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Published ahead of print on December 23, 2004, doi:10.1164/rccm.200407-953OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 8, April 2005, 806-813

A more recent version of this article appeared on April 15, 2005
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Submitted on July 26, 2004
Accepted on December 13, 2004

The Critical Role of Hematopoietic Cells in Lipopolysaccharide Induced Airway Inflammation

John W Hollingsworth II1*, Benny J Chen2, David M Brass3, Katie Berman3, M. Dee Gunn4, Donald N Cook3, and David A Schwartz1

1 Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, NC, USA; Pulmonary and Critical Care Medicine, Veterans Administration Medical Center, Durham, NC, USA, 2 Division of Cellular Therapy, Duke University Medical Center, Durham, NC, USA, 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, NC, USA, 4 Division of Cardiology, Duke University Medical Center, Durham, NC, USA

* To whom correspondence should be addressed. E-mail: holli017{at}mc.duke.edu.

Rapid and selective recruitment of neutrophils into the airspace in response to lipopolysaccharide (LPS) facilitates the clearance of bacterial pathogens. However, neutrophil infiltration can also participate in the development and progression of environmental airway disease. Previous data have revealed that toll-like receptor 4 (tlr4) is required for neutrophil recruitment to the lung following either inhaled or systemically administrated LPS from E. coli. While many cell types express tlr4, endothelial cell expression of tlr4 is specifically required to sequester neutrophils in the lung in response to systemic endotoxin. To identify the cell types requiring trl4 expression for neutrophil recruitment following inhaled LPS, we generated chimeric mice separately expressing tlr4 on either hematopoietic cells, or on structural lung cells. Neutrophil recruitment into the airspace was completely restored in tlr4-/- mice receiving wild type bone marrow. By contrast, wild type animals receiving tlr4-/- marrow had dramatically reduced neutrophil recruitment. Moreover, adoptive transfer of wild type alveolar macrophages also restored the ability of tlr4-/- recipient mice to recruit neutrophils to the lung. These data demonstrate the critical role of hematopoietic cells and alveolar macrophages in initiating LPS induced neutrophil recruitment from the vascular space to the airspace.


Key words: toll-like receptor, macrophage, neutrophil, innate immunity, lipopolysaccharide




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