The overall objective of the proposed studies is to define the mechanism by which the pulmonary consequences following burn injury are exacerbated by ethanol exposure. Nearly 100,000 people each year are admitted to hospitals due to burn injury and about half of those patients are reported to have been drinking ethanol. Ethanol exposure is not only a risk factor for the events that lead up to the fire-related accidents, but also leads to increased morbidity and mortality among burned patients. The lung is a critical organ, which is particularly sensitive to remote injury. This is, in part, because of the organ's extensive vascular bed and delicate alveolar architecture. Acute lung injury results from the overproduction of pro-inflammatory cytokines, which are generated both systemically and locally (in the lung) in response to injury, such as burn, and is amplified if alcohol is present at the time of injury. We hypothesize that the complications which arise in ethanol-exposed individuals who sustain burn injury are triggered by an overexuberant pulmonary inflammatory response. Herein, we propose to employ both in vivo and in vitro approaches to determine the mechanism(s) responsible for the increased magnitude and duration of pulmonary pathology in burn patients with or without prior ethanol consumption, which are paralleled in our well established murine model of acute ethanol exposure and burn injury. Additionally, we plan to define the roles of key pro-inflammatory and fibrogenic cytokines produced locally and systemically during the early and later post-burn period. We will examine the cellular sources of these factors to determine the extent to which the alveolar macrophage dictates the outcome by virtue of its cytokine production capacity. Finally, we plan to exploit our earlier observation that both systemic and organ-specific inflammatory responses seen after ethanol and burn injury can be ameliorated following systemic treatment with anti-inflammatory regimens, including 17?-estradiol. In the proposed studies, we will test whether this treatment will reduce the pulmonary inflammation seen in mice given the combined insult of ethanol exposure followed by burn injury, relative to either insult alone. It is anticipated that these studies will provide valuable information, which can be used to develop more efficacious therapies for the treatment of ethanol-exposed, burn patients.

Public Health Relevance

In the United States, injury remains the primary cause of death during the first four decades of life, outnumbering all other causes of death, including heart disease and cancer, and accounts for millions of disabling injuries per year and an annual cost of over $130 billion. The importance of ethanol as a complicating factor regarding injury is underscored by the finding that up to 50% of burn patients have detectable levels of ethanol in their circulation at the time of admission to the hospital. These patients, the majority of whom are not chronic alcoholics, but rather consumed alcohol on an acute or binge basis, suffer from increased morbidity and mortality compared with that of non-alcohol-consuming subjects with similar injuries.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Jung, Kathy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Loyola University Chicago
Schools of Medicine
United States
Zip Code
Chen, Michael M; O'Halloran, Eileen B; Ippolito, Jill A et al. (2015) Alcohol potentiates postburn remote organ damage through shifts in fluid compartments mediated by bradykinin. Shock 43:80-4
Chen, Michael M; Zahs, Anita; Brown, Mary M et al. (2014) An alteration of the gut-liver axis drives pulmonary inflammation after intoxication and burn injury in mice. Am J Physiol Gastrointest Liver Physiol 307:G711-8
Curtis, Brenda J; Hlavin, Sara; Brubaker, Aleah L et al. (2014) Episodic binge ethanol exposure impairs murine macrophage infiltration and delays wound closure by promoting defects in early innate immune responses. Alcohol Clin Exp Res 38:1347-55
Lowery, Erin M; Kuhlmann, Erica A; Mahoney, Erin L et al. (2014) Heavy alcohol use in lung donors increases the risk for primary graft dysfunction. Alcohol Clin Exp Res 38:2853-61
Zahs, Anita; Bird, Melanie D; Ramirez, Luis et al. (2013) Anti-IL-6 antibody treatment but not IL-6 knockout improves intestinal barrier function and reduces inflammation after binge ethanol exposure and burn injury. Shock 39:373-9
Davis, Christopher S; Janus, Scott E; Mosier, Michael J et al. (2013) Inhalation injury severity and systemic immune perturbations in burned adults. Ann Surg 257:1137-46
Davis, Christopher S; Esposito, Thomas J; Palladino-Davis, Anna G et al. (2013) Implications of alcohol intoxication at the time of burn and smoke inhalation injury: an epidemiologic and clinical analysis. J Burn Care Res 34:120-6
Curtis, Brenda J; Zahs, Anita; Kovacs, Elizabeth J (2013) Epigenetic targets for reversing immune defects caused by alcohol exposure. Alcohol Res 35:97-113
Chen, Michael M; Bird, Melanie D; Zahs, Anita et al. (2013) Pulmonary inflammation after ethanol exposure and burn injury is attenuated in the absence of IL-6. Alcohol 47:223-9
Baker, Todd A; Davis, Christopher S; Bach 4th, Harold H et al. (2012) Ubiquitin and stromal cell-derived factor-1* in bronchoalveolar lavage fluid after burn and inhalation injury. J Burn Care Res 33:57-64

Showing the most recent 10 out of 69 publications