The Macrolide Clarithromycin Inhibits Experimental Post-Transplant Bronchiolitis Obliterans

Abstract

Chronic allograft dysfunction in form of bronchiolitis obliterans is the most important hurdle to improved longterm survival after clinical lung transplantation to date. Recently, it was observed that the progression of bronchiolitis obliterans in lung transplant recipients might be inhibited by macrolide antibiotics. The authors therefore tested whether macrolide therapy can attenuate fibrous obliteration of airways in an animal model of bronchiolitis obliterans. Rats with heterotopic tracheal allografts were treated intraperitoneally with clarithromycin and compared to untreated transplanted animals with respect to allograft histology and expression of selected cytokines. At day 21 after transplantation, the tracheal allografts of treated animals were free of fibrous material or partially occluded dependent of clarithromycin dosage. Untreated animals had completely obliterated allografts. In treated animals, tumor necrosis factor alpha (TNF-alpha) was down-regulated early (5 days) and late (21 days) post transplant, whereas interferon gamma (IFN-gamma) expression was decreased only early after transplantation. Transforming growth factor beta (TGF-beta) expression was not affected. Therapy with low-dose macrolides in post-transplant obliterative bronchiolitis is based on their immunomodulatory rather than antimicrobial properties. In the setting of lung transplantation, macrolides primarily act as modulators of the early inflammatory response to stressed, damaged, or infected cells.

Preemptive Therapy with Steroids but Not Macrolides Improves Gas Exchange in Caustic-Injured Donor Lungs

“…There has been one published study on the role of clarithromycin in the treatment of BOS after lung transplantation, which was equally effective as azithromycin [23]. Moreover, also in a tracheal transplant model, clarithromycin was able to inhibit experimental post-transplant obliterative bronchiolitis in rats [24]. In this study, rats were treated intraperitoneally with clarithromycin.…”

Clinical and immunological evaluation of 12‐month azithromycin therapy in chronic lung allograft rejection

“…In a recent study on the rat model of heterotopic tracheal allotransplantation, Remund et al. (25) demonstrated that the macrolide antibiotic clarithromycin can significantly prevent tracheal fibro‐obliteration by down‐modulating TNF‐α and γ‐IFN production. Increased levels of IL‐8 and other pro‐inflammatory mediators in BAL, as well as neutrophilia, have been observed in some LTRs with established or future BOS, and some of these features have been shown to pre‐date BOS onset (8–13, 30, 31).…”

Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases

“…BOS may be classified into fibroproliferative and neutrophilic, the latter responding to AZM, the former being refractory [259][260][261][262][263][264]. In these patients, macrolides have presented beneficial results in improving respiratory capacity [245,246]. Shirit et al [250] did not demonstrate improvement in respiratory capacity.…”

“…Bronchiolitis obliterans syndrome (BOS) is the leading cause of death in lung transplant recipients. It has recently been noted that the progression of BOS in lung-transplant recipients might be inhibited by macrolides [245][246][247][248][249][250][251][252][253][254][255][256][257][258]. BOS may be classified into fibroproliferative and neutrophilic, the latter responding to AZM, the former being refractory [259][260][261][262][263][264].…”