Abstract
The inhalation of silica particles induces silicosis, an inflammatory and fibrotic lung disease characterized by the early accumulation of macrophages and neutrophils in the airspace and subsequent appearance of silicotic nodules as a result of progressive fibrosis. This study evaluated whether apolipoprotein A1 (ApoA1) protects against ongoing fibrosis and promotes the resolution of established experimental lung silicosis. Crystallized silica was intratracheally administered to 6- to 8-week-old transgenic mice expressing human ApoA1 in their alveolar epithelial cells (day 0). ApoA1 was overexpressed beginning on day 7 (ApoA1_D7 group) or day 15 (ApoA1_D15 group). The mice were sacrificed on day 30 for an evaluation of lung histology; the measurement of collagen, transforming growth factor-b1 and lipoxin A4; and a TUNEL assay for apoptotic cells. The ApoA1_D7 and D15 groups showed significant reductions in the silica-induced increase in inflammatory cells, silicotic nodule area, and collagen deposition compared with the silica-treated ApoA1 non-overexpressing mice. The level of transforming growth factor-b1 decreased in the bronchoalveolar lavage fluid, whereas lipoxin A4 was increased in the ApoA1_D7 and D15 groups compared with the silica-treated ApoA1 non-overexpressing mice. The silica-induced increase in the number of apoptotic cells was significantly reduced in the lungs of mice overexpressing ApoA1. Overexpression of ApoA1 decreased silica-induced lung inflammation and fibrotic nodule formation. The restoration of lipoxin A4 may contribute to the protective effect of ApoA1 overexpression against silica-induced lung fibrosis.
Highlights
Apolipoprotein A1 (ApoA1), the major component of highdensity lipoprotein, plays an important role in reverse cholesterol transport by extracting cholesterol and phospholipids from various cells, including lung cells, and transferring them to the liver
The antibody against human ApoA1 (hApoA1) detected mouse ApoA1 owing to sequence similarity, ApoA1 was 6.6-times more strongly expressed in the lungs of the doxycycline-treated transgenic mice compared with transgenic mice that were not treated with doxycycline and wild-type mice (Fig. 1B)
There was no difference in ApoA1 expression between the transgenic mice not treated with doxycycline and wild-type mice (Fig. 1B). hApoA1 was detected in the bronchoalveolar lavage (BAL) fluid of the doxycycline-treated transgenic mice, but not in those that were not treated with doxycycline (Fig. 1C)
Summary
Apolipoprotein A1 (ApoA1), the major component of highdensity lipoprotein, plays an important role in reverse cholesterol transport by extracting cholesterol and phospholipids from various cells, including lung cells, and transferring them to the liver. Using the lung disease model, it has been reported that treatment with ApoA1 mimetics attenuated allergeninduced airway inflammation in murine models of asthma by decreasing oxidative stress [4]. We reported that ApoA1 is expressed in the lung epithelium, that lung ApoA1 levels were reduced in patients with idiopathic pulmonary fibrosis, and intranasal treatment with ApoA1 significantly attenuated experimental bleomycin-induced lung injury and fibrosis [5]. It is unclear whether ApoA1 administration after an injury can reduce established pulmonary fibrosis. Progressive models of fibrosis are generally used to investigate this issue because the disease resolution observed in the bleomycin model does not mimic permanent human fibrosis [6,7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
