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Defining Mechanisms Induced By Injury That Serve To Enhance Host Defenses Against Infection

Gardner, Jason C.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1382951010

Abstract Details

2013, PhD, University of Cincinnati, Medicine: Pathobiology and Molecular Medicine.
Abstract: Pneumonia is a primary complication and a leading cause of death for burn patients. Conventional antimicrobial strategies to combat pneumonia in burn patients and others have become less effective due to the emergence of multi-resistant organisms. At the inception of these studies, we aimed to develop a mouse model of post thermal injury pneumonia, to interrogate perturbations of pulmonary immune function and to test alternative therapeutic strategies. We found that burn injury induced a surprising paradoxical resistance to pulmonary infection that developed with time after injury. Instead of abandoning the model, we postulated that an understanding of the mechanisms of induced resistance could be exploited for improving strategies for the treatment of pneumonia. Our studies revealed that the protection from infection following thermal injury was dependent on a systemic increase in functionally enhanced neutrophils, which followed a surge in circulating G-CSF. G-CSF stimulation of the marrow resulted in highly specific activation of STAT3 in mature myeloid and myeloid precursors in the bone marrow, and a reprioritization of hematopoiesis, in which myeloid cell production increased at the expense of other lineages. The myeloid shift in the bone marrow and the systemic increase in neutrophils were temporally related to the acquisition of resistance to infection. Finally, we determined that exogenous administration of G-CSF was sufficient to recapitulate the hematopoietic changes and protection from infection. From this study we concluded that the G-CSF STAT3 axis protects the host from post injury pulmonary infection. In parallel experiments, we also explored the hypothesis that keratinocyte growth factor (KGF), which is known to be induced following injury of the skin, plays an important role in burn induced protection. The concept that KGF might be `arming’ cells and enhancing resistance to infection was based in part on prior work from our laboratory demonstrating that KGF augments pulmonary innate immune function. We have found that the absence of KGF in genetically engineered mice blocks post burn resistance to pulmonary infection, and impairs bacterial clearance from the lung. KGF was also found to regulate soluble antimicrobial activity in the lung lining fluid, due in part to enhanced production of antimicrobial collectins, surfactant proteins A and D. We have not yet determined how these collectins are influenced by burn injury. Thermally injured KGF deficient mice develop an excessive increase in circulating neutrophils compared to their wild type counterparts, yet more readily succumb to post burn infection. These data suggest that inflammatory responses are altered in these mice and that protection from infection induced by burn injury is not simply a function of increased neutrophil numbers. Finally, our data, together with in silico evidence of a remarkable degree of identity between the transcriptional programs activated by G-CSF administration and trauma, suggest to us that G-CSF may be the `Eye of the Genomic Storm’ driving the transition towards innate and away from adaptive immune priorities in the injured host.
Francis McCormack, M.D. (Committee Chair)
George Deepe, M.D. (Committee Member)
Daniel Healy, Pharm.D. (Committee Member)
Dennis McGraw, M.D. (Committee Member)
Kathryn Wikenheiser-Brokamp, M.D. Ph.D. (Committee Member)
91 p.
Surgery
Injury; Infection; Lung; Neutrophil; G-CSF; KGF

Recommended Citations

Citations

  • Gardner, J. C. (2013). Defining Mechanisms Induced By Injury That Serve To Enhance Host Defenses Against Infection [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1382951010

    APA Style (7th edition)

  • Gardner, Jason. Defining Mechanisms Induced By Injury That Serve To Enhance Host Defenses Against Infection. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1382951010.

    MLA Style (8th edition)

  • Gardner, Jason. "Defining Mechanisms Induced By Injury That Serve To Enhance Host Defenses Against Infection." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1382951010

    Chicago Manual of Style (17th edition)

ucin1382951010
331
© 2013, some rights reserved.Creative Commons License Defining Mechanisms Induced By Injury That Serve To Enhance Host Defenses Against Infection by Jason C. Gardner is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.