People of advanced age (greater than 55 years old) have significantly increased morbidity and mortality after trauma. Since the elderly population is expanding, research into this disease process is increasingly relevant, especially with the escalating economic and health care burdens on our society. Despite decades of promising preclinical and clinical investigations in trauma, our understanding of this entity and why its effects are exacerbated in the elderly remains incomplete, with few therapies demonstrating success in any patient population. Recently, several aspects of innate immunity have been determined to be of vital importance to the young adult immune response, and this response is suboptimal in the aged after severe injury and subsequent infections. Specifically, neutrophils are replaced after inflammation through a process known as 'emergency myelopoiesis.' This occurs after severe injury when bone marrow granulocyte stores are rapidly released, and increased stem cell proliferation and differentiation along myeloid pathways results. Proper differentiation of myeloid cells from stem cells is dependent on activation of nuclear factor kappa B (NF?B), a protein complex that partially controls DNA transcription after stressful stimuli. An appropriate emergency myelopoietic response to inflammation is essential to host survival but appears to be inadequate in the elderly as compared to younger patients. Specifically, we hypothesize that the myelodysplasia associated with aging modifies the emergency myelopoietic response to traumatic injury, resulting in inappropriate differentiation and maturation of myeloid cells, leaving the host susceptible to subsequent infection. We further propose that this failure of emergency myelopoiesis is due to age-associated, chronic activation of NF?B-dependent inflammatory pathways, and a failure of hematopoietic stems cells (LSK populations) after trauma to create functional myeloid populations in a NF?B-dependent manner. Using a novel murine polytrauma (PT) model of murine hemorrhagic shock and injury that better recapitulates the human condition, we will: (1) determine if certain hematopoietic stem cells (HSCs), specifically short term-HSCs (ST-HSCs), fail to properly expand and differentiate along myeloid pathways in the elderly response to trauma, and, if the resultant dysfunctional neutrophil population seen in the elderly after trauma results from these suboptimal ST-HSCs; (2) determine if the defects in aged ST-HSC function after severe injury, as compared to their juvenile counterparts, are caused by a chronic low-grade NF?B-dependent inflammatory state and a subsequent failure to appropriately activate NF?B-dependent pathways after trauma; and, (3) determine if the HSC senescence associated with elderly humans after severe trauma is also due to a failure to appropriately activate NF?B-dependent pathways in bone marrow HSCs. This work proposes that increased susceptibility to infection after trauma in aging is due, at least in part, to defects in myelopoiesis that lead to genotypically, phenotypically and functionally deranged PMNs that fail to control infection. The third specific aim will translate our 'bench side' animal work to humans and this innovative approach could identify areas for intervention in cell types that are still exhibit plasticity.

Public Health Relevance

Limitations and dysfunction in innate immunity, specifically in emergency myelopoiesis from bone marrow progenitor cells in post-trauma elderly patients, can increase the risk of immune dysregulation and suppression and can specifically lead to the development of neutrophils with a suboptimal ability to kill bacteria. A better understanding of these phenomena may lead to novel therapies, including those directed at altering myelopoiesis, for the treatment of the severally injured elderly patient.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM113945-03
Application #
9206168
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2015-04-05
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$270,000
Indirect Cost
$90,000
Name
University of Florida
Department
Surgery
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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