Alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) and bleomycin-induced pulmonary fibrosis are associated with surfactant system dysfunction, alveolar collapse, and collapse induration (irreversible closure). These events play critical but undefined roles in the loss of lung function and disease progression. To quantify how surfactant inactivation leads to lung injury and fibrosis we employed design-based stereology and invasive pulmonary function tests 1, 3, 7, and 14 days (D) following intratracheal bleomycin-instillation in rats. Active surfactant subtypes declined significantly by D1, leading to progressive alveolar closure (derecruitment) and an associated decrease in organ-scale compliance. Alveolar epithelial damage was more pronounced in closed alveoli compared to ventilated alveoli. At the ultrastructural level, we observed collapse induration in the bleomycin treated rats on D7 and D14 as indicated by collapsed alveoli overgrown by a hyperplastic alveolar epithelium. This pathophysiology was also observed for the first time in human IPF lung explants. Prior to the onset of collapse induration (D7), the lungs were easily recruited, and lung elastance could be kept low after recruitment by application of positive end-expiratory pressure (PEEP). By contrast, at later time points the recruitable fraction of the lung was reduced by collapse induration, causing elastance to be elevated at high levels of PEEP. We conclude that surfactant inactivation leading to alveolar collapse and subsequent collapse induration is the primary pathway for the loss of alveoli in this animal model and is the dominant factor in the degradation of lung function. Our ultrastructural observations suggest that collapse induration is also important in human IPF.