Veronica L Massey1,2, Lauren G Poole1,2, Deanna L Siow1,2, Edilson Torres3, Nikole L Warner4, Robin H Schmidt1,2, Jeffrey D Ritzenthaler3, Jesse Roman3, Gavin E Arteel1,2. 1. Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky. 2. University of Louisville Alcohol Research Center, Louisville, Kentucky. 3. Division of Pulmonary, Critical Care and Sleep Disorders Medicine, Department of Medicine, University of Louisville Health Sciences Center, Louisville, Kentucky. 4. Department of Micriobiology and Immunology, University of Louisville Health Sciences Center, Louisville, Kentucky.
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 (EtOH) 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 EtOH on the lung remains unknown. Therefore, the purpose of this study was to characterize the impact of chronic EtOH exposure on concomitant liver and lung injury. METHODS: Male mice were exposed to EtOH-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 tumor necrosis factor-alpha (TNF-α)-blocking drug, etanercept, for the duration of alcohol exposure. The expression of cytokine mRNA in lung and liver tissue was determined by quantitative PCR. Cytokine levels in the bronchoalveolar lavage fluid and plasma were determined by Luminex assay. RESULTS: As expected, the combination of EtOH and LPS caused liver injury, as indicated by significantly increased levels of the transaminases alanine aminotransferase/aspartate aminotransferase in the plasma and by changes in liver histology. In the lung, EtOH 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., TNF-α) and lung (i.e., macrophage inflammatory protein-2 [MIP-2], keratinocyte chemoattractant [KC]). Systemic depletion of TNF-α (etanercept) blunted injury and the increase in MIP-2 and KC caused by the combination of EtOH and LPS in the lung. CONCLUSIONS: Chronic EtOH 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.
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 (EtOH) 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 EtOH on the lung remains unknown. Therefore, the purpose of this study was to characterize the impact of chronic EtOH exposure on concomitant liver and lung injury. METHODS: Male mice were exposed to EtOH-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 tumor necrosis factor-alpha (TNF-α)-blocking drug, etanercept, for the duration of alcohol exposure. The expression of cytokine mRNA in lung and liver tissue was determined by quantitative PCR. Cytokine levels in the bronchoalveolar lavage fluid and plasma were determined by Luminex assay. RESULTS: As expected, the combination of EtOH and LPS caused liver injury, as indicated by significantly increased levels of the transaminases alanine aminotransferase/aspartate aminotransferase in the plasma and by changes in liver histology. In the lung, EtOH 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., TNF-α) and lung (i.e., macrophage inflammatory protein-2 [MIP-2], keratinocyte chemoattractant [KC]). Systemic depletion of TNF-α (etanercept) blunted injury and the increase in MIP-2 and KC caused by the combination of EtOH and LPS in the lung. CONCLUSIONS: Chronic EtOH 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.
Authors: Pratibha C Joshi; Lisa Applewhite; Jeffrey D Ritzenthaler; Jesse Roman; Alberto L Fernandez; Douglas C Eaton; Lou Ann S Brown; David M Guidot Journal: J Immunol Date: 2005-11-15 Impact factor: 5.422
Authors: Gordon D Rubenfeld; Ellen Caldwell; Eve Peabody; Jim Weaver; Diane P Martin; Margaret Neff; Eric J Stern; Leonard D Hudson Journal: N Engl J Med Date: 2005-10-20 Impact factor: 91.245
Authors: Juliane I Beier; James P Luyendyk; Luping Guo; Claudia von Montfort; Donald E Staunton; Gavin E Arteel Journal: Hepatology Date: 2009-05 Impact factor: 17.425
Authors: Rabih I Bechara; Lou Ann S Brown; Douglas C Eaton; Jesse Roman; David M Guidot Journal: Alcohol Clin Exp Res Date: 2003-06 Impact factor: 3.455
Authors: Lauren G Poole; Veronica L Massey; Deanna L Siow; Edilson Torres-Gonzáles; Nikole L Warner; James P Luyendyk; Jeffrey D Ritzenthaler; Jesse Roman; Gavin E Arteel Journal: Am J Respir Cell Mol Biol Date: 2017-09 Impact factor: 6.914
Authors: Lauren G Poole; Juliane I Beier; Edilson Torres-Gonzales; Connie F Schlueter; Shanice V Hudson; Amanda Artis; Nikole L Warner; Calvin T Nguyen-Ho; Christine E Dolin; Jeffrey D Ritzenthaler; Gary W Hoyle; Jesse Roman; Gavin E Arteel Journal: Alcohol Date: 2018-11-14 Impact factor: 2.405
Authors: Veronica L Massey; Christine E Dolin; Lauren G Poole; Shanice V Hudson; Deanna L Siow; Guy N Brock; Michael L Merchant; Daniel W Wilkey; Gavin E Arteel Journal: Hepatology Date: 2016-12-30 Impact factor: 17.425