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MD-2–Dependent Pulmonary Immune Responses to Inhaled Lipooligosaccharides

Effect of Acylation State

Suzana Haina^1,2, Jerrold P. Weiss^2,3, Paul B. McCray, Jr.^2–4, Katarina Kulhankova^1,2 and Peter S. Thorne^1,2

¹ Department of Occupational and Environmental Health, ² Environmental Health Sciences Research Center, ³ Department of Microbiology and the Inflammation Program, and ⁴ Department of Pediatrics, The University of Iowa, Iowa City, Iowa

Correspondence and requests for reprints should be addressed to Peter S. Thorne, Ph.D., Environmental Health Sciences Research Center, The University of Iowa, 100 Oakdale Campus, 176 IREH, Iowa City, IA 52242-5000. E-mail: peter-thorne{at}uiowa.edu

Endotoxins represent one of the most potent classes of microbial immunoactive components that can cause pulmonary inflammation. The aim of this study was to compare the inflammatory potency of two types of Neisseria meningitidis endotoxins (lipooligosaccharides) in lungs: wild type (hexaacylated, LOS^wt) and mutant type (pentaacylated, LOS^msbB), and to determine the importance of MD-2 in endotoxin responses in lungs in vivo. Endotoxin-normoresponsive mice (BALB/c) were exposed to selected doses of penta- and hexaacylated lipooligosaccharides (LOS) by nasal aspiration. Cellular and cytokine/chemokine inflammatory responses in bronchoalveolar lavage were measured at 1-, 4-, 8-, 16-, 24-, and 48-hour time points. MD-2–null mice were exposed to one dose of hexaacylated LOS and inflammatory responses were measured after 4 and 24 hours. Inhalation of hexaacylated LOS resulted in strong inflammatory responses, while pentaacylated LOS was much less potent in inducing increases of neutrophils, TNF-, macrophage inflammatory protein-1, IL-6, granulocyte colony-stimulating factor, and IL-1β concentration in bronchoalveolar lavage. Similar kinetics of inflammatory responses in lungs were found in both types of endotoxin exposures. Inhalation of hexaacylated LOS in MD-2–null mice resulted in significantly lower numbers of neutrophils in bronchoalveolar lavage than in normoresponsive mice. Markedly lower inflammatory potency of pentaacylated LOS was observed compared with hexaacylated LOS. Hyporesponsiveness in MD-2–null mice after nasal aspiration of wild-type LOS indicate its essential role in airway responsiveness to endotoxin.

Key Words: endotoxin • lipooligosaccharide • inhalation • pulmonary inflammation

CLINICAL RELEVANCE Alteration of fatty acyl chains within lipid A markedly affects inflammatory potency in vivo by impairing Toll-like receptor 4 activation by endotoxin:MD-2 complexes. Blunted airway responses to inhaled endotoxin in MD-2– null mice demonstrates the essential role of MD-2.