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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents

ID: 474542.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
Macrophage tumor necrosis factor-alpha induces epithelial expression of granulocyte-macrophage colony-stimulating factor: impact on alveolar epithelial repair
Authors:Cakarova, L.; Marsh, L. M.; Wilhelm, J.; Mayer, K.; Grimminger, F.; Seeger, W.; Lohmeyer, J.; Herold, S.
Date of Publication (YYYY-MM-DD):2009
Title of Journal:Am J Respir Crit Care Med
Issue / Number:6
Start Page:521
End Page:32
Audience:Not Specified
Abstract / Description:RATIONALE: Resident alveolar macrophages have been attributed a crucial role in host defense toward pulmonary infection. Their contribution to alveolar repair processes, however, remains elusive. OBJECTIVES: We investigated whether activated resident alveolar macrophages contribute to alveolar epithelial repair on lipopolysaccharide (LPS) challenge in vitro and in vivo and analyzed the molecular interaction pathways involved. METHODS: We evaluated macrophage-epithelial cross-talk mediators for epithelial cell proliferation in an in vitro coculture system and an in vivo model of LPS-induced acute lung injury comparing wild-type, granulocyte-macrophage colony-stimulating factor (GM-CSF)-deficient (GM(-/-)), and human SPC-GM mice (GM(-/-) mice expressing an SPC-promotor-regulated GM-CSF transgene). MEASUREMENTS AND MAIN RESULTS: Using reverse transcription-polymerase chain reaction and ELISA we showed that LPS-activated alveolar macrophages stimulated alveolar epithelial cells (AEC) to express growth factors, particularly GM-CSF, in coculture. Antibody neutralization experiments revealed epithelial GM-CSF expression to be macrophage tumor necrosis factor (TNF)-alpha dependent. GM-CSF elicited proliferative signaling in AEC via autocrine stimulation. Notably, macrophage TNF-alpha induced epithelial proliferation in wild-type but not in GM-CSF-deficient AEC as shown by [(3)H]-thymidine incorporation and cell counting. Moreover, intraalveolar TNF-alpha neutralization impaired AEC proliferation in LPS-injured mice, as investigated by flow cytometric Ki-67 staining. Additionally, GM-CSF-deficient mice displayed reduced AEC proliferation and sustained alveolar barrier dysfunction on LPS treatment compared with wild-type mice. CONCLUSIONS: Collectively, these findings indicate that TNF-alpha released from activated resident alveolar macrophages induces epithelial GM-CSF expression, which in turn initiates AEC proliferation and contributes to restoring alveolar barrier function.
Free Keywords:Animals; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Epithelial Cells/immunology/pathology; Flow Cytometry; Granulocyte-Macrophage Colony-Stimulating Factor/*biosynthesis/immunology; Inflammation Mediators/immunology; Lipopolysaccharides/pharmacology; Lung/immunology/pathology; Lung Injury/*immunology/pathology; Macrophage Activation/*immunology; Macrophages, Alveolar/*immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha/*immunology
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:University of Giessen Lung Center, Department of Internal Medicine II, Klinikstr. 36, D-35392 Giessen, Germany.
Identifiers:ISSN:1535-4970 (Electronic) 1073-449X (Linking)
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