PT  - JOURNAL ARTICLE
AU  - C. Seifart
AU  - J.P. Muyal
AU  - A. Plagens
AU  - A.Ö. Yildirim
AU  - K. Kohse
AU  - V. Grau
AU  - S. Sandu
AU  - C. Reinke
AU  - T. Tschernig
AU  - C. Vogelmeier
AU  - H. Fehrenbach
TI  - All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages
AID  - 10.1183/09031936.00123809
DP  - 2011 Aug 01
TA  - European Respiratory Journal
PG  - 425--439
VI  - 38
IP  - 2
4099  - http://erj.ersjournals.com/content/38/2/425.short
4100  - http://erj.ersjournals.com/content/38/2/425.full
SO  - Eur Respir J2011 Aug 01; 38
AB  - All-trans retinoic acid (ATRA) is controversially discussed in emphysema therapy. We re-evaluated ATRA in the elastase model and hypothesised that beneficial effects should be reflected by increased alveolar surface area, elastin expression and downregulation of inflammatory mediators and matrix metalloproteinases (MMPs). 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 body weight) 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 alveolar epithelial cells 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 proinflammatory state and high expression of interleukin-1β, cytokine-induced neutrophil chemoattractant-1, tumour necrosis factor-α, nuclear factor-κB, MMP-2, MMP-9, MMP-12, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in emphysema, with ATRA exerting only few 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.