Effects of Telithromycin in In Vitro and In Vivo Models of Lipopolysaccharide-Induced Airway Inflammation*

Leiva, Magdalena; Ruiz‐Bravo, Alfonso; Jiménez-Valera, Marı́a

doi:10.1378/chest.07-3056

Cited by 41 publications

(27 citation statements)

References 36 publications

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“…Several in vitro studies indicated that macrolides inhibit proinflammatory mediators, such as CXCL8 and TNFa released from monocytes (Iino et al, 1992;Kikuchi et al, 2002), neutrophils (Tsuchihashi et al, 2002), bronchial epithelial cells (Takizawa et al, 1997), and induced sputum cells (Marjanovic et al, 2011). Macrolides also exerted inhibitory effects on neutrophil-dominant inflammation in the in vivo models (Leiva et al, 2008;Bosnar et al, 2009). Furthermore, macrolides inhibited release of inflammatory mediators including TNFa and CXCL8 from sputum cells obtained from patients with COPD (Marjanovic et al, 2011).…”

Section: Discussionmentioning

confidence: 98%

A Novel Macrolide Solithromycin Exerts Superior Anti-inflammatory Effect via NF-κB Inhibition

Kobayashi

Wada

Rossios

et al. 2013

J Pharmacol Exp Ther

103

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Macrolides are reported to reduce exacerbation of chronic inflammatory respiratory disease, such as chronic obstructive pulmonary disease (COPD), and also show anti-inflammatory effects in vitro and in vivo. However the anti-inflammatory efficacies of current macrolides are relatively weak. Here we found that a novel macrolide/fluoroketolide solithromycin (CEM-101) showed superior anti-inflammatory effects to macrolides in current clinical use. The effects of solithromycin (SOL) on lipopolysaccharide-induced TNFa (tumor necrosis factor a) and/ or CXCL8 (C-X-C motif chemokine ligand 8; interleukin-8) release, phorbol 12-myristate 13-acetate-induced MMP9 (matrix metalloproteinase 9) activity and NF-kB (nuclear factor-kB) activity under conditions of oxidative stress have been evaluated and compared with the effects of erythromycin, clarithromycin, azithromycin, and telithromycin in macrophage-like PMA-differentiated U937 cells and peripheral blood mononuclear cells (PBMC) obtained from COPD patients. We also examined effect of SOL on cigarette smoke-induced airway inflammation in mice. SOL exerted superior inhibitory effects on TNFa/CXCL8 production and MMP9 activity in monocytic U937 cells. In addition, SOL suppressed TNFa release and MMP9 activity in PBMC from COPD patients at 10 mM, which is 10 times more potent than the other macrolides tested. Activated NF-kB by oxidative stress was completely reversed by SOL. SOL also inhibited cigarette smoke-induced neutrophilia and pro-MMP9 production in vivo, although erythromycin did not inhibit them. Thus, SOL showed better anti-inflammatory profiles compared with macrolides currently used in the clinic and may be a promising antiinflammatory and antimicrobial macrolide for the treatment of COPD in future.

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Section: Discussionmentioning

confidence: 98%

A Novel Macrolide Solithromycin Exerts Superior Anti-inflammatory Effect via NF-κB Inhibition

Kobayashi

Wada

Rossios

et al. 2013

J Pharmacol Exp Ther

103

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“…In vitro, telithromycin inhibited the production of MIP-2 and TNF-␣ in response to LPS stimulation in the macrophage cell line RAW 264.7, and it decreased the production of MIP-2 by murine lung epithelial (MLE-12) cells cultured with supernatants of LPS-stimulated RAW 264.7 macrophages. NF-B activation was inhibited and apoptosis was increased in both cell lines by use of telithromycin (164). Telithromycin, as well as azithromycin and clarithromycin, can inhibit the increased production of MUC5AC mRNA and protein in NCI-H292 cells stimulated with LPS (108).…”

Section: Other Related Drugs Ketolidesmentioning

confidence: 93%

“…In a septic mouse model, telithromycin downregulated production of TNF-␣ and IL-1␤ and improved the rates of survival after a lethal dose of E. coli LPS was given (165). Acute airway inflammation in mice after airway nebulization of LPS was attenuated by telithromycin pretreatment, and this was associated with decreased neutrophilia and reduced levels of protein, nitrite, MIP-2, and TNF-␣ in the BAL fluid (164). In vitro, telithromycin inhibited the production of MIP-2 and TNF-␣ in response to LPS stimulation in the macrophage cell line RAW 264.7, and it decreased the production of MIP-2 by murine lung epithelial (MLE-12) cells cultured with supernatants of LPS-stimulated RAW 264.7 macrophages.…”

Section: Other Related Drugs Ketolidesmentioning

confidence: 95%

Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

2010

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SUMMARY Macrolides have diverse biological activities and an ability to modulate inflammation and immunity in eukaryotes without affecting homeostatic immunity. These properties have led to their long-term use in treating neutrophil-dominated inflammation in diffuse panbronchiolitis, bronchiectasis, rhinosinusitis, and cystic fibrosis. These immunomodulatory activities appear to be polymodal, but evidence suggests that many of these effects are due to inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and nuclear factor kappa B (NF-κB) activation. Macrolides accumulate within cells, suggesting that they may associate with receptors or carriers responsible for the regulation of cell cycle and immunity. A concern is that long-term use of macrolides increases the emergence of antimicrobial resistance. Nonantimicrobial macrolides are now in development as potential immunomodulatory therapies.

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“…The effects were also found to be caspase-3 dependent. The ketolide telithromycin was recently shown to promote delayed apoptosis in LPS-stimulated RAW 264.7 macrophages (46). The authors of this study postulated that this effect was beneficial in promoting the resolution of inflammation by enhancing apoptosis in macrophages in the later stages of inflammatory responses.…”

Section: Figmentioning

confidence: 93%

Direct and Indirect Anti-Inflammatory Effects of Tulathromycin in Bovine Macrophages: Inhibition of CXCL-8 Secretion, Induction of Apoptosis, and Promotion of Efferocytosis

Fischer

Beatty

Duquette

et al. 2013

Antimicrob Agents Chemother

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Effects of Telithromycin in In Vitro and In Vivo Models of Lipopolysaccharide-Induced Airway Inflammation*

Cited by 41 publications

References 36 publications

A Novel Macrolide Solithromycin Exerts Superior Anti-inflammatory Effect via NF-κB Inhibition

A Novel Macrolide Solithromycin Exerts Superior Anti-inflammatory Effect via NF-κB Inhibition

Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

Direct and Indirect Anti-Inflammatory Effects of Tulathromycin in Bovine Macrophages: Inhibition of CXCL-8 Secretion, Induction of Apoptosis, and Promotion of Efferocytosis

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