The epithelium in idiopathic pulmonary fibrosis: breaking the barrier

Abstract

Idiopathic pulmonary fibrosis is a progressive disease of unknown etiology characterized by a dysregulated wound healing response that leads to fatal accumulation of fibroblasts and extracellular matrix (ECM) in the lung, which compromises tissue architecture and lung function capacity. Injury to type II alveolar epithelial cells is thought to be the key event for the initiation of the disease, and so far both genetic factors, such as mutations in telomerase and MUC5B genes as well as environmental components, like cigarette smoking, exposure to asbestos and viral infections have been implicated as potential initiating triggers. The injured epithelium then enters a state of senescence-associated secretory phenotype whereby it produces both pro-inflammatory and pro-fibrotic factors that contribute to the wound healing process in the lung. Immune cells, like macrophages and neutrophils as well as activated myofibroblasts then perpetuate this cascade of epithelial cell apoptosis and proliferation by release of pro-fibrotic transforming growth factor beta and continuous deposition of ECM stiffens the basement membrane, altogether having a deleterious impact on epithelial cell function. In this review, we describe the role of the epithelium as both a physical and immunological barrier between environment and self in the homeostatic versus diseased lung and explore the potential mechanisms of epithelial cell injury and the impact of loss of epithelial cell permeability and function on cytokine production, inflammation, and myofibroblast activation in the fibrotic lung.

Keywords: TGF-β; apoptosis; epithelium; fibroblasts; idiopathic pulmonary fibrosis.

FIGURE 1

The adult lung epithelium is composed of various different cell types. The tracheo-bronchial epithelium forms a pseudostratified layer consisting of ciliated cells and secretory epithelial cells (Clara) and goblet cells. Underneath this layer, human basal cells (thought to be epithelial progenitor cells) are present at high numbers. Their numbers, however, decrease dramatically as the lung progresses into the alveolar space. Neuroendocrine cells can also be present that become innervated by ganglion cells. Their role is thought to be of regulating cell proliferation and differentiation. The respiratory bronchioles are still very poorly characterized and lead to the alveoli, that are mostly lined by alveolar type I (ATI) and type II (ATII) cells.

FIGURE 2

Airway remodeling can be initiated by either aberrant epithelial cell (genetic mutations) or exposure to external irritants. Genetic mutations in the telomerase enzyme and surfactant protein C (SP-C) are associated with a senescence phenotype in type II alveolar cells (ATII), Both these and reactive oxygen species (ROS) formed as a response to injury (cigarette smoke, asbestos, bleomycin, etc.) can activate the UPR response and induce ER stress and ultimately apoptosis in the epithelial cells. These events lead to a senescence- associated secretory phenotype, where injured epithelial cells release cytokines, chemokines, and danger-associated molecular patterns (DAMPs) which in turn recruit leukocytes to the site of injury and also activate the coagulation cascade, in an attempt to repair the damage. In IPF, these pathways become dysregulated and inflammatory cell types contribute to the unresolved damage/repair by secretion of TGF -β, IL -13, and ROS, which provide repeated injury to epithelial cells and induce their hyper-proliferation. TGF -β is also produced by activated platelets and contributes to the fibrotic state by inducing EMT, fibroblast proliferation and collagen synthesis, and ECM deposition.

FIGURE 3

Integrin activation of TGF-β can occur via αVβ6 (A) and αVβ8 (B). Integrin αVβ6 is restricted to the epithelium and can activate TGF -β following mechanical tension of the cells alongside binding of the large latent complex (LLC) to αVβ6 and extracellular matrix (ECM) proteins. This tension exposes the active TGF -β through opening of the latency-associated peptide (LAP) allowing it to bind to its receptor on neighboring epithelial cells only as TGF -β is not released from the cell surface. Integrin αVβ8 requires metalloproteolytic cleavage by MMP-14 which results in TGF -β being liberated from its latent complex and therefore acting on cells by paracrine diffusion. Although integrin αVβ8 is more widely expressed on several subsets of cells, metalloprotease expression is required for it to activate TGF -β (figure adapted from Nishimura, 2009).