Knowledge translation: airway epithelial cell migration and respiratory diseases

Abstract

Airway epithelial cell migration is essential for lung development and growth, as well as the maintenance of respiratory tissue integrity. This vital cellular process is also important for the repair and regeneration of damaged airway epithelium. More importantly, several lung diseases characterized by aberrant tissue remodeling result from the improper repair of damaged respiratory tissue. Epithelial cell migration relies upon extracellular matrix molecules and is further regulated by numerous local, neuronal, and hormonal factors. Under inflammatory conditions, cell migration can also be stimulated by certain cytokines and chemokines. Many well-known environmental factors involved in the pathogenesis of chronic lung diseases (e.g., cigarette smoking, air pollution, alcohol intake, inflammation, viral and bacterial infections) can inhibit airway epithelial cell migration. Further investigation of cellular and molecular mechanisms of cell migration with advanced techniques may provide knowledge that is relevant to physiological and pathological conditions. These studies may eventually lead to the development of therapeutic interventions to improve lung repair and regeneration and to prevent aberrant remodeling in the lung.

Fig. 1

Signaling mechanisms for cell migration and invasion. 1 The change of physicochemical conditions in the surrounding area of the cell may initiate cell spreading and migration due to lack of contact inhibition. Cell–cell and cell–matrix interaction may initiate “outside-in” signals. 2 Soluble mediators may further influence the direction and velocity of cell migration. 3 Activation of intracellular signal transduction pathways coordinates multiple cellular functions related to cell motility. 4 Alteration of phosphorylation status of cytoskeleton-associated proteins may further control the formation of cellular protrusions and focal adhesions, and activities of proteases

Fig. 2

Epithelial cells in the lung and cellular mechanisms of lung epithelial repair after injury. The respiratory tract is covered by highly differentiated epithelial cells. Pseudostratified, columnar, ciliated epithelial cells line the upper respiratory tree. In the trachea and main bronchi, bronchial epithelial cells provide a physical barrier against microorganisms. In the proximal bronchioles, epithelial cells take on a more cuboidal shape, with both ciliated cells, and secretory non-ciliated Clara cells. In the distal bronchioles, only Clara cells can be identified. Type I pneumocytes are flattened squamous epithelial cells covering most of the surface of alveoli. Type II pneumocytes at the corners of alveoli function as local progenitors for type I cells. The respiratory epithelium is subjected to various chemical, physical, environmental, and inflammatory injuries, which can vary in severity from temporary induction of surface epithelium permeability, to cell death and complete denudation of the epithelial cell lining. The epithelial repair has three steps in common: (1) epithelial cell migration toward the wound; (2) proliferation of the lung epithelial progenitor cells; (3) differentiation. Epithelial cell migration is an early event of the lung repair after injury. PNEC: pulmonary neuroendocrine cells

Fig. 3

ATP mediates airway epithelial cell migration. Mechanical wound induces release of ATP. Extracellular ATP, ADP, and adenosine function through purinergic receptors to activate Duox1, a newly identified NADPH oxidase homolog, to enhance cell migration via ERK1/2 and MMP-9. ATP also triggers cell migration through HB-EGF shedding and subsequent EGF receptor activation