This A1 renewal R01 application is submitted in response to PA-12-025 Alcohol impairment of immune function, host defense and tissue homeostasis. The overall goal of the project is to define the mechanism(s) by which alcohol intoxication exacerbates post-burn pulmonary inflammation and renders subjects unable to combat infectious pathogens. Nearly 40,000 people are admitted to hospitals annually in the United States due to burn injury, and about half of those patients are intoxicated at the time of injury. Burn patients who were intoxicated when they sustained their injuries had increased morbidity and mortality compared to burn patients who had not been drinking. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are among the major complications seen in intoxicated burn patients, even in the absence of inhalation injury. Macrophages play a central role in both the initiation and resolution of inflammatory responses in the lung by exhibiting either a pro-inflammatory M1 or an anti-inflammatory M2 phenotype. We hypothesize that alcohol intoxication at the time of burn injury alters lung macrophage phenotype and function and that these cells are responsible for 1) excessive pulmonary inflammation, 2) the inability to combat respiratory pathogens and 3) aberrant lung function to a greater extent than burn injury alone. Moreover, restoring macrophage phenotype will reestablish pulmonary homeostasis and improve lung function. To test this, we will use the clinically relevant mouse binge ethanol intoxication and burn injury model which we have been using in the lab for 18 years.
In Aim 1, we will examine alveolar macrophage initiation and resolution of the pulmonary inflammation after intoxication and burn by selectively depleting alveolar macrophages. We will also deplete alveolar macrophages in wild type, uninjured mice, and then utilize adoptive transfer methodology to replace them with alveolar macrophages from 1) intoxicated mice or 2) IL-6 knockout (KO) mice, prior to injury.
In Aim 2, we will examine the phenotype and function of alveolar macrophages before and after intoxication and burn. We will also test whether pulmonary inflammation can be reduced by replacing alveolar macrophages with those of macrophage-specific arginase 1 KO animals prior to intoxication and burn. Finally, in Aim 3, we will investigate how intoxication alters signaling in alveolar macrophages, focusing on crosstalk between PPAR and STAT3 pathways. In those studies, we will use macrophage-specific PPAR KO and STAT3 KO mice to test whether manipulating macrophage signaling can reduce lung inflammation and improve pulmonary function. Overall, the results of these studies will gain insight into the mechanisms by which alcohol alters alveolar macrophage function and phenotype and how this plays a role in the pulmonary inflammatory response after burn injury. We believe that this work will also aid in the development of therapies for all burn patients, and that these results may also benefit other patient populations, such as those with idiopathic pulmonary fibrosis.

Public Health Relevance

In the United States, traumatic injury remains the leading cause of death during the first four decades of life, outnumbering heart disease and cancer, and it also accounts for millions of disabling injuries at an annual cost of over $130 billion. Approximately 50% of adult burn trauma patients consumed alcohol prior to sustaining their injuries. Both burn and alcohol exposure independently alter the ability of macrophages to function appropriately in their pivotal role to initiate and resolve inflammation, and combining th two insults results in a more dramatic skewing of macrophage function leaving the host susceptible to bacterial pathogens, which is the focus of this proposal. Findings from these studies may also be helpful in treating other disease conditions involving aberrant pulmonary inflammatory responses ranging from asthma to fibrotic disorders as well as inflammatory disorders outside the lung.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM115257-18
Application #
9458215
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
1999-08-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
18
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Surgery
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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