Transgenic overexpression of granulocyte macrophage-colony stimulating factor in the lung prevents hyperoxic lung injury.

Details

Serval ID
serval:BIB_6214FF1DF625
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Transgenic overexpression of granulocyte macrophage-colony stimulating factor in the lung prevents hyperoxic lung injury.
Journal
American Journal of Pathology
Author(s)
Paine R., Wilcoxen S.E., Morris S.B., Sartori C., Baleeiro C.E., Matthay M.A., Christensen P.J.
ISSN
0002-9440
Publication state
Published
Issued date
2003
Peer-reviewed
Oui
Volume
163
Number
6
Pages
2397-2406
Language
english
Abstract
Granulocyte macrophage-colony stimulating factor (GM-CSF) plays an important role in pulmonary homeostasis, with effects on both alveolar macrophages and alveolar epithelial cells. We hypothesized that overexpression of GM-CSF in the lung would protect mice from hyperoxic lung injury by limiting alveolar epithelial cell injury. Wild-type C57BL/6 mice and mutant mice in which GM-CSF was overexpressed in the lung under control of the SP-C promoter (SP-C-GM mice) were placed in >95% oxygen. Within 6 days, 100% of the wild-type mice had died, while 70% of the SP-C-GM mice remained alive after 10 days in hyperoxia. Histological assessment of the lungs at day 4 revealed less disruption of the alveolar wall in SP-C-GM mice compared to wild-type mice. The concentration of albumin in bronchoalveolar lavage fluid after 4 days in hyperoxia was significantly lower in SP-C-GM mice than in wild-type mice, indicating preservation of alveolar epithelial barrier properties in the SP-C-GM mice. Alveolar fluid clearance was preserved in SP-C-GM mice in hyperoxia, but decreased significantly in hyperoxia-exposed wild-type mice. Staining of lung tissue for caspase 3 demonstrated increased apoptosis in alveolar wall cells in wild-type mice in hyperoxia compared to mice in room air. In contrast, SP-C-GM mice exposed to hyperoxia demonstrated only modest increase in alveolar wall apoptosis compared to room air. Systemic treatment with GM-CSF (9 micro g/kg/day) during 4 days of hyperoxic exposure resulted in decreased apoptosis in the lungs compared to placebo. In studies using isolated murine type II alveolar epithelial cells, treatment with GM-CSF greatly reduced apoptosis in response to suspension culture. In conclusion, overexpression of GM-CSF enhances survival of mice in hyperoxia; this effect may be explained by preservation of alveolar epithelial barrier function and fluid clearance, at least in part because of reduction in hyperoxia-induced apoptosis of cells in the alveolar wall.
Keywords
Animals, Apoptosis/drug effects, Cells, Cultured, Epithelial Cells/drug effects, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism, Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology, Hyperoxia/metabolism, Hyperoxia/pathology, Lung/metabolism, Lung/pathology, Lung Diseases/metabolism, Lung Diseases/pathology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Pulmonary Alveoli/drug effects, Pulmonary Alveoli/metabolism, Recombinant Proteins/pharmacology, Serum Albumin/metabolism, Survival Analysis, Vascular Endothelial Growth Factor A/metabolism
Pubmed
Web of science
Create date
22/02/2008 16:02
Last modification date
20/08/2019 15:19
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