| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Pharmacology and Medicine, University of Melbourne, Parkville, Victoria, Australia
2 Department of Medicine, Arthritis and Inflammation Research Center, Royal Melbourne Hospital, Parkville, Victoria, Australia
* To whom correspondence should be addressed. E-mail: gpa{at}unimelb.edu.au.
The innate immune inflammatory response to lipopolysaccharide (LPS, endotoxin) is essential for lung host defense against infection by Gram-negative bacteria, but is also implicated in the pathogenesis of some lung diseases. Studies in genetically altered mice implicate GM-CSF in lung responses to LPS; however the physiological effects of GM-CSF neutralization are poorly characterized. We performed detailed kinetic and dose-response analyses of the lung inflammation response to LPS in the presence of a specific GM-CSF neutralizing antibody, 22E9. LPS instilled into the lungs of Balb/c mice induced a dose-dependent inflammation comprising of intense neutrophilia, macrophage infiltration and proliferation, TNF
and matrix metalloproteinase release, and MIP2 induction. Neutralizing anti-GM-CSF dose-dependently suppressed these inflammatory indices by up to 85% whether given before or after LPS, or following repeat LPS challenges. Here, we report for the first time that the physiological expression of TLR4 in lung is reduced by anti-GM-CSF . We observed that lower TLR4 expression correlated with a similar decline in peak TNF levels in response to endotoxin. Consequently, sustained expression of key inflammatory mediators over 24h was reduced. These data expand the understanding of the contribution of GM-CSF to innate immune responses in the lung and suggest that blocking GM-CSF might benefit some lung diseases where LPS has been implicated in etiology.
This article has been cited by other articles:
|
|
 |
|
  K. Liu, G. P. Anderson, and S. Bozinovski DNA Vector Augments Inflammation in Epithelial Cells via EGFR-Dependent Regulation of TLR4 and TLR2 Am. J. Respir. Cell Mol. Biol., September 1, 2008; 39(3): 305 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Wengner, S. C. Pitchford, R. C. Furze, and S. M. Rankin The coordinated action of G-CSF and ELR + CXC chemokines in neutrophil mobilization during acute inflammation Blood, January 1, 2008; 111(1): 42 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Chen, M. J. Hansen, J. E. Jones, R. Vlahos, G. P. Anderson, and M. J. Morris Detrimental metabolic effects of combining long-term cigarette smoke exposure and high-fat diet in mice Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1564 - E1571. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ivanov, S. Bozinovski, A. Bossios, H. Valadi, R. Vlahos, C. Malmhall, M. Sjostrand, J. K. Kolls, G. P. Anderson, and A. Linden Functional Relevance of the IL-23-IL-17 Axis in Lungs In Vivo Am. J. Respir. Cell Mol. Biol., April 1, 2007; 36(4): 442 - 451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Uchida, D. C. Beck, T. Yamamoto, P.-Y. Berclaz, S. Abe, M. K. Staudt, B. C. Carey, M.-D. Filippi, S. E. Wert, L. A. Denson, et al. GM-CSF Autoantibodies and Neutrophil Dysfunction in Pulmonary Alveolar Proteinosis N. Engl. J. Med., February 8, 2007; 356(6): 567 - 579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-Y. Berclaz, B. Carey, M.-D. Fillipi, K. Wernke-Dollries, N. Geraci, S. Cush, T. Richardson, J. Kitzmiller, M. O'Connor, C. Hermoyian, et al. GM-CSF Regulates a PU.1-Dependent Transcriptional Program Determining the Pulmonary Response to LPS Am. J. Respir. Cell Mol. Biol., January 1, 2007; 36(1): 114 - 121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. O. Baleeiro, P. J. Christensen, S. B. Morris, M. P. Mendez, S. E. Wilcoxen, and R. Paine III GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress Am J Physiol Lung Cell Mol Physiol, December 1, 2006; 291(6): L1246 - L1255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E.-M. Krinner, J. Hepp, P. Hoffmann, S. Bruckmaier, L. Petersen, S. Petsch, L. Parr, I. Schuster, S. Mangold, G. Lorenczewski, et al. A highly stable polyethylene glycol-conjugated human single-chain antibody neutralizing granulocyte-macrophage colony stimulating factor at low nanomolar concentration Protein Eng. Des. Sel., October 1, 2006; 19(10): 461 - 470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Chen, M. J. Hansen, J. E. Jones, R. Vlahos, S. Bozinovski, G. P. Anderson, and M. J. Morris Cigarette Smoke Exposure Reprograms the Hypothalamic Neuropeptide Y Axis to Promote Weight Loss Am. J. Respir. Crit. Care Med., June 1, 2006; 173(11): 1248 - 1254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Vlahos, S. Bozinovski, J. E. Jones, J. Powell, J. Gras, A. Lilja, M. J. Hansen, R. C. Gualano, L. Irving, and G. P. Anderson Differential protease, innate immunity, and NF-{kappa}B induction profiles during lung inflammation induced by subchronic cigarette smoke exposure in mice Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L931 - L945. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Timoshanko, A. R. Kitching, T. J. Semple, S. R. Holdsworth, and P. G. Tipping Granulocyte Macrophage Colony-Stimulating Factor Expression by Both Renal Parenchymal and Immune Cells Mediates Murine Crescentic Glomerulonephritis J. Am. Soc. Nephrol., September 1, 2005; 16(9): 2646 - 2656. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
