The AAST Research and Education Fund is funding three scholarships for 2017-2018. The scholarship recipients will receive their scholarship plaque at the 76th AAST Annual Meeting in Baltimore, MD and will present their research findings at the 77th Annual Meeting of AAST & Clinical Congress of Acute Care Surgery and 4th World Trauma Congress in San Diego, CA.
Vanessa Nomellini, MD, PhD
Division of Trauma, Surgical Critical Care, and Acute Care Surgery
University of Cincinnati Medical Center
Project Title: “The Role of Sphingosine in the Susceptibility of Pneumonia in the Elderly”
Pulmonary infection from bacterial agents is a leading cause of death for the elderly. This high susceptibility to infection is not only the result of increased medical comorbidities, but also from aging itself. With increasing antibiotic resistance, exploiting alternative means to manage infection in this population is therefore crucial. Sphingosine and ceramide are important molecules of infection control within the multiple lines of antibacterial defense in a healthy lung. Data from our group show that sphingosine expression in healthy airways is associated with very efficient killing of Pseudomonas aeruginosa. In contrast, sphingosine is significantly decreased in the upper airway epithelial cells of older mice, which is a similar observation in humans with cystic fibrosis. After pulmonary infection, bacterial clearance in the lungs of aged mice is significantly decreased compared to young mice. However, when mice are pre-treated with sphingosine, then infected with Pseudomonas, bacterial clearance in the lungs of aged mice is equivalent to that of the young. These data show that sphingosine in the lung is an important component of the antibacterial barrier and a novel mechanism to prevent pulmonary infection, particularly in the elderly. This project further investigates the mechanism of this imbalance between ceramide and sphingosine in the lungs of young and aged mice. We hypothesize that differential activity of the enzymes that catalyze the formation of these sphingolipids is the basis for these observations and that administration of inhaled sphingosine can be an effective therapy for protecting aged mice from pulmonary infection. With the results of this study, we will be able to develop future investigations involving the efficacy of sphingosine as a therapeutic agent against pulmonary infection in humans.
Jonathan Wisler, MD, MS
Department of Surgery, Division of Trauma, Critical Care, and Burns
The Ohio State University Medical Center
Project Title: “Target Aberrant Epigenetic Events in the Treatment of Sepsis”
Each year, sepsis affects over 750,000 individuals with a high mortality rate of 30-40 percent. Despite advances in care, therapeutic options are limited. Key to improved outcomes is understanding the critical mechanistic events underlying the syndrome. The immune response to sepsis involves pro- and anti-inflammatory components, and the magnitude of each
component can negatively affect outcomes in sepsis. The regulation of these opposing immune responses is not well understood, but recent evidence suggests epigenetic changes occur that may be responsible for some of the changes seen. Interestingly, sepsis plasma microvesicles (MVs) produced from different cell types are key mediators of the immune response, having procoagulant activity and causing endothelial cell damage in vitro. Our preliminary data identified that DNA Methyltransferase (DNMT) mRNA is present in MVs of patients with sepsis which when transferred to naïve monocytes results in decreased TNF-α production ex vivo due to promoter methylation. These DNMT mRNAs are not present in the circulating MVs of healthy individuals.
Our intent for this application is to transform the current paradigm for sepsis treatment. We hypothesize that in sepsis, circulating MVs deliver a cargo of epigenetic modifiers, specifically DNMTs that regulate the methylation of genes important to the inflammatory response. Thus, our long-term goals of this proposal are to understand the role of plasma MVs, epigenetic factors, and how modulation of these factors during sepsis alters outcomes. The overall objective is to use plasma MVs and the contained DNA methytransferases as a diagnostic tool and therapeutic target in the management of sepsis and post-sepsis immunosuppression. We will also examine the novel and innovative use of MVs derived from healthy individuals as replenishment therapy for sepsis. Using the preclinical models we have designed in this study, we anticipate that our studies will identify novel therapies and targets for treating sepsis.
Samuel Pierce Mandell, MD, MPH
Assistant Professor of Surgery
University of Washington, Harborview Medical Center
Project Title: “Optical Coherence Tomography to Predict Burn Wound Healing”
The objective measurement of tissue injury in burns remains elusive. Predictions of wound healing remain in the realm of subjective “expert opinion.” Clinical assessment is the most common method of evaluating burns in the United States, but it is only 60–75 percent accurate. It is particularly inaccurate for “indeterminate” burns that are neither clearly superficial nor full thickness. It is thought that most commonly, clinicians overestimate the depth of the burn resulting in early excision and grafting of tissue that might have healed on its own. Other patients may go weeks with painful wound care only to find that they require an operation. Optical coherence tomography (OCT) is a real-time, non-invasive imaging technique that produces cross-sectional morphological images of tissue microstructures in vivo with a micron-level imaging resolution analogous to histology. In addition, by analyzing OCT spectral interferograms, ultrahigh-sensitive optical micro angiography (OMAG) provides a 3-D blood perfusion map that allows imaging of an intact microvasculature network down to the capillary level. Our goal is to evaluate the use of this technology to predict burn wound healing. This has the potential to prevent unnecessary surgery as well as prolonged painful wound care.