Short-Course Rapamycin Treatment Preserves Airway Epithelium and Protects Against Bronchiolitis Obliterans

Abstract

Background Damage to airway epithelium is closely related to the development of bronchiolitis obliterans (BO) in pulmonary transplantation. Rapamycin protects against BO development in a murine model, but its use in lung transplant patients is limited by its side effects. We hypothesized that short-course rapamycin dosing could be used to prevent airway epithelium loss and protect against BO development in a murine model. Methods A total alloantigenic mismatch, murine, heterotopic tracheal transplant model of BO was used. Animals were treated with either rapamycin or dimethyl sulfoxide (controls) according to 1 of 3 treatment regimens: 1) day 1 through 14 post-transplant, 2) day 3 through 7 post-transplant, or 3) day 14 through 28 post-transplant. Epithelial loss was assessed via H&E stains at 14 and 28 days post-transplant. Tracheal luminal obliteration was assessed at 28 days. Results Early rapamycin treatment was protective against epithelial loss at 14 days post-transplant compared to controls (p<0.001). Rapamycin treatment from days 1-14 was more effective at epithelial preservation (p=0.002) and reducing luminal obliteration (p<0.001) at 28 days compared to rapamycin treatment from days 3-7. Late rapamycin treatment (days 14-28) allowed for recovery of the previously denuded epithelium at 28 days (92.5% epithelial loss to 35.6%) and a reduction in BO (p<0.001). Conclusions Short-course rapamycin treatment protects against airway epithelium loss and subsequent development of bronchiolitis obliterans in a murine model. Because of its immunosuppressive and anti-fibrotic effects, rapamycin may prove to be the ideal medication to prevent chronic rejection and BO in lung transplant patients.

Rapamycin prevents bronchiolitis obliterans through increasing infiltration of regulatory B cells in a murine tracheal transplantation model

“…The full mechanism of rapamycin's immunosuppression is still under exploration. When we study the effects of rapamycin on BO development through inhibiting fibrocytes recruitment (10) and promoting epithelial progenitor cell regeneration(11), an unexpected finding was seen that rapamycin significantly reduced luminal obliteration, but markedly increased cellular infiltration in the allografts on days 14 and 28. We and others have reported previously that the cellular infiltration was peaked on day 7, then the inflammatory cells gradually decreased to base levels (6, 7, 27, 28).…”

“…Our previous reports showed that short course treatment of rapamycin, a macrocyclic triene antibiotic pro-drug, prevented development of BO through two different mechanisms in a HTT model: 1) reducing fibrocyte recruitment to the tracheal allografts(10); 2) protects against airway epithelium loss and promotes epithelial progenitor cells(11). During these studies, we appreciated that despite rapamycin significantly reduced BO development-; it simultaneously increased cell infiltration into the allografts.…”

Harnessing regulatory B cells to prevent experimental obliterative bronchiolitis

“…Early research revealed an antifibrotic effect on OB lesions. 6 Lau and colleagues have also demonstrated before that rapamycin has considerable antifibrotic 7 and epitheliumpreserving 8 effects. The finding that rapamycin increases Bregs in chronically rejected allografts, however, indicates a previously unknown mechanism.…”