Glandular Gene Expression of Sinus Mucosa in Chronic Rhinosinusitis with and without Cystic Fibrosis

Abstract

Secretory cells in submucosal glands (SMGs) secrete antibacterial proteins and mucin glycoproteins into the apical lumen of the respiratory tract, and these are critical for innate immune mucosal integrity. Glandular hyperplasia is manifested in diseases with obstructive respiratory pathologies associated with mucous hypersecretion, and is predominant in the sinus mucosa of patients with chronic rhinosinusitis (CRS), cystic fibrosis (CF), and clinical symptoms of CRS. To gain insights into the molecular basis of SMG hyperplasia in CRS, gene expression microarray analyses were performed to identify the differences in global and specific gene expression in the sinus mucosa of control, CRS, and CRS/CF patients. A marked up-regulation of 11 glandular-associated genes in CRS and CRS/CF sinus mucosa was evident. The RNA and protein expressions of the four most highly up-regulated genes (DSG3, KRT14, PTHLH, and OTX2) were evaluated. An increased expression of DSG3, KRT14, and PTHLH was demonstrated at the mRNA and protein levels in both CRS and CRS/CF sinus mucosa, whereas the increased expression of OTX2 was evident only for CRS/CF sinus mucosa, implicating OTX2 as a CF-specific gene. Immunofluorescence analysis localized DSG3, PTHLH, and OTX2 to serous cells, and KRT14 to myoepithelial cells, in SMGs. Because glandular hyperplasia is a central histologic feature of CRS, the identification of overexpressed glandular genes in the sinus mucosa lays the groundwork for future studies of glandular hyperplasia, and may ultimately lead to the development of novel treatments for mucous hypersecretion in patients with CRS.