmembrane conductance regulator (CFTR) or to the inflammatory environment present in this disease. The aim of the present study was to determine whether neutrophils from CF patients demonstrate an intrinsic abnormality of the respiratory burst.The respiratory burst activity of neutrophils isolated from stable DF508 homozygote CF patients and matched healthy controls was quantified by both chemiluminscence and cytochrome C reduction. Expression of NADPH oxidase components and CFTR was determined by Western blotting and RT-PCR.The oxidative output from neutrophils from CF in response to receptor-linked and particulate stimuli did not differ from that of controls. Expression of NADPH oxidase components was identical in CF and non-CF neutrophils. While low levels of CFTR mRNA could be identified in the normal human neutrophil, we were unable to detect CFTR protein in human neutrophil lysates or immunoprecipitates.CFTR has no role in controlling neutrophil oxidative activity; previously reported differences in neutrophil function between CF and non-CF subjects most likely relate to the inflammatory milieu from which the cells were isolated.

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Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects

Cited by 196 publications

References 59 publications

Comparison of β-Lactam and Macrolide Combination Therapy versus Fluoroquinolone Monotherapy in Hospitalized Veterans Affairs Patients with Community-Acquired Pneumonia

Comparison of β-Lactam and Macrolide Combination Therapy versus Fluoroquinolone Monotherapy in Hospitalized Veterans Affairs Patients with Community-Acquired Pneumonia

Azithromycin and Clarithromycin Inhibit Lipopolysaccharide-Induced Murine Pulmonary Neutrophilia Mainly through Effects on Macrophage-Derived Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-1β

Cystic fibrosis neutrophils have normal intrinsic reactive oxygen species generation

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