This is the renewal of a grant entitled """"""""Aging, Macrophage Mediators, and Burn Injury"""""""" (R01 AG18859) which focuses on the mechanisms by which advanced age alters macrophage phenotype and function. The overall goal of the renewal application is to gain new knowledge about how the inflammatory milieu of aged mice is generated and how it predisposes the aged to aberrant pulmonary and systemic responses after traumatic injury. We know from clinical and experimental evidence that even in the absence of injury, healthy aged subjects have an elevated basal inflammatory state, referred to as """"""""inflamm-aging."""""""" Moreover, we believe that inflamm-aging is caused by the release of bacterial products from intestinal lumen and that the continuous exposure to these products, as well as low level of inflammatory cytokines, tumor necrosis factor ?(TNF?), interleukin-1? (IL-1?) and interleukin-6 (IL-6), causes a shift in alveolar macrophages to the M2 anti-inflammatory phenotype. A high level of M2 cells in the lungs would render the host unable to combat a pulmonary infectious challenge. We recently reported that after a moderate size scale burn injury, aged mice have greater accumulation of neutrophils in the lung and more edema than their younger counterparts. New and exciting preliminary data reveal that after burn injury alveolar macrophages collected from young mice exhibit an M2 shift, presumably to help resolve inflammation. In contrast, after burn injury, alveolar macrophages from aged mice have a reduced M2 phenotype, which is markedly lower than that of cells obtained from sham injured aged mice. This reduction in M2 cells would allow lung inflammation to persist. From these pieces of evidence, we hypothesize that in the absence of injury alveolar macrophages from aged mice exhibit an M2 phenotype because of the continuous barrage of bacterial products which are elevated as a result of a breach in the integrity of the intestinal epithelial barrier. Moreover, the elevated intestinal damage seen in aged burn-injured mice exacerbates and prolongs post-burn pulmonary inflammation which, in turn, reduces lung function. To test this hypothesis, in Aim 1, we will first determine if advanced age alters the M1/M2 polarization in the lungs of mice in the absence of injury. We will then go on to examine the impact of burn injury on macrophage phenotype. Next, in Aim 2, we will use adoptive transfer and macrophage specific knockout mice to investigate mechanisms by which advanced age alters alveolar macrophage function.
In Aim 3, we will examine whether alterations in intestinal permeability after burn injury are more extensive in aged mice and account for the prolonged inflammatory response in the lungs. Finally, we will determine if restoring intestinal barrier integrity and wil reduce pulmonary inflammation and improve lung function. Taken together, these studies will expand on the limited knowledge of how advanced age alters alveolar macrophage function and whether therapeutic interventions targeting the lung and gut can be used therapeutically for the treatment of patients with burn and other critical illnesses.

Public Health Relevance

Advanced age is an independent risk factor for mortality after burn injury. While the survival of burn patients over the age of 65 has improved over the last few decades, clinical outcomes are still very poor, in part, because the elderly are unable to combat infectious challenges, like respiratory infections, which are common complications of traumatic injury. The proposed studies will focus on the alveolar macrophage, a cell capable of both initiating and resolving pulmonary inflammation, and examine how a breach in the integrity of the intestinal epithelium can shift macrophage phenotype allowing lung inflammation to continue unchecked. Novel therapeutic interventions will test whether improving intestinal barrier function will reduce lung inflammation and restore pulmonary function. Our findings may also be helpful in treating other inflammatory conditions in the aged, ranging from inflammatory bowel disease to community acquired pneumonia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG018859-11A1
Application #
8760197
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Fuldner, Rebecca A
Project Start
2001-02-01
Project End
2019-03-31
Budget Start
2014-08-15
Budget End
2015-03-31
Support Year
11
Fiscal Year
2014
Total Cost
$371,049
Indirect Cost
$125,321
Name
Loyola University Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Afshar, Majid; Burnham, Ellen L; Joyce, Cara et al. (2018) Injury Characteristics and von Willebrand Factor for the Prediction of Acute Respiratory Distress Syndrome in Patients With Burn Injury: Development and Internal Validation. Ann Surg :
Frankel, John H; Boe, Devin M; Albright, Joslyn M et al. (2018) Age-related immune responses after burn and inhalation injury are associated with altered clinical outcomes. Exp Gerontol 105:78-86
Curtis, Brenda J; Boe, Devin M; Shults, Jill A et al. (2018) Effects of Multi-Day Ethanol Intoxication on Post-Burn Inflammation, Lung Function, and Alveolar Macrophage Phenotype. Shock :
Boule, Lisbeth A; Ju, Cynthia; Agudelo, Marisela et al. (2018) Summary of the 2016 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 66:35-43
Chen, Michael M; Carter, Stewart R; Curtis, Brenda J et al. (2017) Alcohol Modulation of the Postburn Hepatic Response. J Burn Care Res 38:e144-e157
Kovacs, Elizabeth J; Boe, Devin M; Boule, Lisbeth A et al. (2017) Inflammaging and the Lung. Clin Geriatr Med 33:459-471
Rech, Megan A; Mosier, Michael J; Zelisko, Susan et al. (2017) Comparison of Automated Methods Versus the American Burn Association Sepsis Definition to Identify Sepsis and Sepsis With Organ Dysfunction/Septic Shock in Burn-Injured Adults. J Burn Care Res 38:312-318
Boe, D M; Boule, L A; Kovacs, E J (2017) Innate immune responses in the ageing lung. Clin Exp Immunol 187:16-25
Skloot, Gwen S; Busse, Paula J; Braman, Sidney S et al. (2016) An Official American Thoracic Society Workshop Report: Evaluation and Management of Asthma in the Elderly. Ann Am Thorac Soc 13:2064-2077
Plackett, Timothy P; Deburghraeve, Cory R; Palmer, Jessica L et al. (2016) Effects of Estrogen on Bacterial Clearance and Neutrophil Response After Combined Burn Injury and Wound Infection. J Burn Care Res 37:328-33

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