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

Abstract

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-1β, 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.

Mechanical stretch activates piezo1 in caveolae of alveolar type I cells to trigger ATP release and paracrine stimulation of surfactant secretion from alveolar type II cells

“…88 Restoring surfactant homeostasis via surfactant replacement therapy reduced lung remodeling in a bleomycin model of pulmonary fibrosis. 89 Therefore, it is tempting to speculate that impaired stimulation of surfactant secretion due to the loss of caveolin-1 might contribute to the surfactant dysfunction and development of the fibrotic phenotype observed in cavelin-1 deficient mice and rare human patients that lack caveolae due to mutations in cav1. 90 Overall, our findings support the notion that the high density of caveolae in ATI cells suggests an important role of these invaginations in the physiology of the lungs.…”

Intratracheal Transplantation of Trophoblast Stem Cells Attenuates Acute Lung Injury in Mice

“…Intratracheal BLM in mice causes ALI within the first 7 days of exposure (34,35). We hypothesized that transplantation of TSCs would have a benefit to decrease the injurious effect of BLM.…”

“…In this study, we will intratracheally delivery Bleomycin (BLM) to induce ALI and then transplant TSCs into the lungs of mice. BLM, a chemotherapeutic drug, causes acute lung inflammation and alveolar epithelial cell death in the first week after exposure (34,35). The effect of TSCs in ALI was assessed for tissue inflammation, alveolar cell injury/death, and engraftment of TSCs during this 7 day period after BLM exposure.…”

The tempest in a cubic millimeter: Image-based refinements necessitate the reconstruction of 3D microvasculature from a large series of damaged alternately-stained histological sections

“…b. Lung To demonstrate that our method works also on very different sections, we took a subseries of a rat lung serial sections [37,38,98]. Specifically, 2604 semithin sections with thickness of 1 µm of a pathological lung from a 12 week old Fischer F344 male rat were produced.…”