This R01 application in response to NIAAA PA-12-025 is to investigate the mechanism by which alcohol exposure enhances post burn pathogenesis. Studies have shown that patients who are intoxicated at the time of burn injury are more susceptible to infection and exhibit significantly higher morbidity and mortality compared to burn patients who are not intoxicated at the time of injury. The mechanism by which ethanol enhances post burn pathogenesis remains largely unclear. Gut is the major reservoir of bacteria within the body; under healthy conditions it maintains a barrier which prevents these bacteria from crossing the intestinal lumen. However, this barrier is compromised following alcohol (ethanol) exposure and burn injury. We found that ethanol intoxication combined with burn injury: 1) suppresses gut associated lymphoid [Peyer's patches (PP) and mesenteric lymph nodes (MLN)] Th1 (IL-2 and IFN-?), and Th17 (IL-17 and IL-22) cytokine production; 2) increases IL-18 levels in the gut; 3) causes gut tissue damage and leakiness; and 4) increases gut bacterial growth and bacterial translocation within 24 hours after injury. Such an increase in the translocation of bacteria and/or their products may perpetuate the systemic inflammatory response and ultimately contribute to poorer outcomes following ethanol exposure and burn injury. Recent findings indicate that Th17 lymphocytes and their effector cytokines, IL-17 and IL-22, play a crucial role in maintaining mucosal immunity and barrier integrity. Our findings suggest a role for IL-22 and IL-18 in maintaining mucosal integrity The overall goal of our studies is to delineate the mechanism(s) by which ethanol combined with burn injury suppresses Th17 effector cytokines and how this decrease in Th17 cytokines with or without IL-18 contributes to impaired gut immunity and epithelial barrier following alcohol and burn injury. We hypothesize that Ethanol intoxication prior to burn injury results in decreased Th17 effector cytokines, IL-17 and IL-22, which when combined with an increase in IL-18 compromises gut immunity and barrier integrity, facilitating gut bacterial growth and subsequent gut bacterial translocation. The hypothesis will be tested in 3 Aims using a well-established mouse model of ethanol intoxication and burn injury. Studies in Aim 1 will determine the mechanism(s) by which ethanol exposure prior to burn injury results in decreased Th17 cytokines in the intestine.
Aim 2 will investigate the mechanism(s) by which ethanol exposure prior to burn injury results in increased gut leakiness.
Aim 3 will investigate whether IL-22 restoration alone or in combination with IL-18 inhibition normalizes antimicrobial peptides (e.g. Reg3 and Reg3?) and whether this prevents increased gut bacterial load and their translocation following ethanol exposure and burn injury. Overall, our studies will yield novel insights into the mechanism by which ethanol intoxication combined with burn injury disrupts the gut barrier and may help in developing better therapeutic strategies for this patient population.

Public Health Relevance

Gut barrier dysfunction is an important initiator of the systemic inflammatory response syndrome, sepsis and multiple organ failure in critically burn injured patients, as well as in patients with alcohol exposure or suffering from other inflammatory disorders. Our studies will provide valuable insights into the mechanism by which ethanol intoxication combined with burn injury disrupts the gut barrier. Furthermore, studies delineating the potential role of IL-18 and IL-22 in maintaining this barrier will help in developig effective therapy for the treatment of this critically-ill patient population. Additionally, these findings may also be helpful in treating other disease conditions requiring immuno-modulation at mucosal barriers, such as inflammatory bowel disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA015731-09
Application #
8877372
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Jung, Kathy
Project Start
2005-04-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
9
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Loyola University Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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Hulsebus, Holly J; Curtis, Brenda J; Molina, Patricia E et al. (2018) Summary of the 2017 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 69:51-56
Hammer, Adam M; Morris, Niya L; Cannon, Abigail R et al. (2017) Interleukin-22 Prevents Microbial Dysbiosis and Promotes Intestinal Barrier Regeneration Following Acute Injury. Shock 48:657-665
Morris, Niya L; Hammer, Adam M; Cannon, Abigail R et al. (2017) Dysregulation of microRNA biogenesis in the small intestine after ethanol and burn injury. Biochim Biophys Acta Mol Basis Dis 1863:2645-2653
van Langeveld, Ilse; Gagnon, Robin C; Conrad, Peggie F et al. (2017) Multiple-Drug Resistance in Burn Patients: A Retrospective Study on the Impact of Antibiotic Resistance on Survival and Length of Stay. J Burn Care Res 38:99-105
Cannon, Abigail R; Akhtar, Suhail; Hammer, Adam M et al. (2016) Effects of Mesalamine Treatment on Gut Barrier Integrity After Burn Injury. J Burn Care Res 37:283-92
Cannon, Abigail R; Morris, Niya L; Hammer, Adam M et al. (2016) Alcohol and inflammatory responses: Highlights of the 2015 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 54:73-7
Hammer, Adam M; Khan, Omair M; Morris, Niya L et al. (2016) The Effects of Alcohol Intoxication and Burn Injury on the Expression of Claudins and Mucins in the Small and Large Intestines. Shock 45:73-81
Morris, Niya L; Li, Xiaoling; Earley, Zachary M et al. (2015) Regional variation in expression of pro-inflammatory mediators in the intestine following a combined insult of alcohol and burn injury. Alcohol 49:507-11
Hammer, Adam M; Morris, Niya L; Cannon, Abigail R et al. (2015) Summary of the 2014 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 49:767-72

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