Alveolar Micromechanics in Bleomycin-induced Lung Injury.

Lung injury results in intratidal alveolar recruitment and derecruitment and alveolar collapse, creating stress concentrators that increase strain and aggravate injury. In this work, we sought to describe alveolar micromechanics during mechanical ventilation in bleomycin-induced lung injury and surfactant replacement therapy. Structure and function were assessed in rats 1 day and 3 days after intratracheal bleomycin instillation and after surfactant replacement therapy. Pulmonary system mechanics were measured during ventilation with positive end-expiratory pressures (PEEPs) between 1 and 10 cm H2O, followed by perfusion fixation at end-expiratory pressure at airway opening (Pao) values of 1, 5, 10, and 20 cm H2O for quantitative analyses of lung structure. Lung structure and function were used to parameterize a physiologically based, multicompartment computational model of alveolar micromechanics. In healthy controls, the numbers of open alveoli remained stable in a range of Pao = 1-20 cm H2O, whereas bleomycin-challenged lungs demonstrated progressive alveolar derecruitment with Pao < 10 cm H2O. At Day 3, ∼40% of the alveoli remained closed at high Pao, and alveolar size heterogeneity increased. Simulations of injured lungs predicted that alveolar recruitment pressures were much greater than the derecruitment pressures, so that minimal intratidal recruitment and derecruitment occurred during mechanical ventilation with a tidal volume of 10 ml/kg body weight over a range of PEEPs. However, the simulations also predicted a dramatic increase in alveolar strain with injury that we attribute to alveolar interdependence. These findings suggest that in progressive lung injury, alveolar collapse with increased distension of patent (open) alveoli dominates alveolar micromechanics. PEEP and surfactant substitution reduce alveolar collapse and dynamic strain but increase static strain.

Surfactant replacement therapy reduces acute lung injury and collapse induration-related lung remodeling in the bleomycin model.

Bleomycin-induced lung injury leads to surfactant dysfunction and permanent loss of alveoli due to a remodeling process called collapse induration. Collapse induration also occurs in acute interstitial lung disease and idiopathic pulmonary fibrosis in humans. We hypothesized that surfactant dysfunction aggravates lung injury and early remodeling resulting in collapse induration within 7 days after lung injury. Rats received bleomycin to induce lung injury and either repetitive surfactant replacement therapy (SRT: 100 mg Curosurf/kg BW = surf group) or saline (0.9% NaCl = saline group). After 3 (D3) or 7 (D7) days, invasive pulmonary function tests were performed to determine tissue elastance (H) and static compliance (Cst). Bronchoalveolar lavage (BAL) was taken for surfactant function, inflammatory markers, and protein measurements. Lungs were fixed by vascular perfusion for design-based stereology and electron microscopic analyses. SRT significantly improved minimum surface tension of alveolar surfactant as well as H and Cst at D3 and D7. At D3 decreased inflammatory markers including neutrophilic granulocytes, IL-1ß, and IL-6 correlated with reduced BAL-protein levels after SRT. Numbers of open alveoli were significantly increased at D3 and D7 in SRT groups whereas at D7 there was also a significant reduction in septal wall thickness and parenchymal tissue volume. Septal wall thickness and numbers of open alveoli highly correlated with improved lung mechanics after SRT. In conclusion, reduction in surface tension was effective to stabilize alveoli linked with an attenuation of parameters of acute lung injury at D3 and collapse induration at D7. Hence, SRT modifies disease progression to collapse induration.