The overall objective of the proposed studies is to determine the mechanism by which the combined insult of radiation exposure and burn injury cause greater acute lung injury (ALI) than either insult alone. 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 radiation injury, and is likely to be amplified after a combined insult. We hypothesize that the complications which arise in radiation-exposed individuals who sustain burn injury are triggered by an overexuberant pulmonary inflammatory response which is triggered by systemic inflammatory mediators. Herein, during the R21 component of this application, we will determine whether there is an increase in the magnitude and duration of pulmonary pathology and greater impairment in function in burn-injured mice who are also subjected to radiation injury relative to animals given either insult alone. This will be accomplished using an established murine model of dorsal scald (burn) injury in combination with sublethal radiation exposure. If we see differences in response to the combined insult, then we will go on to define the roles of key pro-inflammatory and fibrogenic cytokines which are produced locally and systemically during the early and later post-injury period. During the R33 phase, we will explore both the mechanisms responsible for the aberrant pulmonary response, including the cellular sources of these factors and the signaling cascades which turn on their expression in order to determine the extent to which the alveolar macrophage dictates the outcome by virtue of its cytokine production capacity. Additionally, we will determine if therapeutic interventions designed to decrease pulmonary inflammation improve lung pathology using anti-chemokine receptor and anti-adhesion molecule receptor antibodies, as well as if decreasing permeability of critical barriers in the lung and the intestine is beneficial. Taken together, it is anticipated that the proposed experiments will provide valuable information about the mechanisms responsible for the elevated level of tissue damage after the combined injury of radiation and burn. In addition, subsequent experiments will explore therapeutic interventions designed to diminish pulmonary inflammatory responses after injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33AI080528-05
Application #
8307471
Study Section
Special Emphasis Panel (NSS)
Program Officer
Dicarlo-Cohen, Andrea L
Project Start
2008-07-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$354,058
Indirect Cost
$117,230
Name
Loyola University Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Carter, Stewart R; Chen, Michael M; Palmer, Jessica L et al. (2014) Neutrophil Accumulation in the Small Intestine Contributes to Local Tissue Destruction After Combined Radiation and Burn Injury. J Burn Care Res :
Carter, Stewart R; Zahs, Anita; Palmer, Jessica L et al. (2013) Intestinal barrier disruption as a cause of mortality in combined radiation and burn injury. Shock 40:281-9
Palmer, Jessica L; Deburghgraeve, Cory R; Bird, Melanie D et al. (2013) Combined radiation and burn injury results in exaggerated early pulmonary inflammation. Radiat Res 180:276-83
Palmer, Jessica L; Deburghgraeve, Cory R; Bird, Melanie D et al. (2011) Development of a combined radiation and burn injury model. J Burn Care Res 32:317-23