Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

Objective: In addition to their antibiotic effect, macrolides appear to modulate the inflammatory response in cystic fibrosis (CF) and could influence oxidative stress. The objective of this study was to assess oxidation biomarkers and levels of inflammation and to determine whether there is an association between these parameters and the intake of macrolides. Materials and Methods:The subjects included in this cross-sectional study were, on the one hand, clinically stable patients with CF and, on the other, healthy controls. The following serum and plasma inflammatory and oxidative stress biomarkers were measured: interleukin-6 (IL-6), reactive C protein (RCP), tumor necrosis alpha (TNF-α), glutathione peroxidase (GPx), total antioxidant capacity (TAC), catalase (CAT), and superoxide dismutase (SOD), together with markers of lipid peroxidation (8-isoprostanes and thiobarbituric acid reactive substances [TBARS]). Clinical, anthropometric, lung function, radiological, and analytical variables (albumin, prealbumin, vitamins, and zinc) were also recorded. Results:We studied 36 adults with CF and 41 controls. No differences were observed in age, gender, or anthropometric variables. The patients had significantly higher levels of IL-6, TNF-α, RCP, TBARS, and isoprostanes, and lower levels of SOD than the controls. Twenty-three of the patients were treated with azithromycin, and they had more severe clinical and radiological parameters than those who were not but nevertheless presented significantly lower levels of TNF-α. No differences were observed in the markers of oxidation.Conclusion: Inflammation and oxidation biomarkers were increased in patients with CF compared with controls. The use of azithromycin was associated with reduced TNF-α levels and did not influence oxidation parameters.

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Bronchiolitis obliterans syndrome (BOS) is thought to represent chronic allograft rejection. Primary graft dysfunction (PGD), acute cellular rejection (AR), lymphocytic bronchiolitis (LB), abnormal gastroesophageal reflux (GER) with microaspiration, and allograft infection have all been implicated as causes of BOS. Although BOS is generally considered to be caused by alloimmune responses to non-self tissue, more recent findings suggest that autoimmune responses to self-antigens and the triggering of innate immune responses to environment stimuli may play a significant role in the pathobiology of BOS. Effective treatment of BOS remains elusive, but azithromycin may stabilize and possibly improve FEV1 in patients who meet criteria for BOS, and gastric fundoplication may be beneficial if abnormal GER is detected. Augmented immunosuppression is generally ineffective, and other treatments such as total lymphoid irradiation (TLI) or extracorporeal photopheresis (ECP) may not have a significant impact on loss of function. Retransplantation can be considered in carefully selected patients.