This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200303-412OCv1 168/7/810    most recent 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mizgerd, J. P. Articles by Topulos, G. P. Search for Related Content PubMed PubMed Citation Articles by Mizgerd, J. P. Articles by Topulos, G. P.

Nuclear Factor-B p50 Limits Inflammation and Prevents Lung Injury during Escherichia coli Pneumonia

Physiology Program, Harvard School of Public Health; Center for Animal Resources and Comparative Medicine, Harvard Medical School; and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Joseph P. Mizgerd, Sc.D., Physiology Program, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115. E-mail: jmizgerd{at}hsph.harvard.edu

Inflammatory responses to infection must be precisely regulated to facilitate microbial killing while limiting host tissue damage. Many inflammatory genes are regulated by B sites, and the p50 subunit of nuclear factor-B suppresses the expression of B-associated genes in vitro. We hypothesized that p50 is essential to prevent excessive inflammation and injury during infection. During pulmonary infection with Escherichia coli, the gene-targeted deficiency of p50 did not affect bacterial clearance from mouse lungs, but it resulted in increased expression of proinflammatory cytokines 6 to 24 hours after infection. This dysregulation exacerbated inflammation (neutrophil recruitment), respiratory distress (pulmonary edema and blood gas exchange impairment), and decompartmentalization (transit of protein and bacteria from the air spaces to the blood). We interpret these studies to indicate that endogenous p50 protects the host by curbing inflammatory responses to prevent injury, essential to survive pneumonia.

Key Words: acute lung injury • bacterial pneumonia • cytokines • neutrophil recruitment • transcription factors

This article has been cited by other articles:

				U. Panzer, O. M. Steinmetz, J.-E. Turner, C. Meyer-Schwesinger, C. von Ruffer, T. N. Meyer, G. Zahner, C. Gomez-Guerrero, R. M. Schmid, U. Helmchen, et al. Resolution of renal inflammation: a new role for NF-{kappa}B1 (p50) in inflammatory kidney diseases Am J Physiol Renal Physiol, August 1, 2009; 297(2): F429 - F439. [Abstract] [Full Text] [PDF]

				S. X. L. Liu, R. Tian, H. Baskind, W. Hsueh, and I. G. De Plaen Platelet-activating factor induces the processing of nuclear factor-{kappa}B p105 into p50, which mediates acute bowel injury in mice Am J Physiol Gastrointest Liver Physiol, July 1, 2009; 297(1): G76 - G81. [Abstract] [Full Text] [PDF]

				W. Han, M. Joo, M. B. Everhart, J. W. Christman, F. E. Yull, and T. S. Blackwell Myeloid cells control termination of lung inflammation through the NF-{kappa}B pathway Am J Physiol Lung Cell Mol Physiol, March 1, 2009; 296(3): L320 - L327. [Abstract] [Full Text] [PDF]

				A. Craig, J. Mai, S. Cai, and S. Jeyaseelan Neutrophil Recruitment to the Lungs during Bacterial Pneumonia Infect. Immun., February 1, 2009; 77(2): 568 - 575. [Full Text] [PDF]

				J. P. Mizgerd and S. J. Skerrett Animal models of human pneumonia Am J Physiol Lung Cell Mol Physiol, March 1, 2008; 294(3): L387 - L398. [Abstract] [Full Text] [PDF]

				J. P. Mizgerd Acute Lower Respiratory Tract Infection N. Engl. J. Med., February 14, 2008; 358(7): 716 - 727. [Full Text] [PDF]

				Y. S. Choi, J. Hur, and S. Jeong {beta}-Catenin binds to the downstream region and regulates the expression C-reactive protein gene Nucleic Acids Res., August 17, 2007; (2007) gkm547v1. [Abstract] [Full Text] [PDF]

				C. Pantano, V. Anathy, P. Ranjan, N. H. Heintz, and Y. M. W. Janssen-Heininger Nonphagocytic Oxidase 1 Causes Death in Lung Epithelial Cells via a TNF-RI-JNK Signaling Axis Am. J. Respir. Cell Mol. Biol., April 1, 2007; 36(4): 473 - 479. [Abstract] [Full Text] [PDF]

				L. J. Quinton, M. R. Jones, B. T. Simms, M. S. Kogan, B. E. Robson, S. J. Skerrett, and J. P. Mizgerd Functions and Regulation of NF-{kappa}B RelA during Pneumococcal Pneumonia J. Immunol., February 1, 2007; 178(3): 1896 - 1903. [Abstract] [Full Text] [PDF]

				A. S. Prince, J. P. Mizgerd, J. Wiener-Kronish, and J. Bhattacharya Cell signaling underlying the pathophysiology of pneumonia Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L297 - L300. [Abstract] [Full Text] [PDF]

				S. Jeyaseelan, R. Manzer, S. K. Young, M. Yamamoto, S. Akira, R. J. Mason, and G. S. Worthen Toll-IL-1 Receptor Domain-Containing Adaptor Protein Is Critical for Early Lung Immune Responses against Escherichia coli Lipopolysaccharide and Viable Escherichia coli J. Immunol., December 1, 2005; 175(11): 7484 - 7495. [Abstract] [Full Text] [PDF]

				F. Oakley, J. Mann, S. Nailard, D. E. Smart, N. Mungalsingh, C. Constandinou, S. Ali, S. J. Wilson, H. Millward-Sadler, J. P. Iredale, et al. Nuclear Factor-{kappa}B1 (p50) Limits the Inflammatory and Fibrogenic Responses to Chronic Injury Am. J. Pathol., March 1, 2005; 166(3): 695 - 708. [Abstract] [Full Text] [PDF]

				M. J. Tobin Critical Care Medicine in AJRCCM 2003 Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 239 - 253. [Full Text] [PDF]

				M. J. Tobin Tuberculosis, Lung Infections, Interstitial Lung Disease, Social Issues and Journalology in AJRCCM 2003 Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 288 - 300. [Full Text] [PDF]

				J. P. Mizgerd Competing Benefits of Tumor Necrosis Factor-{alpha} for Bacteria and for Host Defense Am. J. Respir. Crit. Care Med., December 15, 2003; 168(12): 1410 - 1411. [Full Text] [PDF]