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Erythromycin inhibits mucin secretion in the inflamed ferret trachea.
... Although our results showed that quite high concentrations of RXT metabolites are required to inhibit NOS activity, the relevance of this in vitro observations should be taken into consideration since there are clear and compelling data demonstrating their nonantimicrobial properties of macrolide, such as their ability to decrease the hypersecretion of key regulators of the inflammatory response in cell culture, in animal models of disease, and in persons with chronic inflammatory pulmonary diseases (Kanoh and Rubin, 2010). It has been proven that macrolides can decrease mucus hypersecretion both in vitro (Okamoto et al., 1999) and in vivo (Tamaoki et al., 1995;Rubin et al., 1997). In particular, physiological concentrations of ERY and CLT inhibit IL-8 mRNA and protein in bronchial epithelial cells from healthy subjects and those with chronic inflammatory airway diseases (Takizawa et al., 1997). ...
... As general mechanism of in vivo inhibition, we propose two compatible approaches. First, as previously described alveolar macrophages represent a clear evidence for co-expression of these enzymes (CYP450s and NOS) and this can be consider as a common fact to other cell types in primary sites of exposure for chemical toxicants such as hepatic macrophages which present an expression pattern of CYP450 specifically adapted for their major role in the protection of the organism (Rubin et al., 1997;Okamoto et al., 1999;Hukkanen et al., 2002). Therefore it makes sense to expect that compound biotransformation and NOS inhibition might take place in the same cell. ...
Nitric-oxide synthase, the enzyme responsible for mammalian nitric oxide generation, and cytochrome P450, the major enzymes involved in drug metabolism, share striking similarities. Therefore, it makes sense that cytochrome P450 drug mediated biotransformations might play an important role in the pharmacological modulation of nitric oxide synthase. In this work, we have undertaken an integrated in vitro assessment of the hepatic metabolism and nitric oxide modulation of previously described dual inhibitors (imidazoles and macrolides) of these enzymes in order assess the implication of CYP450 activities over production of nitric oxide. In vitro systems based in human liver microsomes and activated mouse macrophages were developed for these purposes. Additionally in vitro production the hepatic metabolites of dual inhibitor, roxithromycin, was investigated achieving the identification and isolation of main hepatic biotransformation products. Our results suggested that for some macrolide compounds, the cytochrome P450 3A4 derived drug metabolites have an important effect on nitric oxide production and might critically contribute to the pharmacological immunomodulatory activity observed.
... Hypersecretion is a feature of chronic airway inflammation and can cause airflow limitation, impairment of mucociliary transport, and recurrent respiratory infection. Macrolides can decrease mucus hypersecretion both in vitro (214) and in vivo (241,290). Clarithromycin has been shown to improve the transportability of secretions in human subjects (241,290). ...
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-kappaB) 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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