Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium

Abstract

Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative.

Figure 1. Two-hit model of pulmonary fibrosis.

We postulate that genetic and epigenetic etiologic drivers establish a vulnerable bronchiolar and alveolar epithelia (first hit) and that this results in homeostatic adaptation without the development of lung fibrosis. Persistent and progressive lung fibrosis can be triggered by a second hit (such as tobacco smoke, air pollution, inflammation, and/or aging) to the bronchiolar and alveolar epithelia, resulting in epithelial reprogramming, endoplasmic reticulum (ER) stress, unfolded protein response (UPR), apoptosis, and ultimately leading to fibroblast accumulation and activation, fibrosis, and abnormal lung remodeling.

Figure 2. Model of the development of vulnerable bronchoalveolar epithelium as a contributing pathway to persistent pulmonary fibrosis.

(A) In the healthy lung, the bronchoalveolar epithelium consists of proximal epithelial cells in the terminal airways (basal cells, ciliated cells, club cells, and goblet cells) and alveolar type II (ATII) and type I (ATI) cells in the alveoli and minimal if any expression of MUC5B. Identified epithelial progenitor populations, including ITGB4β⁺/H2-K1^hi cells in the conducting airways, BASCs at bronchoalveolar ducts in mice, and newly identified TASC, RASC, and AT0 cells in the preterminal and terminal respiratory bronchioles in humans, nonhuman primates, and ferrets are thought to be quiescent in the absence of injury. (B) In the presence of genetic variants (e.g., MUC5B), increased expression of MUC5B protein in goblet cells, and other cell types that do not typically express MUC5B protein (e.g., ATII cells), causes homeostatic ER stress, resulting in a vulnerable state that primes epithelial cell responses to subsequent injury. Repair of the bronchiolar and alveolar epithelia (B, left) is governed by epithelial cell/fibroblast/immune cell interactions near the site of injury that direct facultative epithelial progenitor cell (ATII) proliferation and differentiation into ATI cells and suppress fibroblast proliferation/activation. In addition, epithelial progenitor cells located at sites distant to the site of injury are activated and migrate to the injured alveolus (ITGB4β⁺/H2-K1^hi cells, BASCs) to restore formation of the air/blood barrier. However, in the context of repetitive secondary injuries (below B), the persistent and enhanced ER stress induces detrimental responses in the vulnerable epithelium, causing epithelial dysfunction during injury/repair, as indicated by aberrant epithelial cell differentiation, arrested transitional cell states, and activation of aberrant basaloid cells in the alveoli. (C) This leads to profibrotic fibroblast and pericyte activation, proliferation, and excess extracellular matrix deposition. The consequence of respiratory bronchiole dropout in patients with early-stage IPF and the role of RASCs, TASCs, and AT0 progenitor populations in homeostatic repair versus a persistent fibrotic state has yet to be determined.