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Pulmonary and Systemic Endotoxin Tolerance in Preterm Fetal Sheep Exposed to Chorioamnionitis¹

Suhas G. Kallapur^2,*, Alan H. Jobe^*, Molly K. Ball^*, Ilias Nitsos, Timothy J. M. Moss, Noah H. Hillman^*, John P. Newnham and Boris W. Kramer^,

^* Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229; School of Women’s and Infants’ Health, University of Western Australia, Perth, Australia; University Hospital, Maastricht, The Netherlands; and University Children’s Hospital, Würzburg, Germany

In a model of human chorioamnionitis, fetal sheep exposed to a single injection, but not repeated injections, of intra-amniotic endotoxin develop lung injury responses. We hypothesized that repeated exposure to intra-amniotic endotoxin induces endotoxin tolerance. Fetal sheep were given intra-amniotic injections of saline (control) or Escherichia coli LPS O55:B5 (10 mg) either 2 days (2-day group, single exposure), 7 days (7-day group, single exposure), or 2 plus 7 days (2- and 7-day repeat exposure) before preterm delivery at 124 days gestation (term = 150 days). Endotoxin responses were assessed in vivo in the lung and liver, and in vitro in monocytes from the blood and the lung. Compared with the single 2-day LPS exposure group, the (2 plus 7 days) repeat LPS-exposed lambs had: 1) decreased lung neutrophil and monocyte inducible NO synthase (NOSII) expression, and 2) decreased lung cytokine and liver serum amyloid A3 mRNA expression. In the lung, serum amyloid A3 mRNA expression decreased in the airway epithelial cells but not in the lung inflammatory cells. Unlike the single 7-day LPS exposure group, peripheral blood and lung monocytes from the repeat-LPS group did not increase IL-6 secretion or hydrogen peroxide production in response to in vitro LPS. Compared with controls, TLR4 expression did not change but IL-1R-associated kinase M expression increased in the monocytes from repeat LPS-exposed lambs. These results are consistent with the novel finding of endotoxin tolerance in preterm fetal lungs exposed to intra-amniotic LPS. The findings have implications for preterm infants exposed to chorioamnionitis for both responses to lung injury and postnatal nosocomial infections.

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 K08 HL 70711 (to S.G.K.), AI-069716 and HL-65397 (to A.H.J.), Grant A-27 of the Interdisciplinary Center for Clinical Research, University of Wurzburg/Germany (to B.W.K.), and CDA-303261 from the National Health and Medical Research Council, Australia (to T.J.M.M.).

² Address correspondence and reprint requests to Dr. Suhas G. Kallapur, Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229-3039. E-mail address: suhas.kallapur{at}cchmc.org

³ Abbreviations used in this paper: FIRS, fetal inflammatory response syndrome; BALF, bronchoalveolar fluid; LBP, LPS-binding protein; SAA3, serum amyloid A3; iNOS, inducible NO synthase; IRAK, IL-1R-associated kinase.

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