Impaired respiratory function and heightened pulmonary inflammation in episodic binge ethanol intoxication and burn injury

Abstract

Clinical data indicate that cutaneous burn injuries covering greater than ten percent total body surface area are associated with significant morbidity and mortality, where pulmonary complications, including acute respiratory distress syndrome (ARDS), contribute to nearly half of all patient deaths. Approximately 50% of burn patients are intoxicated at the time of hospital admission, which increases days on ventilators by three-fold, and doubles length of hospital admittance, compared to non-intoxicated burn patients. The most common drinking pattern in the United States is binge drinking, where one rapidly consumes alcoholic beverages (4 for women, 5 for men) in 2 hours and an estimated 38 million Americans binge drink, often several times per month. Experimental data demonstrate a single binge ethanol exposure prior to scald injury, impairs innate and adaptive immune responses, thereby enhancing infection susceptibility and amplifying pulmonary inflammation, neutrophil infiltration, and edema, and is associated with increased mortality. Since these characteristics are similar to those observed in ARDS burn patients, our study objective was to determine whether ethanol intoxication and burn injury and the subsequent pulmonary congestion affects physiological parameters of lung function using non-invasive and unrestrained plethysmography in a murine model system. Furthermore, to mirror young adult binge drinking patterns, and to determine the effect of multiple ethanol exposures on pulmonary inflammation, we utilized an episodic binge ethanol exposure regimen, where mice were exposed to ethanol for a total of 6 days (3 days ethanol, 4 days rest, 3 days ethanol) prior to burn injury. Our analyses demonstrate mice exposed to episodic binge ethanol and burn injury have higher mortality, increased pulmonary congestion and neutrophil infiltration, elevated neutrophil chemoattractants, and respiratory dysfunction, compared to burn or ethanol intoxication alone. Overall, our study identifies plethysmography as a useful tool for characterizing respiratory function in a murine burn model and for future identification of therapeutic compounds capable of restoring pulmonary functionality.

Alcohol, aging, and innate immunity

“…However, those are the minority of studies, and the discrepancies likely reflect the difference in pathogen-and injury-mediated signals driving neutrophil migration. Binge alcohol consumption impairs neutrophil recruitment to sites of infection in mice and humans; nevertheless, in some cases, the neutrophils remain at, and/or continue to be recruited to, inflammatory sites longer in rodents given alcohol compared with controls, leading to prolonged inflammation and tissue damage [119][120][121][122][123][124][125][126][127][128][129][130]. Reduction in surface expression of critical integrins (e.g., CD11b/c and CD18) or their ligands on endothelial cells (e.g., ICAM-1) might contribute to the altered ability of neutrophils to enter tissues after alcohol ingestion [131][132][133][134][135][136] because of the importance of these receptors for neutrophil migration [137].…”

Kupffer Cell p38 Mitogen-Activated Protein Kinase Signaling Drives Postburn Hepatic Damage and Pulmonary Inflammation When Alcohol Intoxication Precedes Burn Injury

“…ARDS is characterized by inflammation and edema in the lung parenchyma leading to impaired gas exchange which is exacerbated when alcohol precedes burn (11, 13, 43, 44). The degree of reduction in pulmonary inflammation observed with p38i treatment matches the level of reduction found in studies of IL-6 deficient mice undergoing the same combined injury (11), suggesting the pulmonary benefit in p38i-treated animals may be related to decreased IL-6 levels.…”

Effects of Multiday Ethanol Intoxication on Postburn Inflammation, Lung Function, and Alveolar Macrophage Phenotype

“…(14). We previously demonstrated that mice subjected to our multi-day episodic binge ethanol treatment paradigm, modeling college student drinking behavior, had increased pulmonary congestion and neutrophil infiltration, elevated lung levels of neutrophil chemoattractants, and impaired respiratory function, when compared to burn injury alone (11). In addition, survival studies showed that multi-day ethanol treatment in the absence of injury was non-lethal, that mice exposed to multi-day binge ethanol prior to burn had 48% survival at 7-days post burn, whereas mice exposed to burn alone had 84% survival.…”

“…Almost immediately after burn injury, local and systemic release of pro-inflammatory molecules, referred to the "cytokine storm," causes damage to the delicate alveolar architecture, which is compounded by excessive neutrophil infiltration and retention in the interstitium, and extracellular fluid accumulation, which is worsened when ethanol intoxication precedes injury (10,11). The pulmonary inflammatory response to distal burn is characterized by the release of pro-inflammatory and chemotactic molecules, leukocyte infiltration, oxidative stress, and extracellular fluid accumulation, yet the underlying pathophysiological mechanisms remain largely undescribed, and even less is known regarding the mechanism(s) by which alcohol intoxication augments this response.…”