3.4-Immunomodulatory in vitro and animal data
Azithromycin exerts its immunomodulatory effects on different points in
the inflammatory cascade, modulating cell functions and cell signaling
processes[7,37,38].
In airway epithelial cells macrolides can maintain cell integrity by
stabilizing the cell membrane, increasing the transepithelial electrical
barrier and inducing processing of the tight junction proteins claudins
and junctional adhesion molecule-A [37,39,40]. They can also
decrease mucus hypersecretion in vitro and in vivo, even when not
produced by bacteria, which may improve mucociliary clearance
[37,41,42]. Azithromycin use directly relaxed pre-contracted airway
smooth muscle cells [7].
This macrolide can decrease the hypersecretion of pro-inflammatory
cytokines and chemokines by acting in many inflammatory cells as
monocytes, macrophages and fibroblasts [7]. Its use has been related
with a reduction of IL-1β, IL-4, IL-5, IL-6, IL-8, IL-12, IFN-γ, IP-10,
TNF-α, and GM-CSF [7,37,38,43]. In alveolar macrophages,
azithromycin attenuated Th-1 cell responses, shifting polarization of
alveolar macrophages to their alternative activated anti-inflammatory M2
phenotype [7]. It also increased phagocytosis of apoptotic bronchial
epithelial cells by macrophages [44]. In fibroblasts, macrolides
have demonstrated to inhibit fibroblast proliferation, collagen
production and to decrease transforming growth factor (TGF-β) levels
[45]. In lymphocytes, azithromycin has shown to suppress CD4+ T-cell
activation [46] All these findings have been demonstrated in vitro.
On the contrary, azithromycin can increase the release of IL-10, an
anti-inflammatory cytokine related to the reparation of the inflamed
tissues [7,37,43,45].
In animal models, the treatment with azithromycin reduced mortality in
pneumococcal pneumonia, viral bronchiolitis and polymicrobial sepsis in
mice[47–49]. These findings were found even in the setting of
macrolide-resistant strains, suggesting that the immunomodulatory
properties, including the aversion of cytokine storm, may explain these
benefits. Azithromycin reduced the accumulation of inflammatory cells
(macrophages, lymphocytes, and neutrophils) in bronchoalveolar lavage
and in lung tissue[47]. In addition, downregulated the expression of
chemokines (G-CSF, CCL3/MIP-1α, CCL4/MIP-1β) and cytokines (IL-1β, IL-6,
IL-12, TNF-α and IFN-γ) in the lung[47,49].
In the late fibroproliferative-fibrotic phase of ARDS, azithromycin may
suppress lung fibrosis[19]. In a murine model of acute lung injury
caused by bleomycin, it significantly reduced fibrosis and restrictive
lung function pattern[50]. Once fibrosis has been established,
azithromycin could also have antifibrotic and proapoptotic effects on
primary fibroblasts[51].