Chronic Alcohol Exposure Enhances Lipopolysaccharide-Induced Lung Injury in Mice: Potential Role of Systemic Tumor Necrosis Factor-Alpha

Abstract

Background It is well known that liver and lung injury can occur simultaneously during severe inflammation (e.g. multiple organ failure). However, whether these are parallel or interdependent (i.e. liver:lung axis) mechanisms is unclear. Previous studies have shown that chronic ethanol consumption greatly increases mortality in the setting of sepsis-induced acute lung injury (ALI). The potential contribution of subclinical liver disease in driving this effect of Ethanol on the lung remains unknown. Therefore, the purpose of this study was to characterize the impact of chronic Ethanol exposure on concomitant liver and lung injury. Methods Male mice were exposed to ethanol-containing Lieber-DeCarli diet or pair-fed control diet for 6 weeks. Some animals were administered lipopolysaccharide (LPS) 4 or 24 hours prior to sacrifice to mimic sepsis-induced ALI. Some animals received the TNFα blocking drug, etanercept, for the duration of alcohol exposure. The expression of cytokine mRNA in lung and liver tissue was determined by qPCR. Cytokine levels in the bronchoalveolar lavage fluid (BALF) and plasma were determined by Luminex assay. Results As expected, the combination of Ethanol and LPS caused liver injury, as indicated by significantly increased levels of the transaminases ALT/AST in the plasma and by changes in liver histology. In the lung, Ethanol preexposure enhanced pulmonary inflammation and alveolar hemorrhage caused by LPS. These changes corresponded with unique alterations in the expression of pro-inflammatory cytokines in the liver (i.e TNFα) and lung (i.e. MIP-2, KC). Systemic depletion of TNFα (etanercept) blunted injury and the increase in MIP-2 and KC caused by the combination of ethanol and LPS in the lung. Conclusions Chronic Ethanol preexposure enhanced both liver and lung injury caused by LPS. Enhanced organ injury corresponded with unique changes in the pro-inflammatory cytokine expression profiles in the liver and the lung.

The hepatic “matrisome” responds dynamically to injury: Characterization of transitional changes to the extracellular matrix in mice

“…Male (8 weeks old) C57BL6/J mice were purchased from The Jackson Laboratory. Animals were given alcohol‐containing Lieber DeCarli diet ad libitum or pair‐fed isocaloric (maltose‐dextrin) control diet . After 6 weeks of feeding, animals were injected with either lipopolysaccharide (LPS; Escherichia coli ; 10 mg/kg intraperitoneally; Sigma‐Aldrich) or vehicle (saline) and euthanized 24 hours later …”

Modulation of innate and adaptive immune responses by arabinoxylans

“…LPS binds to the LPS Binding Protein (LBP) in serum, before being transferred to CD14 and then to MD2, which is associated with TLR4 (Ryu et al, ). The receptor complex then promotes secretion of NO and proinflammatory cytokines such as TNFα and IL‐8 in monocytes and macrophages (Johnson, Brunn, Kodaira, & Platt, ; Lee, Jeong, Sung, & Kim, ; Massey et al, ; Miller et al, ; Termeer et al, ).…”

Novel insight into the liver-lung axis in alcohol-enhanced acute lung injury.

“…In the setting of chronic alcohol exposure, ethanol feeding enhances glutathione depletion and oxidative stress in a rat model of endotoxemia-induced ALI (4,28). Additionally, this group recently characterized the effects of chronic ethanol pre-exposure on endotoxemiainduced ALI (35). Therefore, experimental endotoxemia with chronic ethanol pre-…”

“…In rats and mice, the Lieber-DeCarli liquid diet produces hepatic steatosis, mild elevations in plasma transaminases, and some necroinflammatory changes in the liver. In the lung, chronic alcohol exposure via ethanol containing liquid diet depletes glutathione levels (76), causes remodeling of the ECM (62), causes mitochondrial dysfunction (77), and sensitizes the lung to endotoxemia-induced ALI (35).…”

“…In a more recent study from the Arteel group, mice were exposed to chronic ethanol on the Lieber DeCarli liquid diet for six weeks, followed by intraperitoneal injection of LPS to produce endotoxemia-induced ALI (35). The differential effects on cytokine expression in systemic circulation and locally in the lung (i.e., in the BALF) were examined.…”