title: Lectins offer new perspectives in the development of macrophage-targeted therapies for COPD/emphysema.
abstract: We have previously shown that the defective ability of alveolar macrophages (AM) to phagocytose apoptotic cells ('efferocytosis') in chronic obstructive pulmonary disease/emphysema (COPD) could be therapeutically improved using the C-type lectin, mannose binding lectin (MBL), although the exact mechanisms underlying this effect are unknown. An S-type lectin, galectin-3, is also known to regulate macrophage phenotype and function, via interaction with its receptor CD98. We hypothesized that defective expression of galectin/CD98 would be associated with defective efferocytosis in COPD and that mechanisms would include effects on cytoskeletal remodeling and macrophage phenotype and glutathione (GSH) availability. Galectin-3 was measured by ELISA in BAL from controls, smokers and current/ex-smokers with COPD. CD98 was measured on AM using flow cytometry. We assessed the effects of galectin-3 on efferocytosis, CD98, GSH, actin polymerisation, rac activation, and the involvement of PI3K (using β-actin probing and wortmannin inhibition) in vitro using human AM and/or MH-S macrophage cell line. Significant decreases in BAL galectin-3 and AM CD98 were observed in BAL from both current- and ex-smoker COPD subjects vs controls. Galectin 3 increased efferocytosis via an increase in active GTP bound Rac1. This was confirmed with β-actin probing and the role of PI3K was confirmed using wortmannin inhibition. The increased efferocytosis was associated with increases in available glutathione and expression of CD98. We provide evidence for a role of airway lectins in the failed efferocytosis in COPD, supporting their further investigation as potential macrophage-targeted therapies.
authors: Department of Thoracic Medicine, Royal Adelaide Hospital and Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia.
authors: Violet R
authors: VR
authors: Mukaro
authors: Johan
authors: J
authors: Bylund
authors: Greg
authors: G
authors: Hodge
authors: Mark
authors: M
authors: Holmes
authors: Hubertus
authors: H
authors: Jersmann
authors: Paul N
authors: PN
authors: Reynolds
authors: Sandra
authors: S
authors: Hodge
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D005260:Female; D027261:Fusion Regulatory Protein-1 / Q000378:metabolism; D037502:Galectin 3 / Q000378:metabolism / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D037102:Lectins / Q000378:metabolism* / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000378:metabolism*; D011656:Pulmonary Emphysema / Q000276:immunology* / Q000378:metabolism*; D012907:Smoking; D000077191:Wortmannin; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D000730:Androstadienes; D027261:Fusion Regulatory Protein-1; D037502:Galectin 3; D037102:Lectins; D019869:Phosphatidylinositol 3-Kinases; D001119:Arginase; D020830:rac1 GTP-Binding Protein; D005978:Glutathione; D000077191:Wortmannin