Project 7: Host antibacterial resistance influenced by androgen-mediated corticosteroid modulation

University Of Texas Med Br Galveston, Galveston TX

Investigators

Linked publications & trials

Abstract

Project Summary Severe burn injury is accompanied by hypercatabolic responses, and the testosterone analog oxandrolone (OX) works to improve net muscle protein synthesis and increase lean body mass. Therefore, we wish to add OX to our standard of care (SOC) therapy for severely burned patients. However, clinical use of OX is attended with some difficulties. OX initially suppresses cortisol-induced transcriptional activity in cells expressing both androgen receptors and glucocorticoid receptors (GRs). Consequently, a large amount of TNF-? is produced by cells involved in inflammation due to the suppression of GR transcriptional activity. TNF-? induces systemic inflammatory response syndrome (SIRS) through the mass production of pro-inflammatory cytokines. Exacerbated SIRS is frequently accompanied by serious immunoparalysis, which is characterized by simultaneous persistence of SIRS and CARS (compensatory anti-inflammatory response syndrome). Patients with serious immunoparalysis are extremely susceptible to various opportunistic infections. In our studies, however, SIRS did not seriously develop in severely burned patients treated with propranolol (Prop, a ?- adrenergic receptor antagonist). Also, the number of myeloid-derived suppressor cells (typical cells for CARS biomarkers) is not increased in severely burned mice treated with Prop. All severely burned patients at Galveston Shriners Burns Hospital and the Blocker Burn Unit at the University of Texas Medical Branch are currently treated with Prop as a part of our SOC for the improvement of burn-associated hypermetabolic responses. The possibility thus arises that OX does not accelerate immunoparalysis states in severely burned patients treated with the SOC therapy including Prop (Prop/SOC-patients). This possibility will be examined in Project 7. Our central hypothesis is that OX can be given to severely burned patients treated with the SOC including Prop without increasing immunoparalysis and impairing host antibacterial defenses. To test our hypothesis, three series of experiments will be performed: in Aim 1 the effect of OX on the production of TNF-? and activation of NF?B will be analyzed in Prop/SOC patients. TNF-? plays a key role in the development of immunoparalysis, and is produced via NF?B activation. In Aim 2, the effect of OX on the development of immunoparalysis in Prop/SOC patients will be explored. Finally, in Aim 3 the antibacterial defenses of Prop/SOC patients treated with OX to opportunistic Staphylococcus aureus and Pseudomonas aeruginosa infections will be tested in comparison with those of Prop/SOC patients in a murine chimera model of these patients. If our hypothesis holds true, OX can be added to our Prop-included SOC for severely burned patients without any risk of serious immunoparalysis and impairing host antibacterial defenses.