Wound healing in diabetes is impaired due to excessive inflammation, reduced angiogenesis, and other pathological changes, leading to delayed healing. Diabetic patients face higher risks of wound infections, dehiscence, and abnormal scarring. These complications contribute to significant medical and economic burdens globally. The healing process is hindered across all phases of inflammation, proliferation, and remodeling, resulting in prolonged recovery times. There is a critical need for novel therapies that not only accelerate wound closure but also improve skin biomechanical recovery to address this challenge effectively. Here, we report a new approach in which the use of histamine receptor agonists (HiRAs) promotes inflammatory stages of wound healing and accelerates wound closure in diabetic, obese mice, and helps in subsequent tissue repair processes. In a splinted, full-thickness excisional wound model in diabetic, obese mice (Db/Db), the topical delivery of HiRAs significantly accelerated wound closure and repair between days 8-11post-wounding. Additionally, it decreased the barrier restoration function (trans epidermal water loss) of the healed skin by day 11 compared to saline treatment. Increased dose of histamine receptor agonists 4 (HRH4 ag) treatment has also showed significantly greater wound closure compared to saline.
Treatment with histamine receptor agonists 1 and 4 increased alpha-smooth muscle actin (α-SMA) expression, crucial for tissue contraction and remodeling, and enhanced CD31+ cells on endothelial cells, supporting angiogenesis and vascular integrity. Additionally, HiRAs promoted M2 macrophage (Arginase-1) production, which shortened the pro-inflammatory phase, facilitated extracellular matrix synthesis, and promoted angiogenesis. The approach focuses on topical HiRAs delivery to activate myofibroblasts and enhance tissue repair, highlighting new therapeutic targets that could lead to clinical trials for wound healing treatment.
