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Acute Pulmonary Lipopolysaccharide Tolerance Decreases TNF- without Reducing Neutrophil Recruitment¹

Sudha Natarajan^*,, Jiyoun Kim^* and Daniel G. Remick^2,*

^* Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118; and Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109

Pulmonary LPS exposure plays a key role in exacerbation of lung diseases such as chronic obstructive pulmonary disease and asthma. However, little is known about the effects of repeated LPS exposure in the lung microenvironment. We have developed a novel murine model of pulmonary LPS tolerance induced by intratracheal (i.t.) administration of LPS. First, we show that pulmonary LPS exposure does not induce whole-body refractoriness to systemic LPS, because i.t. administration followed by i.p. administration did not decrease plasma TNF-. However, a local refractory state can be induced with two i.t. LPS exposures. Pulmonary LPS tolerance was induced by i.t. administration of 100 ng LPS at time 0 and 48 h. Nontolerant mice received PBS at time 0 and LPS at 48 h. Bronchoalveolar lavage levels of TNF- were significantly attenuated in tolerant mice vs nontolerant mice (1597 pg/ml vs 7261 pg/ml). TNF- mRNA was significantly reduced in bronchoalveolar lavage cells (5-fold) and lung tissue (10-fold). No reduction was seen in neutrophil numbers in the bronchoalveolar lavage fluid, myeloperoxidase activity, or expression of neutrophil chemoattractants CXCL1 and CXCL2, reflecting the specificity of the response. The reduction in TNF- was accompanied by a significant increase in soluble receptors, TNF-SRI (159 pg/ml vs 206 pg/ml) and TNF-SRII (1366 pg/m vs 2695 pg/ml). In conclusion, pulmonary LPS tolerance results in a specific reduction in TNF- expression, while the neutrophilic response is unaffected. This response may be a mechanism to limit tissue damage by reducing TNF- levels, while still maintaining the antimicrobial capacity of the lung.

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 Grant R01 ES013528.

² Address correspondence and reprint requests to Dr. Daniel G. Remick, 670 Albany Street, Room 407, Boston, MA 02118. E-mail address: remickd{at}bu.edu

³ Abbreviations used in this paper: BAL, bronchoalveolar lavage; LAL, Limulus amoebocyte lysate; MPO, myeloperoxidase; IRAK, IL receptor-associated kinase.

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