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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/L320    most recent 90485.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Han, W. Articles by Blackwell, T. S. Search for Related Content PubMed PubMed Citation Articles by Han, W. Articles by Blackwell, T. S.

Myeloid cells control termination of lung inflammation through the NF-B pathway

¹Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, ²Department of Cell and Developmental Biology, and ³Department of Cancer Biology, Vanderbilt University School of Medicine, and ⁴Department of Veterans Affairs, Nashville, Tennessee; and ⁵Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois at Chicago, Chicago, Illinois

Submitted 16 September 2008 ; accepted in final form 16 December 2008

Although acute lung inflammation in response to local or systemic infection involves myeloid and nonmyeloid cells, the interplay between different cell types remains poorly defined. Since NF-B is a key transcription factor for innate immunity, we investigated whether dysregulated NF-B activation in myeloid cells impacts inflammatory signaling in nonmyeloid cells and generation of neutrophilic lung inflammation in response to systemic endotoxemia. We generated bone marrow chimeras by fetal liver transplantation of cells deficient in IB or p50 into lethally irradiated NF-B reporter transgenic mice. No differences were apparent between bone marrow chimeras in the absence of an inflammatory stimulus; however, following intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS), IB- or p50-deficient bone marrow chimeras showed increased NF-B activation in nonhematopoietic cells, exaggerated neutrophilic inflammation, and higher mortality compared with untransplanted reporter mice and wild-type bone marrow chimeras. Primary bone marrow-derived macrophages (BMDM) from IB^–/– or p50^–/– exhibited increased NF-B activation and macrophage inflammatory protein-2 production after LPS treatment compared with wild-type cells, and coculture of BMDM with lung epithelial (A549) cells resulted in increased NF-B activation in A549 cells and excess IL-8 production by these epithelial cells. These studies indicate an important role for inhibitory members of the NF-B family acting specifically within myeloid cells to limit inflammatory responses in the lungs.

macrophage; neutrophil; acute respiratory distress syndrome; chemokine; endotoxin