The role of Beta-adrenoceptor (βAR) antagonists in promoting healing of chronic wounds

Chronic wounds are wounds that fail to heal or take a longer time than normal wounds to heal. There are three main types of chronic wounds: pressure ulcers; diabetic ulcers and venous ulcers. The predominant features of chronic wounds are infection, sustained inflammation, senescent cells and the altered composition of the wound fluid. Dermal fibroblasts (HDF) are the main cell type in the dermis. They differentiate into myofibroblasts which express α smooth muscle actin (αSMA), are more contractile and secrete large amounts of extracellular matrix (ECM), promoting wound closure. Keratinocytes are the main cells of epidermis and they proliferate and migrate to promote reepithelialization. Macrophages, especially the pro-inflammatory M1 phenotype, are the predominant macrophages in chronic wounds, responsible for persistent inflammation. Dermal microvascular endothelial cells (DMECs) can proliferate and form tubules to promote angiogenesis which is impaired in chronic wounds. Here the ability of βAR antagonists, Timolol (Tim) and ICI 118,551 to promote wound healing was explored. Tim modulated HDF function through increasing HDF differentiation via fibroblast growth factor 2 (FGF2), cyclic adenosine monophosphate (cAMP) and extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent mechanisms. Indeed, Tim decreased FGF2 secretion from HDFs and promoted differentiation. Tim also increased HDF proliferation via inhibiting mothers against decapentaplegic homolog 2 and 3 (SMAD2/3) nuclear localisation and downregulated HDF and NHK apoptosis via reducing active caspase 3 expression. In addition, Tim increased HDF migration via RAC1 and RHOA dependent mechanisms. Tim also increased CTGF secretion from HDFs and macrophages, and VEGF secretion from macrophages and HDMECs. Overall, Tim, could promote healing of chronic wounds via reducing inflammation, promoting HDF migration and proliferation increasing granulation tissue formation and wound closure. Indeed, a number of successful clinical case studies of Tim promoting chronic wound healing are reported and a human clinical trial commenced in September 2015.