Epithelial repair mechanisms in the lung

Abstract

The recovery of an intact epithelium following lung injury is critical for restoration of lung homeostasis. The initial processes following injury include an acute inflammatory response, recruitment of immune cells, and epithelial cell spreading and migration upon an autologously secreted provisional matrix. Injury causes the release of factors that contribute to repair mechanisms including members of the epidermal growth factor and fibroblast growth factor families (TGF-alpha, KGF, HGF), chemokines (MCP-1), interleukins (IL-1beta, IL-2, IL-4, IL-13), and prostaglandins (PGE(2)), for example. These factors coordinate processes involving integrins, matrix materials (fibronectin, collagen, laminin), matrix metalloproteinases (MMP-1, MMP-7, MMP-9), focal adhesions, and cytoskeletal structures to promote cell spreading and migration. Several key signaling pathways are important in regulating these processes, including sonic hedgehog, Rho GTPases, MAP kinase pathways, STAT3, and Wnt. Changes in mechanical forces may also affect these pathways. Both localized and distal progenitor stem cells are recruited into the injured area, and proliferation and phenotypic differentiation of these cells leads to recovery of epithelial function. Persistent injury may contribute to the pathology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. For example, dysregulated repair processes involving TGF-beta and epithelial-mesenchymal transition may lead to fibrosis. This review focuses on the processes of epithelial restitution, the localization and role of epithelial progenitor stem cells, the initiating factors involved in repair, and the signaling pathways involved in these processes.

Fig. 1.

Sequence of events in epithelial repair. Following injury, macrophages, neutrophils, and localized stem cells become activated, and growth factors, cytokines, interleukins, and matrix materials are released. Some of these factors recruit other immune cells to the site of injury. Cells adjacent to the site of injury secrete extracellular matrix (ECM) through integrin and growth factor signaling, reorganize their cytoskeleton to facilitate movement, secrete MMPs that degrade cell-matrix attachments, and spread and migrate along the autologously secreted provisional matrix using filopodial and lamellipodial extensions. Both localized and recruited progenitor cells proliferate and continue to secrete ECM. Dysregulated repair may lead to epithelial-mesenchymal transition (EMT) and fibrosis. Resolution occurs by means of cell cycle arrest, apoptosis, disappearance of immune cells, and deactivation of macrophages.

Fig. 2.

Processes involved in epithelial repair in the airways. Injury (1) initiates activation of macrophages (M) to activated macrophages (AM) and the recruitment of immune cells (2), mesenchymal stem cells (MSC), or niche stem cells (NSC). Soluble factors (S) secreted by immune and nonimmune cells (3) act on epithelial cells and fibroblasts, which spread and migrate (4) closing the wound and reestablishing intact barrier function. TGF-β signaling results in trans-differentiation of epithelial cells to myofibroblasts (MY), the EMT, and the initiation of a chronic inflammatory response (5) with further elaboration of ECM. During resolution (6), immune cells disappear from the site of injury, macrophages are deactivated, cells differentiate, and hyperproliferation is reduced through apoptosis, allowing tissue remodeling (7).