Estrogen Effects after a Crush Muscle Injury and Acute Exposure to Hypobaric Hypoxia

PI: Joachim Voss

Joachim Voss PhD, RN, ACRN Associate Professor Biobehavioral Nursing and Health Systems Box 357266 University of Washington Seattle, WA 98195-7262 Email: vossj@u.washington.edu

• Sponsor: University of Nevada, Las Vegas
• Project Period: 8/23/2010 - 8/22/2012
• Current Faculty
  • Joachim Voss - Principal Investigator (3 active projects)
  • Adrian Dobra  - Key Personnel

Aeromedical evacuation provides a mechanism to transport and provide care to critically wounded soldiers from the field to a medical treatment facility. However, a major challenge of aeromedical evacuation is its hypobaric hypoxia (HH) environment. Although acute HH effects on cognitive function are well-known, such effects on inflammatory responses are unclear. Previous data suggest that acute HH enhances inflammatory responses, which could exacerbate combat-related injuries. Because estrogen reduces the movement of leukocytes into injured muscle and proinflammatory cytokine levels in other tissues, estrogen may counteract HH effects and limit an exacerbation of combat injuries, such as crush muscle injury. Objective/Hypothesis: The four study hypotheses are as follows: Hypothesis 1: As a single insult, acute HH exposure will enhance neutrophil and macrophage infiltration and pro-inflammatory cytokine production, and alter gene expression in lower extremity (uninjured) muscle of mice. Hypothesis 2: As a single insult, a crush injury will induce neutrophil and macrophage infiltration and pro-inflammatory cytokine production, and alter gene expression in lower extremity muscle of mice in a normobaric environment. Hypothesis 3: Acute HH exposure will enhance neutrophil and macrophage infiltration and proinflammatory cytokine production, and alter gene expression in lower extremity crush-injured muscle of mice. Hypothesis 4: Estradiol will attenuate neutrophil and macrophage infiltration and pro-inflammatory cytokine production, and altered gene expression in lower extremity crush-injured muscle of mice exposed to acute HH. Study Design: This project will consist of two phases: 1) to validate a HH model for mice with lower extremity crush muscle injury and 2) to test whether estrogen attenuates neutrophil and macrophage infiltration, pro-inflammatory cytokine production, and altered gene expression in lower extremity crush-injured muscle exposed to HH. In phase 1, validation measures include histological muscle damage, neutrophil and macrophage infiltration, pro-inflammatory cytokine production, and gene expression. After these Validation Experiments, in Phase 2, ovariectomized female mice treated with estradiol or placebo will undergo a lower extremity crush muscle injury followed by exposure to acute HH. Muscles will be harvested and analyzed for neutrophil and macrophage infiltration, proinflammatory cytokine production, and gene expression. Relevance: The long-range usefulness of this research is that its findings might contribute to the scientific foundation for managing wounded troops in flight. Estrogen or estrogen-like substances may counteract enhanced inflammatory or altered genetic responses induced by HH.