Alveolar epithelial disintegrity in pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive decline in lung function, resulting in significant morbidity and mortality. Current concepts of the pathogenesis of IPF primarily center on dysregulated epithelial cell repair and altered epithelial-mesenchymal communication and extracellular matrix deposition following chronic exposure to cigarette smoke or environmental toxins. In recent years, increasing attention has been directed toward the role of the intercellular junctional complex in determining the specific properties of epithelia in pulmonary diseases. Additionally, recent genomewide association studies suggest that specific genetic variants predictive of epithelial cell dysfunction may confer susceptibility to the development of sporadic idiopathic pulmonary fibrosis. A number of genetic disorders linked to pulmonary fibrosis and familial interstitial pneumonias are associated with loss of epithelial integrity. However, the potential links between extrapulmonary clinical syndromes associated with defects in epithelial cells and the development of pulmonary fibrosis are not well understood. Here, we report a case of hereditary mucoepithelial dysplasia that presented with pulmonary fibrosis and emphysema on high-resolution computed tomography. This case illustrates a more generalizable concept of epithelial disintegrity in the development of fibrotic lung diseases, which is explored in greater detail in this review article.

Keywords: cell-cell adhesion; epithelial barrier dysfunction; epithelial junctional complex; pulmonary fibrosis.

Fig. 1.

High-resolution computed tomography sections of a patient with hereditary mucoepithelial dysplasia demonstrating subpleural reticulation with honeycombing and traction bronchiectasis in a peripheral and basilar distribution with coexistent paraseptal emphysema.

Fig. 2.

Cell-cell junctions: Tight junctions, adherens junctions, and desmosomes are the three main junctional complexes connecting adjacent epithelial cells. Tight junctions are the most apical protein complexes and regulate epithelial barrier paracellular permeability. Adherens junctions and desmosomes stabilize cell-to-cell adhesion and maintain lung homeostasis. They also regulate the actin-cytoskeletal organization and confer mechanical strength to the alveolar epithelial barrier. Gap junctions are essential for intercellular communication and secretion of surfactant. Hemidesmosomes bind basal epithelial cells to the basement membrane. Hereditary mucoepithelial dysplasia (HMD) affects desmosomal structures. ZO, zona occludens; IFs, intermediate filaments.

Fig. 3.

Epithelial-mesenchymal cross talk in pulmonary fibrosis: Cellular homeostasis of the alveolar structure is dependent on bidirectional signaling between alveolar epithelial cells (AECs) and mesenchymal cells. Loss of homeostasis and ineffective reepithelialization may occur with loss of cell-cell adhesion, impaired AEC migration, senescence, and/or apoptosis. The resultant epithelial disintegrity leads to integrin-mediated activation of transforming growth factor-β1 (TGF-β1), altered biomechanics, and release of proteases, cytokines, and growth factors from the epithelium that activate the underlying mesenchyme. In turn, activated fibroblasts and myofibroblasts that acquire an apoptosis-resistant phenotype secrete a number of soluble factors that can induce apoptosis/senescence of AECs; these soluble factors include TGF-β1, hydrogen peroxide (H₂O₂), angiotensin-II (AT-II), and Fas ligand, thus perpetuating the injury-repair cycle leading to extracellular matrix (ECM) modification and accumulation.