p38 MAPK inhibition reduces diabetes-induced impairment of wound healing

Satyanarayana Medicherla¹, Scott Wadsworth², Breda Cullen³, Derek Silcock³, Jing Y Ma¹, Ruban Mangadu¹, Irene Kerr¹, Sarvajit Chakravarty¹, Gregory L Luedtke¹, Sundeep Dugar¹, Andrew A Protter¹, Linda S Higgins¹

¹Scios Inc., Fremont, CA, USA; ²Center for Biomaterials and Advanced Technologies, Somerville, NJ, USA; ³Johnson & Johnson Wound Management, Gargrave, UK

Abstract: In healthy tissue, a wound initiates an inflammatory response characterized by the presence of a hematoma, infiltration of inflammatory cells into the wound and, eventually, wound healing. In pathological conditions like diabetes mellitus, wound healing is impaired by the presence of chronic nonresolving inflammation. p38 mitogen-activated protein kinase (MAPK) inhibitors have demonstrated anti-inflammatory effects, primarily by inhibiting the expression of inflammatory cytokines and regulating cellular traffic into wounds. The db/db mouse model of type 2 diabetes was used to characterize the time course of expression of activated p38 during impaired wound healing. The p38α-selective inhibitor, SCIO-469, was applied topically and effects on p38 activation and on wound healing were evaluated. A topical dressing used clinically, Promogran^TM, was used as a comparator. In this study, we established that p38 is phosphorylated on Days 1 to 7 post-wounding in db/db mice. Further, we demonstrated that SCIO-469, at a dose of 10 µg/wound, had a positive effect on wound contraction, granulation tissue formation, and re-epithelialization, and also increased wound maturity during healing. These effects were similar to or greater than those observed with Promogran^TM. These results suggest a novel approach to prophylactic and therapeutic management of chronic wounds associated with diabetes or other conditions in which healing is impaired.

Keywords: p38 MAPK ihibition, diabetic wound healing, db/db mouse, nonresolving healing, Promogran^TM