HIF-1α signaling by airway epithelial cell K-α1-tubulin: Role in fibrosis and chronic rejection of human lung allografts

Long term survival of the human lung allografts are hindered by chronic rejection, manifested clinically as bronchiolitis obliterans syndrome (BOS). We previously demonstrated significant correlation between the development of antibodies (Abs) to K-alpha 1-tubulin (K alpha 1T) and BOS. In this study, we investigated the molecular basis for fibrinogenesis mediated by ligation of K alpha 1T expressed on airway epithelial cells by its specific Abs. Using RT-PCR we demonstrate that normal human bronchial epithelial (NHBE) cells upon ligation of K alpha 1T with specific Abs caused upregulation of pro-fibrotic growth factors. Western blot analysis of NHBE incubated with K alpha 1T Abs increased hypoxia inducible factor (HIF-1 alpha). K alpha 1T Ab-mediated growth factor expression is dependent on HIF-1 alpha as inhibition of HIF-1 alpha returned fibrotic growth factor expression to basal levels. In conclusion, we propose that HIF-1 alpha-mediated upregulation of fibrogenic growth factors induced by ligation of K alpha 1T Abs is critical for development of fibrosis leading to chronic rejection of lung allograft. (C) 2011 Elsevier Inc. All rights reserved.