Journal article

Publication year: 2009

Pages: 521-532

Journal: American Journal of Respiratory and Critical Care Medicine

Volume number: 180

Issue number: 6

ISSN: 1073-449X

eISSN: 1535-4970

DOI Link: https://doi.org/10.1164/rccm.200812-1837OC

Publisher: American Thoracic Society

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 wildtype but not in GM-CSF-deficient AEC as shown by [H-3]-thymidine incorporation and cell counting. Moreover, intraalveolar TNF-alpha neutralization impaired AEC proliferation in LIPS-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 LIPS treatment compared with wildtype mice.

Conclusions: Collectively, these findings indicate that TNF-alpha released from activated resident alveolar macrophages induces epithelial GMCSF expression, which in turn initiates AEC proliferation and contributes to restoring alveolar barrier function.

Harvard Citation style: Cakarova, L., Marsh, L., Wilhelm, J., Mayer, K., Grimminger, F., Seeger, W., et al. (2009) Macrophage Tumor Necrosis Factor-α Induces Epithelial Expression of Granulocyte-Macrophage Colony-stimulating Factor Impact on Alveolar Epithelial Repair, American Journal of Respiratory and Critical Care Medicine, 180(6), pp. 521-532. https://doi.org/10.1164/rccm.200812-1837OC

APA Citation style: Cakarova, L., Marsh, L., Wilhelm, J., Mayer, K., Grimminger, F., Seeger, W., Lohmeyer, J., & Herold, S. (2009). Macrophage Tumor Necrosis Factor-α Induces Epithelial Expression of Granulocyte-Macrophage Colony-stimulating Factor Impact on Alveolar Epithelial Repair. American Journal of Respiratory and Critical Care Medicine. 180(6), 521-532. https://doi.org/10.1164/rccm.200812-1837OC