Project Details
Projekt
Surfactant inactivation, alveolar collapsibility and their role in the progression to pulmonary fibrosis in animal models of lung injury and fibrosis
Subject Area
Pneumology, Thoracic Surgery
Term
from 2014 to 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 242799095
Pulmonary surfactant is critical for physiological alveolar dynamics during breathing as it prevents end-expiratory collapse. Dysfunctions of the intraalveolar surfactant have been observed in acute lung injury as well as in human idiopathic pulmonary fibrosis (IPF). IPF is a fatal disease resulting from ongoing injury of alveolar epithelium. Whereas alveolar collapsibility leading to alveolar recruitment/derecruitment (R/D) during the respiratory cycle has been discussed in animal models of lung injury, nothing is known regarding changes in alveolar dynamics during disease progression from injury to fibrosis. Repetitive alveolar R/D due to surfactant dysfunction may also cause harmful mechanical stress into the alveolar lining, aggravating injury and triggering fibrotic remodelling. Ultrastructural data indicate that initially collapsed but recruitable alveoli are later irreversibly lost due to a mechanism known as collapse induration, meaning that alveolar R/D changes with time. This concept is supported by our preliminary data in a bleomycin-induced model of lung injury and fibrosis demonstrating that inactivation of the intraalveolar surfactant represents the initial event leading to progressive alveolar collapse. Collapse induration is thought to represent the most important mechanism for the loss of functional alveoli in this model. In a model of lung fibrosis overexpressing biological active TGF-beta1 we have also observed signs of an increased alveolar R/D at an early timepoint. The aim of this study is to assess the exact degree of airspace R/D during the respiratory cycle at different timepoints from injury to fibrotic remodelling in two animal models: the bleomycin and the TGF-beta1 model. This will be accomplished by design-based stereology to quantify structural changes as well as by invasive pulmonary function tests to establish structure-function relationships. Alterations of alveolar closing pressures during disease progression will be determined, since these might represent direct functional correlates to surfactant function. We hypothesize that alveolar closing pressures increase during disease progression, resulting finally in an irreversible loss of alveoli due to collapse induration. In a second step, we aim to elucidate the pathogenetic role of initial surfactant inactivation in alveolar R/D, progression of alveolar epithelial injury, collapse induration and pulmonary fibrosis by means of repetitive exogenous surfactant substitution. We hypothesize that in these animal models of pulmonary injury and fibrosis, initial surfactant dysfunction and related changes in alveolar dynamics (alveolar R/D) significantly contribute to injury of the alveolar epithelium, triggering pulmonary fibrosis and collapse induration.
DFG Programme
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