title: All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Division of Respiratory Medicine, University Hospital Giessen and Marburg GmbH, 35043 Marburg, Germany. seifart@med.uni-marburg.de
authors.forename: C
authors.initials: C
authors.lastname: Seifart
authors.forename: J P
authors.initials: JP
authors.lastname: Muyal
authors.forename: A
authors.initials: A
authors.lastname: Plagens
authors.forename: A Ö
authors.initials: AÖ
authors.lastname: Yildirim
authors.forename: K
authors.initials: K
authors.lastname: Kohse
authors.forename: V
authors.initials: V
authors.lastname: Grau
authors.forename: S
authors.initials: S
authors.lastname: Sandu
authors.forename: C
authors.initials: C
authors.lastname: Reinke
authors.forename: T
authors.initials: T
authors.lastname: Tschernig
authors.forename: C
authors.initials: C
authors.lastname: Vogelmeier
authors.forename: H
authors.initials: H
authors.lastname: Fehrenbach
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D053331:Ectodysplasins / Q000032:analysis; D004549:Elastin / Q000032:analysis; D004646:Emphysema / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D010196:Pancreatic Elastase / Q000633:toxicity; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D014212:Tretinoin / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D053331:Ectodysplasins; C506019:Eda protein, mouse; D053583:Interleukin-1beta; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2; D014212:Tretinoin; D004549:Elastin; D010196:Pancreatic Elastase; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12