Novel Formulation of Topical Losartan for Treatment of Wounds in Aging

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DESCRIPTION (provided by applicant): The development of pressure ulcers is one of the most painful, debilitating, and costly conditions that impact older adults. The increased risk for skin breakdown and poor healing in older adults is both extrinsic (incontinence, immobility) and intrinsic (decreased elasticity, perfusion, and oxygenation). Although improvements in wound care have been made over the past several years, few pharmacological agents targeting the biological pathways that impact wound healing have been developed. Dysregulation in the renin-angiotensin system (RAS) has been increasingly implicated in abnormal wound healing. The purpose of this proposal is to further develop the use of a topical form of the angiotensin receptor blocker, losartan, during the proliferative/remodeling phases of wound healing in an aging mouse model. The study is designed to optimize dosing and safety information in this animal model in order to accelerate translation into human subjects. The first aim of this grant is to compare efficacy and safety of 5%, 10%, and 15% losartan ointment applied during proliferation/remodeling phase of wound healing in 24 month old C57Bl/6 mice through determining the difference in time to wound closure, through the comparison of healed tissue tensile strength, and through comparison of blood pressure, renal function, and mortality between treatment and placebo groups. The second aim is to study the differential mechanistic impact of the 3 losartan doses compared to placebo ointment on wound healing through Doppler and histological studies and through quantification and comparison of angiotensin receptors type 1 and 2 and TGF-¿ protein and gene expression in wound tissue. An experienced, multidisciplinary team with expertise in animal models, wound care, wound study, RAS biology, biostatistics and aging focused clinical translation has been formed to complete this study. Wound closure will be measured with acetate tracings, and tensile strength and elasticity will be measured by tensiometry from healed skin. Doppler measurements will be made with Doppler laser scanner, and histology will target adnexal and vascular tissues. Standard quantitative PCR and western blot analyses will be used to assess RAS and TGF-¿ related components in wound healing. Expected findings include the identification of an optimal, safe and effective dose of losartan ointment that accelerates wound healing and maximizes the quality of the healed tissue, and the identification of RAS and TGF-¿ related changes in response to losartan that influence wound healing. Such results will facilitate the rapid translation of these findings into human subjects, and have great potential to rapidly shift the present wound healing care paradigm in older adults.