Abstract
Background
Alcohol significantly impairs antioxidant defenses and innate immune function in the
lung and increases matrix metalloproteinase 9 (MMP-9) activity. The receptor for advanced
glycation end products (RAGE) is a well-characterized marker of lung injury that is
cleaved by MMP-9 into soluble RAGE and has not yet been examined in the alcoholic
lung. We hypothesized that chronic alcohol ingestion would impair RAGE signaling via
MMP-9 in the alveolar macrophage and thereby impair innate immune function.
Materials and Methods
Primary alveolar macrophages were isolated from control-fed or alcohol-fed rats. Real-time
polymerase chain reaction (qRT-PCR), Western blotting, and enzyme-linked immunosorbent
assays were performed to evaluate RAGE expression. Silencing of MMP-9 ribonucleic
acid (RNA) in a rat alveolar macrophage cell line was confirmed by qRT-PCR, and immunofluorescence
(IF) was used to assess the association between alcohol, MMP-9, and RAGE. Phagocytosis
was assessed using flow cytometry. Sulforaphane and glutathione were used to assess
the relationship between oxidative stress and RAGE.
Results
RAGE messenger RNA expression was significantly increased in the alveolar macrophages
of alcohol-fed rats, but IF showed that membrane-bound RAGE protein expression was
decreased. Lavage fluid demonstrated increased levels of soluble RAGE (sRAGE). Decreasing
MMP-9 expression using si-MMP-9 abrogated the effects of alcohol on RAGE protein.
Phagocytic function was suppressed by direct RAGE inhibition, and the impairment was
reversed by antioxidant treatment.
Conclusions
Chronic alcohol ingestion reduces RAGE protein expression and increases the amount
of sRAGE in alveolar lavage fluid, likely via cleavage by MMP-9. In addition, it impairs
phagocytic function. Antioxidants restore membrane-bound RAGE and phagocytic function.
Key Indexing Terms
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References
- Alcohol abuse, the alveolar macrophage and pneumonia.Am J Med Sci. 2012; 343: 244-247
- The effect of chronic alcohol abuse on the incidence of ARDS and the severity of the multiple organ dysfunction syndrome in adults with septic shock: an interim and multivariate analysis.Chest. 1999; 116: 97S-98SS
- Alcohol, immunosuppression, and the lung.Proc Am Thorac Soc. 2005; 2: 428-432
- The alcoholic lung: epidemiology, pathophysiology, and potential therapies.Am J Physiol Lung Cell Mol Physiol. 2007; 292: L813-L823
- Zinc supplementation restores PU.1 and Nrf2 nuclear binding in alveolar macrophages and improves redox balance and bacterial clearance in the lungs of alcohol-fed rats.Alcohol Clin Exp Res. 2011; 35: 1519-1528
- Alcohol ingestion disrupts alveolar epithelial barrier function by activation of macrophage-derived transforming growth factor beta1.Respir Res. 2013; 14
- Effect of chronic ethanol ingestion on alveolar type II cell: glutathione and inflammatory mediator-induced apoptosis.Alcohol Clin Exp Res. 2001; 25: 1078-1085
- Advanced glycation end products and their receptor in age-related, non-communicable chronic inflammatory diseases; overview of clinical evidence and potential contributions to disease.Int J Biochem Cell Biol. 2016;
- Advanced glycation end products enhance macrophages polarization into M1 phenotype through activating RAGE/NF-kappaB pathway.Biomed Res Int. 2015; 2015: 732450
- Soluble form of the receptor for advanced glycation end products is a marker of acute lung injury but not of severe sepsis in critically ill patients.Crit Care Med. 2011; 39: 480-488
- Chronic alcohol ingestion exacerbates lung epithelial barrier dysfunction in HIV-1 transgenic rats.Alcohol Clin Exp Res. 2011; 35: 1866-1875
- HMGB1 Contributes to the expression of P-glycoprotein in mouse epileptic brain through toll-like receptor 4 and receptor for advanced glycation end products.PLoS One. 2015; 10: e0140918
- Glutathione attenuates ethanol-induced alveolar macrophage oxidative stress and dysfunction by downregulating NADPH oxidases.Am J Physiol Lung Cell Mol Physiol. 2014; 306: L429-L441
- Alcohol causes alveolar epithelial oxidative stress by inhibiting the nuclear factor (erythroid-derived 2)-like 2-antioxidant response element signaling pathway.Am J Respir Cell Mol Biol. 2013; 48: 511-517
- Ethanol ingestion increases activation of matrix metalloproteinases in rat lungs during acute endotoxemia.Am J Respir Crit Care Med. 1999; 160: 1354-1360
- Alcoholism causes alveolar macrophage zinc deficiency and immune dysfunction.Am J Respir Crit Care Med. 2013; 188: 716-723
- Peroxisome proliferator-activated receptor gamma regulates chronic alcohol-induced alveolar macrophage dysfunction.Am J Respir Cell Mol Biol. 2016; 55: 35-46
- Chronic ethanol ingestion in rats decreases granulocyte-macrophage colony-stimulating factor receptor expression and downstream signaling in the alveolar macrophage.J Immunol. 2005; 175: 6837-6845
- A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease.J Clin Invest. 2012; 122: 1377-1392
- Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury.Am J Respir Crit Care Med. 2006; 173: 1008-1015
Article info
Publication history
Accepted:
December 23,
2017
Received:
May 14,
2017
Footnotes
☆The first 2 authors (BSS, EEE) shared first authorship.
☆☆The authors have no conflicts of interest to disclose.
☆☆Dr. Staitieh was supported by K08AA024512, Dr. Egea and Ms. Amah were supported by T32HL116271, and Dr. Guidot was supported by R01AA017627.
Identification
Copyright
© 2017 Southern Society for Clinical Investigation. Published by All rights reserved.
