Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Cakarova, L; Marsh, LM; Wilhelm, J; Mayer, K; Grimminger, F; Seeger, W; Lohmeyer, J; Herold, S.
Macrophage tumor necrosis factor-alpha induces epithelial expression of granulocyte-macrophage colony-stimulating factor: impact on alveolar epithelial repair.
Am J Respir Crit Care Med. 2009; 180(6): 521-532.
Doi: 10.1164/rccm.200812-1837OC
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- Co-Autor*innen der Med Uni Graz
- Marsh Leigh
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- Abstract:
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Blotting, Western -
- Enzyme-Linked Immunosorbent Assay -
- Epithelial Cells - immunology Epithelial Cells - pathology
- Flow Cytometry -
- Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis Granulocyte-Macrophage Colony-Stimulating Factor - immunology
- Inflammation Mediators - immunology
- Lipopolysaccharides - pharmacology
- Lung - immunology Lung - pathology
- Lung Injury - immunology Lung Injury - pathology
- Macrophage Activation - immunology
- Macrophages, Alveolar - immunology
- Mice -
- Mice, Inbred C57BL -
- Mice, Transgenic -
- Reverse Transcriptase Polymerase Chain Reaction -
- Tumor Necrosis Factor-alpha - immunology
- Find related publications in this database (Keywords)
- acute lung injury
- epithelial proliferation
- alveolar repair