Lidija Cakarova1, Leigh M. Marsh1, Jochen Wilhelm2, Konstantin Mayer1, Friedrich Grimminger1, Werner Seeger1, Juergen Lohmeyer1 and Susanne Herold1 Published ahead of print on July 9, 2009. American Journal of Respiratory and Critical Care Medicine Vol 180. pp. 521-532, (2009)
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)– dependent. GM-CSF elicited proliferative signaling in AEC via autocrine stimulation. Notably, macrophage TNF- induced epithelial proliferation in wild-type but not in GM-CSF–deficient AEC as shown by [3H]-thymidine incorporation and cell counting. Moreover, intraalveolar TNF- 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- released from activated resident alveolar macrophages induces epithelial GM-CSF expression, which in turn initiates AEC proliferation and contributes to restoring alveolar barrier function.

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