title: Immune modulation of ovalbumin-induced lung injury in mice using β-glucosylceramide and a potential role of the liver.
abstract: CD1d-restricted natural killer T (NKT) cells are implicated in the pathogenesis of asthma. β-Glucosylceramide (GC), a naturally occurring lipid, was previously shown to alter NKT cell distribution in the liver. We hypothesized that GC can affect lung and liver NKT cell distribution and ameliorate asthma. Mice were sensitized by intra-peritoneal injection of ovalbumin (OVA) for 2 weeks followed by repeated intranasal OVA challenges to induce lung injury mimicking asthma. OVA induced asthma groups were either treated by intranasal instillation of normal saline, intranasal instillation of GC or inhaled budesonide. To investigate the role of the liver, hepatic fibrosis was induced using carbon tetrachloride prior to asthma induction. Allergen induced bronchoconstriction was measured prior to sacrifice. Isolated lymphocytes from lungs, livers and spleens were analyzed for OVA induced proliferation and flow cytometry. Liver and lung histology, serum aminotransferase and anti-OVA antibodies level were assessed. Treatment with GC significantly reduced OVA induced airway responsiveness (p<0.001) similar to inhaled budesonide. GC significantly reduced the peri-bronchial and peri-vascular inflammatory infiltration mainly through an effect on T cells, as suggested by decreased T cell proliferation (p=0.009). Liver CD4 and NKT cells significantly increased after GC treatment suggesting liver involvement. Inducing hepatic fibrosis blunted the propagation of asthma in spite of sufficient increase of serum anti-OVA titers. GC has an immunomodulatory effect on a murine model of experimental asthma. We also suggest that the liver acts as an immunomodulatory organ and might have a regulatory effect on pulmonary diseases.
authors.affiliation: Department of Pediatrics and Pediatric Respiratory Research, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Amjad
authors.initials: A
authors.lastname: Horani
authors.forename: David
authors.initials: D
authors.lastname: Shoseyov
authors.forename: Sarit
authors.initials: S
authors.lastname: Doron
authors.forename: Rufayda
authors.initials: R
authors.lastname: Mruwat
authors.forename: Johnny
authors.initials: J
authors.lastname: Amer
authors.forename: Eitan
authors.initials: E
authors.lastname: Kerem
authors.forename: Rifaat
authors.initials: R
authors.lastname: Safadi
mesh_terms: D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002251:Carbon Tetrachloride / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005963:Glucosylceramides / Q000008:administration & dosage* / Q000009:adverse effects; D056747:Immunomodulation; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000485:Allergens; D005963:Glucosylceramides; D010047:Ovalbumin; D002251:Carbon Tetrachloride