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B Pathway1
,¶,
,
* Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine,
Department of Cancer Biology, and
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; and
Department of Veterans Affairs and
¶ Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois, Chicago, IL 60605
Although airway epithelial cells provide important barrier and host defense functions, a crucial role for these cells in development of acute lung inflammation and injury has not been elucidated. We investigated whether NF-
B pathway signaling in airway epithelium could decisively impact inflammatory phenotypes in the lungs by using a tetracycline-inducible system to achieve selective NF-B activation or inhibition in vivo. In transgenic mice that express a constitutively active form of IB kinase 2 under control of the epithelial-specific CC10 promoter, treatment with doxycycline induced NF-B activation with consequent production of a variety of proinflammatory cytokines, high-protein pulmonary edema, and neutrophilic lung inflammation. Continued treatment with doxycycline caused progressive lung injury and hypoxemia with a high mortality rate. In contrast, inducible expression of a dominant inhibitor of NF-B in airway epithelium prevented lung inflammation and injury resulting from expression of constitutively active form of IB kinase 2 or Escherichia coli LPS delivered directly to the airways or systemically via an osmotic pump implanted in the peritoneal cavity. Our findings indicate that the NF-B pathway in airway epithelial cells is critical for generation of lung inflammation and injury in response to local and systemic stimuli; therefore, targeting inflammatory pathways in airway epithelium could prove to be an effective therapeutic strategy for inflammatory lung diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants HL61419, HL66196, and HL07123; the U.S. Department of Veterans Affairs; Vanderbilt Ingram Cancer Center; Susan G. Komen Foundation Grant BCTR02-1728; and Department of Defense Breast Cancer Program Grant WX1XWH-04-1-0456.
2 F.E.Y. and T.S.B. contributed equally to this manuscript.
3 Address correspondence and reprint requests to Dr. Timothy S. Blackwell, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, TN 37232. E-mail address: timothy.blackwell{at}vanderbilt.edu
4 Abbreviations used in this paper: IKK2, IB kinase 2; ARDS, acute respiratory distress syndrome; cIKK2, constitutively active human IKK2; DNTA, IB-
DN-transactivated mice, transgenic mice expressing IB-DN under control of the CC10 promoter; dox, doxycycline; IB-DN, IB- dominant negative; IKTA, cIKK2-transactivated mice, transgenic mice expressing cIKK2 under control of the CC10 promoter; MTEC, mouse tracheal epithelial cell; RPA, RNase protection assay; rtTA, reverse tetracycline transactivator; tTS, tetracycline-controlled transcriptional silencer; WT, wild type.
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