The Beta 2 Adrenergic Receptor Antagonist Timolol Improves Healing of Combined Burn and Radiation Wounds

In a scenario involving a nuclear detonation during war or a terrorist attack, acute radiation exposure combined with thermal and blast effects results in severe skin injury. Although the cutaneous injury in such a scenario may not be lethal, it may lead to inflammation, delayed wound healing and loss of the skin barrier, resulting in an increased risk of infection. In this study, we tested the potential use of timolol, a beta-adrenergic receptor antagonist, to improve epidermal wound closure after combined burn and radiation injury using an ex vivo human skin culture model. Daily application of 10 μ M timolol after combined injury (burn and 10 Gy ex vivo irradiation) increased wound epithelialization by 5-20%. In addition, exposure to 10 Gy significantly suppressed epidermal keratinocyte proliferation by 46% at 48 h postirradiation. Similar to what has been observed in a thermal burn injury, the enzyme phenylethanolamine N-methyltransferase (PNMT), which generates epinephrine, was elevated in the combined thermal burn and radiation wounds. This likely resulted in elevated tissue levels of this catecholamine, which has been shown to delay healing. Thus, with the addition of timolol to the wound to block the binding of locally generated epinephrine to the beta-adrenergic receptor, healing is improved. This work suggests that by antagonizing local epinephrine action within the wound, a beta-adrenergic receptor antagonist such as timolol may be a useful adjunctive treatment to improve healing in the combined burn and radiation injury

Co-immunization with IL-15 enhances cellular immune responses induced by a vif-deleted simian immunodeficiency virus proviral DNA vaccine and confers partial protection against vaginal challenge with SIVmac251

AbstractSimian immunodeficiency virus (SIV) infection of rhesus macaques is a valuable animal model for human immunodeficiency virus (HIV)-1 vaccine development. Our laboratory recently described the immunogenicity and limited efficacy of a vif-deleted SIVmac239 proviral DNA (SIV/CMVΔvif) vaccine. The current report characterizes immunogenicity and efficacy for the SIV/CMVΔvif proviral DNA vaccine when co-inoculated with an optimized rhesus interleukin (rIL)-15 expression plasmid. Macaques co-inoculated with rIL-15 and SIV/CMVΔvif proviral plasmids showed significantly improved SIV-specific CD8 T cell immunity characterized by increased IFN-γ ELISPOT and polyfunctional CD8 T cell responses. Furthermore, these animals demonstrated a sustained suppression of plasma virus loads after multiple low dose vaginal challenges with pathogenic SIVmac251. Importantly, SIV-specific cellular responses were greater in immunized animals compared to unvaccinated controls during the initial 12 weeks after challenge. Taken together, these findings support the use of IL-15 as an adjuvant in prophylactic anti-HIV vaccine strategies