ATRA results in irregular repair of septa and fails to inhibit proinflammatory macrophages

Abstract

ATRA is controversially discussed in emphysema therapy. We re-evaluated ATRA in the elastase-model and hypothesized that beneficial effects should be reflected by increased alveolar surface area, elastin expression, and downregulation of inflammatory mediators and matrix metalloproteinases (MMP).

Emphysema was induced by porcine pancreatic elastase versus saline in Sprague-Dawley rats. On days 26–37, rats received daily intraperitoneal injections with ATRA (500 μg·kg⁻¹ b.w.) versus olive-oil. Lungs were removed at day 38. Rat alveolar epithelial L2 cells were incubated with/without elastase followed by ATRA- or vehicle-treatment, respectively.

ATRA only partially ameliorated structural defects. Alveolar walls exhibited irregular architecture: increased arithmetic mean thickness, reduction in surface coverage by AEC type II. ATRA only partially restored reduced soluble elastin. It tended to increase the ratio of ED1⁺:ED2⁺ macrophages. Bronchoalveolar lavage (BAL) cells exhibited a pro-inflammatory state with high expression of IL-1β, CINC-1, TNF-α, NF-ĸB, MMP-2, -9, -12, TIMP-1, and -2 in emphysema with ATRA exerting only little effects. MMP-7 was highly induced by ATRA in healthy but not in emphysematous lungs. ATRA reduced both MMP-2 and TIMP-1 activity in BAL fluid of emphysematous lungs.

ATRA-therapy may bear the risk of unwanted side-effects on alveolar septal architecture in emphysematous lungs.