This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200812-1837OCv1 180/6/521    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Cakarova, L. Articles by Herold, S. PubMed PubMed Citation Articles by Cakarova, L. Articles by Herold, S.

Macrophage Tumor Necrosis Factor- Induces Epithelial Expression of Granulocyte–Macrophage Colony-stimulating Factor

Impact on Alveolar Epithelial Repair

¹ University of Giessen Lung Center (UGLC), Department of Internal Medicine II/V, and ² Department of Pathology, Justus-Liebig-University, Giessen, Germany

Correspondence and requests for reprints should be addressed to Susanne Herold, M.D., Ph.D., University of Giessen Lung Center, Department of Internal Medicine II, Klinikstr. 36, D-35392 Giessen, Germany. E-mail: susanne.herold{at}innere.med.uni-giessen.de

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.

Key Words: acute lung injury • epithelial proliferation • alveolar repair

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Little is known about the contribution of activated alveolar macrophages to alveolar epithelial repair processes in inflammatory lung injury. What This Study Adds to the Field This study demonstrates that alveolar macrophage tumor necrosis factor- initiates alveolar epithelial repair on LPS challenge by induction of autocrine epithelial granulocyte–macrophage colony-stimulating factor signaling. Macrophage tumor necrosis factor- thereby contributes to epithelial renewal and restoration of alveolar barrier function.