The airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of functionMUC5Bpromoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

Rationale: Interstitial macrophages (IMs) and airspace macrophages (AMs) play critical roles in lung homeostasis and host-defense and are central to the pathogenesis of a number of lung diseases. However, the absolute numbers of macrophages and the precise anatomic locations they occupy in the healthy human lung have not been quantified. Objectives: To determine the precise number and anatomic location of human pulmonary macrophages in non-diseased lungs and to quantify how this is altered in chronic cigarette smokers. Methods: Whole right upper lobes from 12 human donors without pulmonary disease (6 smokers and 6 nonsmokers) were evaluated using design-based stereology. CD206+/CD43+ AMs and CD206+/CD43- IMs were counted in five distinct anatomical locations using the optical disector probe. Measurements and Main Results: An average of 2.1x10⁹ IMs and 1.4x10⁹ AMs were estimated per right upper lobe. 95% of AMs were contained in diffusing airspaces and 5% in airways. 78% of IMs were located within the alveolar septa, 14% around small vessels and 7% around the airways. The local density of IMs was greater in the alveolar septa than in the connective tissue surrounding the airways or vessels. The total number and density of IMs was 36–56% greater in the lungs of cigarette smokers versus nonsmokers. Conclusions: The precise locations occupied by pulmonary macrophages were defined in non-diseased human lungs from smokers and nonsmokers. IM density was greatest in the alveolar septa. Lungs from chronic smokers had increased IM numbers and overall density, supporting a role for IMs in smoking-related disease.

Despite the development of improved ventilator strategies, the morbidity and mortality associated with acute respiratory distress syndrome (ARDS) remain unacceptably high.^1,2 To prevent ARDS and its associated complications, it is important, first and foremost, to prevent ventilator-induced lung injury by using mechanical ventilation strategies that both maintain alveolar recruitment and avoid tissue overdistension. Protective mechanical ventilation, as it is currently used clinically, aims to avoid overdistension by reducing tidal volume (V_t). Nevertheless, regional overdistension of alveolar tissue can still occur when lung mechanical properties become heterogeneous because the V_t delivered is then forced into tissue regions that have higher compliance. The less compliant regions either remain completely collapsed (atelectatic) or experience damaging cycles of recruitment and derecruitment with each breath.³ Furthermore, the parenchyma at the boundary between atelectatic and ventilated parenchyma may be subject to increased strain owing to geometric effects.⁴ Thus, ventilator-induced lung injury can arise from heterogeneous mechanical behavior at the level of the microanatomy when some alveoli remain collapsed throughout the breath cycle while their more compliant or surfactant-replete neighbors become overdistended.⁵ We call this phenomenon dynamic alveolar heterogeneity.

Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure yet has few pharmacologic therapies, reflecting the mechanistic heterogeneity of lung injury. We hypothesized that damage to the alveolar epithelial glycocalyx, a layer of glycosaminoglycans interposed between the epithelium and surfactant, contributes to lung injury in patients with ARDS. Using mass spectrometry of airspace fluid noninvasively collected from mechanically ventilated patients, we found that airspace glycosaminoglycan shedding (an index of glycocalyx degradation) occurred predominantly in patients with direct lung injury and was associated with duration of mechanical ventilation. Male patients had increased shedding, which correlated with airspace concentrations of matrix metalloproteinases. Selective epithelial glycocalyx degradation in mice was sufficient to induce surfactant dysfunction, a key characteristic of ARDS, leading to microatelectasis and decreased lung compliance. Rapid colorimetric quantification of airspace glycosaminoglycans was feasible and could provide point-of-care prognostic information to clinicians and/or be used for predictive enrichment in clinical trials.

Many of the signaling pathways and growth factors involved with pulmonary fibrosis are well-described but little is known about why the fibroproliferative process progresses over time. Ventilation-induced lung injury occurs as a result of epithelial stress and strain from atelectrauma and volutrauma, respectively, both of which occur in the setting of alveolar collapse. We suggest that ventilation-induced lung injury may be a unifying process explaining perpetuation of the fibrosis on the basis that (a) alveolar collapse has been repeatedly described in patients with pulmonary fibrosis, thereby providing a setting in which ventilation-induced lung injury can occur, and (b) patients with pulmonary fibrosis, many of the risk factors and genetic variants associated with pulmonary fibrosis as well as most of models used to study pulmonary fibrosis are all associated with surfactant abnormalities and/or with alveolar type 2 cell injury that would predispose to surfactant abnormalities, thereby increasing surface tension and causing alveolar collapse. The purpose of this Perspective is to review the literature documenting that alveolar collapse is an important aspect of the pathology and pathophysiology of pulmonary fibrosis, to summarize the abnormalities in surfactant and/or in type 2 cells that occur in patients with pulmonary fibrosis, and in association with the risk factors, genetic variations and animal models of pulmonary fibrosis and to estimate the strain resulting from alveolar collapse that could result in ventilation-induced lung injury.