Articles |

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

Timothy S. Blackwell, MD; F.E. Yull; C.-L. Chen; A. Venkatakrishnan; T.R. Blackwell; D.J. Hicks; L.H. Lancaster, MD; J.W. Christman, MD, FCCP; L.D. Kerr
Author and Funding Information

*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

Chest. 1999;116(suppl_1):73S-74S. doi:10.1378/chest.116.suppl_1.73S
Text Size: A A A
Published online

Production of many inflammatory cytokines and adhesion molecules in vitro is regulated by the ubiquitous transcription factor complex, nuclear factor-kappa B (NF-κB), but the extent to which NF-κB controls specific biological processes in vivo remains unanswered. To examine the function of NF-κB in vivo, we generated a line of transgenic mice expressing Photinusluciferase complementary DNA under the control of an NF-κB-dependent promoter (from the 5′ HIV-1 long terminal repeat). Using these mice, we evaluated NF-κB-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-κB-dependent luciferase expression, showing that NF-κB activation is induced in multiple organs by systemic LPS administration. Additionally, NF-κB 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-κB 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-κB-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-κB-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.




Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543