Airway Epithelial Differentiation and Mucociliary Clearance

Abstract

The lung is continuously exposed to particles, toxicants, and microbial pathogens that are cleared by a complex mechanical, innate, and acquired immune system. Mucociliary clearance, mediated by the actions of diverse conducting airway and submucosal gland epithelial cells, plays a critical role in a multilayered defense system by secreting fluids, electrolytes, antimicrobial and antiinflammatory proteins, and mucus onto airway surfaces. The mucociliary escalator removes particles and pathogens by the mechanical actions of cilia and cough. Abnormalities in mucociliary clearance, whether related to impaired fluid secretion, ciliary dysfunction, lack of cough, or the disruption of epithelial cells lining the respiratory tract, contribute to the pathogenesis of common chronic pulmonary disorders. Although mucus and other airway epithelial secretions play a critical role in protecting the lung during acute injury, impaired mucus clearance after chronic mucus hyperproduction causes airway obstruction and infection, which contribute to morbidity in common pulmonary disorders, including chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, bronchiectasis, and primary ciliary dyskinesia. In this summary, the molecular and cellular mechanisms mediating airway mucociliary clearance, as well as the role of goblet cell metaplasia and mucus hyperproduction, in the pathogenesis of chronic respiratory diseases are considered.

Keywords: airway ciliated cells; goblet cell; mucus hyperproduction.

Figure 1.

(A) Schematic demonstrating the genetic network controlling ciliated cell differentiation from basal or club cells. In the absence of Notch signaling, Gmnc (geminin coiled-coil domain containing, also called geminin coiled-coil containing protein 1 [gemc1]) controls a transcriptional pathway activity to regulate ciliary proteins. Forkhead box J1 (FoxJ1) regulates their assembly. (B) The airway surface and submucosal gland mediating mucociliary clearance. Reprinted by permission from Reference . (C and D) Confocal images of human submucosal gland and airway surfaces. Tubulin α-4A (TUBA4A; white) stains cilia. Mucin 5B (MUC5B; green) stains goblet cells. Reprinted by permission from Reference . (D) Club cells (red) are stained for secretoglobin family 1A member 1 (SCGB1A1). NK2 homeobox 1 (NKX2.1; green) stains epithelial cell nuclei. E2F4/5 = E2F transcription factor; DEUP1 = deuterosome assembly protein 1; KRT14 = keratin 14; MCIDAS = multiciliate differentiation and DNA synthesis associated cell cycle protein; Myb = MYB proto-oncogene; Rfx = regulatory factor X.

Figure 2.

Left panel shows a network of genes regulating airway goblet cell differentiation. Sam-pointed domain Ets-like factor (SPDEF) is a transcription factor regulating for airway goblet cell differentiation. Increased Notch activates SPDEF, which regulates synthesis of mucins and influences pulmonary T-helper cell type 2 (Th2) inflammation and airway hyperactivity. Right panel is a confocal immunofluorescence image of human submucosal gland. Keratin 14 (KRT14; red) stains myoepithelial cells, MUC5B (green) stains goblet cells. Agr2 = anterior gradient 2; FoxA3 = forkhead box A3; FoxP1/2 = forkhead box protein P1/2; IL = interleukin; Jag2 = Jagged2; Muc5AC = mucin 5AC; Stat6 = signal transducer and activator of transcription 6; Tslp = thymic stromal lymphopoietin.