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Use of Genetically Altered Mice to Investigate the Role of Nuclear Factor-Kappa B Activation and Cytokine Gene Expression in Sepsis-Induced ARDS^*

^* From Vanderbilt University School of Medicine and the Veterans Affairs Medical Center, Nashville, TN.

Correspondence to: Timothy S. Blackwell, MD, Department of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, T-1217 MCN, Nashville, TN 37232-2650

Production of many inflammatory cytokines and adhesion molecules in vitro is regulated by the ubiquitous transcription factor complex, nuclear factor-kappa B (NF-B), but the extent to which NF-B controls specific biological processes in vivo remains unanswered. To examine the function of NF-B in vivo, we generated a line of transgenic mice expressing Photinusluciferase complementary DNA under the control of an NF-B-dependent promoter (from the 5' HIV-1 long terminal repeat). Using these mice, we evaluated NF-B-dependent luciferase production in a variety of tissues following intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS) at 1 mg/kg. The transgenic animals displayed a time-dependent, organ-specific pattern of NF-B-dependent luciferase expression, showing that NF-B activation is induced in multiple organs by systemic LPS administration. Additionally, NF-B activity in tissue nuclear protein extracts was assayed by electrophoretic mobility shift assay and found to have an organ-specific pattern of activation that correlated well with luciferase activity.

NF-B activation peaked in lung tissue at 2 h after LPS, in liver at 1 to 2 h, and in spleen at 1 to 4 h. NF-B-dependent luciferase activity in lung and liver, as well as serum concentrations of the mouse CXC chemokine KC and interleukin-6, cytokines thought to be NF-B-dependent, peaked at 4 to 6 h after LPS injection. In this model, intraperitoneal injection of LPS resulted in a significant neutrophilic alveolitis by 24 h as assessed by differential cell counts from lung lavage. These studies show that systemic LPS orchestrates a multiorgan response that is tissue specific and time dependent, resulting in a defined pattern of cytokine production and neutrophilic lung inflammation. Further defining this complex series of events in this model system will increase our understanding of the pathobiology of sepsis-induced ARDS and may lead to novel treatment strategies.

This Article Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Blackwell, T. S. Articles by Kerr, L.D. Search for Related Content PubMed PubMed Citation Articles by Blackwell, T. S. Articles by Kerr, L.D.