Impaired Alveolar Re-Epithelialization in Pulmonary Emphysema

Abstract

Alveolar type II (ATII) cells are progenitors in alveoli and can repair the alveolar epithelium after injury. They are intertwined with the microenvironment for alveolar epithelial cell homeostasis and re-epithelialization. A variety of ATII cell niches, transcription factors, mediators, and signaling pathways constitute a specific environment to regulate ATII cell function. Particularly, WNT/β-catenin, YAP/TAZ, NOTCH, TGF-β, and P53 signaling pathways are dynamically involved in ATII cell proliferation and differentiation, although there are still plenty of unknowns regarding the mechanism. However, an imbalance of alveolar cell death and proliferation was observed in patients with pulmonary emphysema, contributing to alveolar wall destruction and impaired gas exchange. Cigarette smoking causes oxidative stress and is the primary cause of this disease development. Aberrant inflammatory and oxidative stress responses result in loss of cell homeostasis and ATII cell dysfunction in emphysema. Here, we discuss the current understanding of alveolar re-epithelialization and altered reparative responses in the pathophysiology of this disease. Current therapeutics and emerging treatments, including cell therapies in clinical trials, are addressed as well.

Keywords: alveolar epithelium; alveolar type II cells; emphysema; lung repair; regeneration; tissue homeostasis.

Figure 1

Various cell types are part of the ATII cell niche, providing a specific microenvironment to support alveolar re-epithelialization after injury. (A) Mesenchyme, including fibroblasts, extracellular matrix (ECM), and pericytes around endothelium and alveoli, can sense microenvironmental changes and mechanical stress and interact with alveolar epithelium, contributing to tissue remodeling. (B) Activated endothelial cells proliferate and regulate alveolar epithelial cell repair after injury to maintain alveolar–capillary function and integrity. (C) Immune cells are a component of the regenerative alveolar type II (ATII) cell niche. Alveolar macrophages (AM) are important in innate immunity, regulating adaptive immunity, and recruiting neutrophils and monocytes into the lungs. They defend against pathogens while supporting ATII cell proliferation and differentiation to alveolar type I (ATI) cells. Together, various reciprocal interactions, transcription factors, mediators, and signaling pathways among different cell types orchestrate complex lung repair and homeostasis.

Figure 2

The regulation of ATII cell proliferation and differentiation. WNT/β-catenin, TGF-β, and NOTCH pathways dynamically regulate ATII cell proliferation and differentiation into ATI cells, although there are still many unknowns during the transitional state. Other transcription factors, growth factors, and signaling molecules are also involved.

Figure 3

Alveolar wall destruction and impaired re-epithelialization in pulmonary emphysema.