Macrophage tumor necrosis factor-alpha induces epithelial expression of granulocyte-macrophage colony-stimulating factor: impact on alveolar epithelial repair.

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.

• Authors: Lidija Cakarova, Leigh M Marsh, Jochen Wilhelm, Konstantin Mayer, Friedrich Grimminger, Werner Seeger, Juergen Lohmeyer, Susanne Herold
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 180 Issue 6 Pg. 521-32 (Sep 15 2009) ISSN: 1535-4970 [Electronic] United States
• PMID: 19590023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• Lipopolysaccharides
• Tumor Necrosis Factor-alpha
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Animals
• Blotting, Western
• Enzyme-Linked Immunosorbent Assay
• Epithelial Cells (immunology, pathology)
• Flow Cytometry
• Granulocyte-Macrophage Colony-Stimulating Factor (biosynthesis, immunology)
• In Vitro Techniques
• 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)