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Ethanol Exposure Impairs LPS-Induced Pulmonary LIX Expression: Alveolar Epithelial Cell Dysfunction as a Consequence of Acute Intoxication

Authors

  • James E. Walker Jr,

    1. From the Section of Pulmonary and Critical Care Medicine, Department of Medicine (JEW, PZ, SN, KIH), Louisiana State University Health Sciences Center, New Orleans, Louisiana; Louisiana State University Health Sciences Center, Alcohol Research Center (ARO, PZ, GJB, SN, KIH), New Orleans, Louisiana; School of Veterinary Medicine (SJ), Louisiana State University, Baton Rouge, Louisiana; and Department of Physiology (GJB), Louisiana State University Health Sciences Center, New Orleans, Louisiana.
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  • Anthony R. Odden,

    1. From the Section of Pulmonary and Critical Care Medicine, Department of Medicine (JEW, PZ, SN, KIH), Louisiana State University Health Sciences Center, New Orleans, Louisiana; Louisiana State University Health Sciences Center, Alcohol Research Center (ARO, PZ, GJB, SN, KIH), New Orleans, Louisiana; School of Veterinary Medicine (SJ), Louisiana State University, Baton Rouge, Louisiana; and Department of Physiology (GJB), Louisiana State University Health Sciences Center, New Orleans, Louisiana.
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  • Samithamby Jeyaseelan,

    1. From the Section of Pulmonary and Critical Care Medicine, Department of Medicine (JEW, PZ, SN, KIH), Louisiana State University Health Sciences Center, New Orleans, Louisiana; Louisiana State University Health Sciences Center, Alcohol Research Center (ARO, PZ, GJB, SN, KIH), New Orleans, Louisiana; School of Veterinary Medicine (SJ), Louisiana State University, Baton Rouge, Louisiana; and Department of Physiology (GJB), Louisiana State University Health Sciences Center, New Orleans, Louisiana.
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  • Ping Zhang,

    1. From the Section of Pulmonary and Critical Care Medicine, Department of Medicine (JEW, PZ, SN, KIH), Louisiana State University Health Sciences Center, New Orleans, Louisiana; Louisiana State University Health Sciences Center, Alcohol Research Center (ARO, PZ, GJB, SN, KIH), New Orleans, Louisiana; School of Veterinary Medicine (SJ), Louisiana State University, Baton Rouge, Louisiana; and Department of Physiology (GJB), Louisiana State University Health Sciences Center, New Orleans, Louisiana.
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  • Gregory J. Bagby,

    1. From the Section of Pulmonary and Critical Care Medicine, Department of Medicine (JEW, PZ, SN, KIH), Louisiana State University Health Sciences Center, New Orleans, Louisiana; Louisiana State University Health Sciences Center, Alcohol Research Center (ARO, PZ, GJB, SN, KIH), New Orleans, Louisiana; School of Veterinary Medicine (SJ), Louisiana State University, Baton Rouge, Louisiana; and Department of Physiology (GJB), Louisiana State University Health Sciences Center, New Orleans, Louisiana.
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  • Steve Nelson,

    1. From the Section of Pulmonary and Critical Care Medicine, Department of Medicine (JEW, PZ, SN, KIH), Louisiana State University Health Sciences Center, New Orleans, Louisiana; Louisiana State University Health Sciences Center, Alcohol Research Center (ARO, PZ, GJB, SN, KIH), New Orleans, Louisiana; School of Veterinary Medicine (SJ), Louisiana State University, Baton Rouge, Louisiana; and Department of Physiology (GJB), Louisiana State University Health Sciences Center, New Orleans, Louisiana.
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  • Kyle I. Happel

    1. From the Section of Pulmonary and Critical Care Medicine, Department of Medicine (JEW, PZ, SN, KIH), Louisiana State University Health Sciences Center, New Orleans, Louisiana; Louisiana State University Health Sciences Center, Alcohol Research Center (ARO, PZ, GJB, SN, KIH), New Orleans, Louisiana; School of Veterinary Medicine (SJ), Louisiana State University, Baton Rouge, Louisiana; and Department of Physiology (GJB), Louisiana State University Health Sciences Center, New Orleans, Louisiana.
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Reprint requests: Kyle I. Happel, MD, Section of Pulmonary/Critical Care, LSU Health Sciences Center, 1901 Perdido St, Suite 3205, New Orleans, LA 70112; Fax: 504-568-4295; E-mail: khappe@lsuhsc.edu

Abstract

Background:  Alcohol intoxication impairs innate immune responses to bacterial pneumonia, including neutrophil influx. Lipopolysaccharide (LPS)-induced chemokine (LIX or CXCL5) is a recently described chemokine produced by type-II alveolar epithelial (AE2) cells which facilitates neutrophil recruitment. The effect of acute alcohol intoxication on AE2 cell expression of LIX is unknown.

Methods:  C57BL/6 mice were given an intraperitoneal (i.p.) injection of ethanol (4 g/kg) or saline 30 minutes prior to intratracheal (i.t.) injection with 10 μg Escherichia coli LPS. In vitro stimulation of primary AE2 cells or murine AE2 cell line MLE-12 was performed with LPS and tumor necrosis factor-alpha (TNF-α).

Results:  LIX protein is readily detectable in the lung but not in plasma following LPS administration, demonstrating “compartmentalization” of this chemokine during pulmonary challenge. In contrast to the CXC chemokines keratinocyte-derived chemokine and macrophage inflammatory protein-2, which are abundantly expressed in both lung tissue and alveolar macrophages, LIX expression is largely confined to the lung parenchyma. Compared to controls, intoxicated animals show a decrease in LIX and neutrophil number in bronchoalveolar lavage fluid following LPS challenge. Ethanol inhibits LIX at the transcriptional level. In vitro studies show that LPS and TNF-α are synergistic in inducing LIX by either primary AE2 or MLE-12 cells. Acute ethanol exposure potently and dose-dependently inhibits LIX expression by AE2 cells. Activation of nuclear factor-κB is critical to LIX expression in MLE-12 cells, and acute ethanol treatment interferes with early activation of this pathway as evidenced by impairing phosphorylation of p65 (RelA). Inhibition of p38 mitogen-activated protein kinase signaling, but not ERK1/2 activity, in MLE-12 cells by acute alcohol is likely an important cause of decreased LIX expression during challenge.

Conclusions:  These data demonstrate direct suppression of AE2 cell innate immune function by ethanol and add to our understanding of the mechanisms by which acute intoxication impairs the lung’s response to microbial challenge.

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