Using different models of acute lung injury, a decrease in neutrophilic lung infil tration has been demonstrated in clarithromycin treated animals. This effect though could be mediated by several mechanisms. Activation of the NF��B pathway is one of the critical steps during a proinflammatory response. Our immunohistochemical findings show this activation to occur in isolated cells that could correspond Inhibitors,Modulators,Libraries to infil trating leukocytes, although the lack of double immuno staining precludes any firm conclusion. It has been reported that both macrolides and quinolones may block NF��B activation, resembling our own results. However, we did not find any differences in Cxcl2 expres sion that could explain the decreased neutrophilic infil trates in animals receiving clarithromycin.
Different intracellular mechanisms other than NF��B could be responsible for this increased chemokine expression. Additionally, macrolides may decrease the levels of ad hesion molecules such as ICAM Inhibitors,Modulators,Libraries 1, VCAM, E selectin and P selectin. The increase in adhesion molecules during VILI has been described previously, and is needed for the attachment of neutrophils to the endothelium as an initial step for cell migration. Our results fit with these, showing Inhibitors,Modulators,Libraries an increase in ICAM 1 and E selectin during VILI. However, mice treated with clarithromycin showed significantly lower levels of E selectin after VILI. Lastly, al though macrolides may also decrease MMP expression, we have found no differences in MMP 2 or ?9 in our experimental model. A wide range of strategies aimed to the limitation of the inflammatory response has shown positive results in models of VILI.
Although none of them have been translated to the clinical Inhibitors,Modulators,Libraries practice yet, a pharmaco logical strategy to ameliorate VALI could be a promising approach in ventilated patients. Our results may have clinical implications that must be discussed. First, they could explain the beneficial effects observed in ventilated, macrolide treated patients in both experimental models and the clinical practice. Moreover, clarithromycin could be used in ventilated patients only for its immunomodulatory effects. The recent finding of a decreased mortality Inhibitors,Modulators,Libraries in patients with acute lung injury receiving macrolide ther apy opens this possibility, as the benefit was independ ent of other variables such as severity scores, tidal volume or organ failures.
The positive results observed in our study correlate with these studies showing an improved outcome in cases of pneumonia and/or septic shock re ceiving these drugs, and even with the use of macrolides to limit the inflammatory response in chronic lung diseases. Our methodology has some limitations that must be clarified Kyprolis before any firm recommendation on macrolide use, especially with indications other than their anti microbial properties. First, although widely used and ac cepted, our experimental model has no clear clinical correlate.