This Article Full Text Full Text (PDF) 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 Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sallenave, J.-M. Articles by Haslett, C. Search for Related Content PubMed PubMed Citation Articles by Sallenave, J.-M. Articles by Haslett, C.

 Previous Article  |  Next Article 

Infection and Immunity, July 2003, p. 3766-3774, Vol. 71, No. 7
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.7.3766-3774.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation of Pulmonary and Systemic Bacterial Lipopolysaccharide Responses in Transgenic Mice Expressing Human Elafin

J.-M. Sallenave,^* G. A. Cunningham, R. M. James, G. McLachlan, and C. Haslett

Rayne Laboratory, Respiratory Medicine Unit, MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh EH8 9AG, Scotland, United Kingdom

Received 3 December 2002/ Returned for modification 21 January 2003/ Accepted 2 April 2003

The control of lung inflammation is of paramount importance in a variety of acute pathologies, such as pneumonia, the acute respiratory distress syndrome, and sepsis. It is becoming increasingly apparent that local innate immune responses in the lung are negatively influenced by systemic inflammation. This is thought to be due to a local deficit in cytokine responses by alveolar macrophages and neutrophils following systemic bacterial infection and the development of a septic response. Recently, using an adenovirus-based strategy which overexpresses the human elastase inhibitor elafin locally in the lung, we showed that elafin is able to prime lung innate immune responses. In this study, we generated a novel transgenic mouse strain expressing human elafin and studied its response to bacterial lipopolysaccharide (LPS) when the LPS was administered locally in the lungs and systemically. When LPS was delivered to the lungs, we found that mice expressing elafin had lower serum-to-bronchoalveolar lavage ratios of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-), macrophage inflammatory protein 2, and monocyte chemoattractant protein 1, than wild-type mice. There was a concomitant increase in inflammatory cell influx, showing that there was potential priming of innate responses in the lungs. When LPS was given systemically, the mice expressing elafin had reduced levels of serum TNF- compared to the levels in wild-type mice. These results indicate that elafin may have a dual function, promoting up-regulation of local lung innate immunity while simultaneously down-regulating potentially unwanted systemic inflammatory responses in the circulation.

Editor: J. N. Weiser

Present address: Department of Biochemistry, Conway Institute of Biomolecular and Biomedical Research, Belfield, Dublin 4, Ireland.

Present address: Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland, United Kingdom.

This article has been cited by other articles:

• Horne, A. W, Stock, S. J, King, A. E (2008). Innate immunity and disorders of the female reproductive tract. Reproduction 135: 739-749 [Abstract] [Full Text]  
• Yin, L., Dale, B. A. (2007). Activation of protective responses in oral epithelial cells by Fusobacterium nucleatum and human {beta}-defensin-2. J Med Microbiol 56: 976-987 [Abstract] [Full Text]  
• Roghanian, A., Williams, S. E., Sheldrake, T. A., Brown, T. I., Oberheim, K., Xing, Z., Howie, S. E. M., Sallenave, J.-M. (2006). The Antimicrobial/Elastase Inhibitor Elafin Regulates Lung Dendritic Cells and Adaptive Immunity. Am. J. Respir. Cell Mol. Bio. 34: 634-642 [Abstract] [Full Text]  
• McMichael, J. W., Maxwell, A. I., Hayashi, K., Taylor, K., Wallace, W. A., Govan, J. R., Dorin, J. R., Sallenave, J.-M. (2005). Antimicrobial Activity of Murine Lung Cells against Staphylococcus aureus Is Increased In Vitro and In Vivo after Elafin Gene Transfer. Infect. Immun. 73: 3609-3617 [Abstract] [Full Text]  
• McMichael, J. W., Roghanian, A., Jiang, L., Ramage, R., Sallenave, J.-M. (2005). The Antimicrobial Antiproteinase Elafin Binds to Lipopolysaccharide and Modulates Macrophage Responses. Am. J. Respir. Cell Mol. Bio. 32: 443-452 [Abstract] [Full Text]  
• Rojas, M., Woods, C. R., Mora, A. L., Xu, J., Brigham, K. L. (2005). Endotoxin-induced lung injury in mice: structural, functional, and biochemical responses. Am. J. Physiol. Lung Cell. Mol. Physiol. 288: L333-L341 [Abstract] [Full Text]  
• Banno, T., Gazel, A., Blumenberg, M. (2004). Effects of Tumor Necrosis Factor-{alpha} (TNF{alpha}) in Epidermal Keratinocytes Revealed Using Global Transcriptional Profiling. J. Biol. Chem. 279: 32633-32642 [Abstract] [Full Text]  
• Henriksen, P. A., Hitt, M., Xing, Z., Wang, J., Haslett, C., Riemersma, R. A., Webb, D. J., Kotelevtsev, Y. V., Sallenave, J.-M. (2004). Adenoviral Gene Delivery of Elafin and Secretory Leukocyte Protease Inhibitor Attenuates NF-{kappa}B-Dependent Inflammatory Responses of Human Endothelial Cells and Macrophages to Atherogenic Stimuli. J. Immunol. 172: 4535-4544 [Abstract] [Full Text]