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- W1780971830 abstract "Lung inflammation is a key feature of CF pathology. We have previously shown that, even in basal conditions, CFTRtm1Eur (homozygous F508del-CFTR) mice display an increased number of alveolar and peritoneal macrophages compared to their WT littermates. Promising anti-inflammatory properties have been reported for Vardenafil, a phosphodiesterase type 5 inhibitor (iPDE5). We have recently demonstrated that this iPDE5 reduces LPS-induced inflammatory responses in CF mice (Lubamba et al., 2012). We hypothesized that: 1) the activity of macrophages is altered in CF and 2) macrophages represent target effector cells of the anti-inflammatory effect of vardenafil. Macrophages were isolated and purified from lung homogenates and peritoneal lavages from CF and WT mice. To test the hypothesis that the activity of macrophages is altered in CF, LPS-induced inflammatory responses were first evaluated. Then macrophage differentiation in pro- (M1) and anti-inflammatory (M2) effectors was studied after polarization with LPS and IFN-γ or IL-4 and IL-13, respectively. Pro- (TNF-α, IL-1β and CCL-2) and anti-inflammatory (FIZZ-1 and mYm1) mediators were quantified by ELISA (in culture supernatants) or by quantitative RT-PCR (in cultured macrophages). In each condition, the effect of vardenafil (50µM) was evaluated. CF lung and peritoneal macrophages displayed an exaggerated pro-inflammatory response to LPS and vardenafil treatment reduced it. M1/M2 polarization was altered in CF macrophages. In lung and peritoneal macrophages, M1 response was at least 4-fold larger in CF than in WT cells. In contrast, the M2 response was reduced in CF macrophages. These results confirm a deregulation of the pro/anti-inflammatory balance in CF macrophages. Vardenafil restores the balance by reducing the expression of pro-inflammatory mediators (particularly TNF-α and IL-1β) in lung and peritoneal macrophages. Moreover, vardenafil corrects the overproduction of FIZZ-1 in CF macrophages. Our results show that macrophages play a critical role in inflammatory responses in CF. Differentiation of macrophages from different body compartments is oriented towards a pro-inflammatory profile associated with a decreased anti-inflammatory status. The immunomodulatory effect of vardenafil could thus be beneficial in CF pharmacotherapy." @default.
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- W1780971830 date "2013-01-01" @default.
- W1780971830 modified "2023-09-27" @default.
- W1780971830 title "Vardenafil Restores Pro/Anti Inflammatory Balance in Mouse CF Macrophages" @default.
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