Pulmonary irradiation-induced expression of VCAM-I and ICAM-I is decreased by manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) gene therapy.
Pulmonary toxicity is a major complication of total body irradiation used in preparation of patients for bone marrow transplantation. The mechanism of the late pulmonary damage manifested by fibrosis is unknown. In C57BL/6NHsd mice, manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) intratracheal injection 24 hours prior to 20 Gy single-fraction irradiation to both lungs significantly reduced late irradiation damage. Single intratracheal injections of MnSOD-PL, at concentrations as low as 250 microg of plasmid DNA, in a constant volume of 78 microL of liposomes, reduced late damage. To determine whether a slowly proliferating population of cells in the lung was responsible for initiation of fibrosis and was altered by MnSOD-PL therapy, 20 Gy total lung-irradiated mice were examined at serial time points for bromodeoxyuridine (BrdU) uptake in sites of cell division. There was low-level, but nonsignificant, increased cell proliferation detected at 80 days, with a significant increase at 100 days, 120 days, and at the time of death. Immunohistochemical assay for up-regulation of adhesion molecules associated with recruitment, transendothelial migration, and proliferation of bronchoalveolar macrophages revealed significant up-regulation of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) at 100 days with further increases up to the time of death. Increases were first detected in endothelin-positive endothelial cells. MnSOD-PL administration prior to irradiation decreased both BrdU incorporation and delayed expression of VCAM-1 and ICAM-1. The data indicate that the appearance of late irradiation-induced pulmonary fibrosis is associated with the up-regulation of adhesion molecules and suggest that potential targets for intervention may focus on the pulmonary vascular endothelium.
Epperly
Michael W
MW
Department of Radiation Oncology, University of Pittsburgh Cancer Center Institute, Pennsylvania 15213, USA.
Sikora
Christine A
CA
DeFilippi
Stacy J
SJ
Gretton
Joan E
JE
Bar-Sagi
Dafna
D
Archer
Herbert
H
Carlos
Timothy
T
Guo
HongLiang
H
Greenberger
Joel S
JS
D000818:Animals; D002455:Cell Division / Q000528:radiation effects; D002478:Cells, Cultured / Q000378:metabolism / Q000528:radiation effects; D004274:DNA, Recombinant / Q000032:analysis; D019583:Dose Fractionation, Radiation; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D005786:Gene Expression Regulation / Q000528:radiation effects*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D008081:Liposomes; D008168:Lung / Q000098:blood supply / Q000528:radiation effects*; D008345:Manganese; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D019007:P-Selectin / Q000096:biosynthesis / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology*; D019172:Transplantation Conditioning / Q000009:adverse effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D014916:Whole-Body Irradiation / Q000009:adverse effects
D004274:DNA, Recombinant; D019040:E-Selectin; D008081:Liposomes; D019007:P-Selectin; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D008345:Manganese; D013482:Superoxide Dismutase