Epithelial Injury and Dysregulated Repair in Small and Large Airways of Lung Transplant Patients is Ameliorated by Azithromycin

Dysregulated airway epithelial repair following injury is a suggested mechanism of post-transplant obliterative bronchiolitis (OB), but there is limited direct evidence of this or whether epithelial repair is a feasible treatment target. The aim of this study was to compare gene and cellular characteristics of injury and repair pre/post azithromycin in the small (SA) and large (LA) airway epithelium of transplant patients. Primary airway epithelial cells (pAECs) were obtained from OB, non-OB and healthy control subjects. Initially, markers of injury and dysregulated repair were determined via qPCR. Proliferative capacity of SA and LA epithelial cells were determined via proliferation assays. Wound repair experiments (+/-) azithromycin (1µg/ml) were performed and repair assessed. Gene expression of MMP7 post transplantation was downregulated (1.3 fold SA & LA), but was significantly upregulated in OB SA (2.8 fold) compared to control. There was significant upregulation in the expression of MMP3 (2.6 fold SA; 1.8 fold LA) and Integrin B6 (2.8 fold SA; 2.6 fold LA), and a significant downregulation in Integrin B8 (3.5 fold SA; 3.3 fold LA) in OB AEC compared to controls. Small AEC were observed to proliferate at a significantly higher rate than their large airway counterparts (p < 0.05). Despite a higher proliferative capacity SA were found to have a dysregulated repair process post injury. Addition of azithromycin significantly induced repair in these cells (2 fold; p < 0.05) however, complete repair was still not achieved. Chronic airway epithelial injury and dysregulated repair appear evident in the airway of post-transplant patients. Azithromycin appears to partially mitigate this process and assist epithelial repair post injury.