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

• Published in: Alcoholism, clinical and experimental research Vol. 33; no. 2; pp. 357 - 365
• Main Authors: Walker Jr, James E., Odden, Anthony R., Jeyaseelan, Samithamby, Zhang, Ping, Bagby, Gregory J., Nelson, Steve, Happel, Kyle I.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-02-2009; Wiley
• Subjects: Alcohol; Alcoholic Intoxication - metabolism; Alcoholic Intoxication - pathology; Alcoholism and acute alcohol poisoning; Alveolar Epithelium; Animals; Biological and medical sciences; Bronchoalveolar Lavage Fluid - cytology; Cell Separation; Cells, Cultured; Central Nervous System Depressants - administration & dosage; Central Nervous System Depressants - blood; Central Nervous System Depressants - toxicity; Chemokine CXCL5 - biosynthesis; Chemokine CXCL5 - genetics; Chemokines; CXCL5; Escherichia coli; Ethanol - administration & dosage; Ethanol - blood; Ethanol - toxicity; Extracellular Signal-Regulated MAP Kinases - metabolism; Injections, Spinal; Lipopolysaccharide; Lipopolysaccharides - pharmacology; LIX; Lung; Lung - drug effects; Lung - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Neutrophils - drug effects; Neutrophils - metabolism; NF-κB; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - metabolism; Pulmonary Alveoli - pathology; Reverse Transcriptase Polymerase Chain Reaction; Toxicology; Transcription Factor RelA - metabolism; CXCL5 chemokine; Ethanol; Acute; Lung; Alcohol; Exposure; Epithelium; Respiratory system; In vitro; CXCL5; Alcoholic beverage; NF-κB; Dysfunction; Alveolar Epithelium; Lipopolysaccharide; Epithelial cell; Poisoning; LIX; Transcription factor NFκB; Chemokines
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/j.1530-0277.2008.00844.x

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.