Fetal ethanol exposure and the developing alveolar macrophage

Abstract

Excessive consumption of alcohol (EtOH), the 3 leading preventable cause of death in the USA, has been shown to lead to increased incidence and severity of acute respiratory distress syndrome. The increased risk of respiratory infections in alcoholics is believed to be due to alterations in alveolar macrophage (AM) function. Previous studies have shown chronic EtOH ingestion leads to increased oxidant stress, increased TGFb production, increased fibronectin production, and decreased phagocytosis in AMs. Alternative (M2) activation of AMs has also been shown to lead to similar alterations. Classical ‘‘M1’’ by T helper 1 (TH1) cytokines leads to a proinflammatory response that is required for the respiratory burst necessary for phagocytosis. However, M2 is induced by TH2 cytokines leads to increased arginase production, increased arginase activity, and increased proline and polyamine production. These events promote fibroblast proliferation, collagen production and fibrosis within the lung. Our aim was to determine if chronic EtOH treatment leads to alterations in the expression of markers of M2 activation in AMs. To test this hypothesis, NR8383 cells, a rat-derived alveolar macrophage cell line, were treated with 0.08% EtOH, 25mM acetylaldehyde (AA), or IL-13, a know activator of M2 activation, 6 GSH or 6 IL-13 neutralizing antibody for 5 days. The cells were then analyzed for arginase activity and expression, active TGF-b production in cell culture media, and fibronectin production by 3T3 cells, a fibroblast cell line. In NR8383 cells, treatment with EtOH, AA, or IL-13 led to increased arginase activity, increased arginase expression, active TGF-b production, and secretion of factors that promoted fibronectin production in 3T3 cells. Supplementation with GSH or IL-13 neutralizing antibody during the 5 day treatment led to partial normalization of arginase activity, arginase expression, active TGF-b production, and activation of 3T3 cells in fibronectin production. In conclusion, several markers of M2 activation were greatly increased in response to EtOH, AA, and IL-13 treatment and GSH/ IL-13 neutralizing antibody treatment blocked these effects suggesting chronic EtOH treatment leads to M2 activation of AMs and antioxidant treatment can partially prevent that switch.