Background: Pressure injuries (PI’s), also known as bedsores or pressure ulcers, are areas of localized damage to the skin and underlying tissue caused by pressure, shear or friction. Minimal therapeutic options are available to treat PI’s, which are expected to become more prevalent in response to an aging population. Granzyme B (GzmB) is a serine protease minimally expressed in normal skin but drastically elevated in multiple chronic inflammatory skin diseases. Elevated GzmB is known to cleave numerous substrates within the extracellular matrix, including decorin, fibronectin and E-cadherin, contributing to impaired wound healing. In GzmB-/- mice, diabetic wounds exhibit improved wound closure and increased tensile strength. We hypothesize GzmB contributes to the development, severity and impaired healing of PI's, with GzmB inhibition providing a potential therapeutic option.
Methods: To evaluate GzmB expression, human PI wound fluid (ELISA) and excised tissue (histology) was collected and examined. The role of GzmB was assessed in a murine model of PI using wild-type or GzmB-/- mice. PI's were induced though multiple rounds of ischemia-reperfusion injury using magnets. Wound morphometry, inflammation, decorin, picosirius red, Masson’s Trichrome, Collagen I/III ratio and skin tensiometry were assessed.
Results: PI wound fluid showed elevated GzmB protein concentration compared to acute blister fluid controls, with a direct correlation identified between GzmB concentration and wound severity. An elevated number of GzmB+ cells was observed in the dermis of human PI tissue compared to healthy skin. There was an almost complete absence of decorin in the dermis of affected skin and impaired collagen organization. GzmB-/- mice displayed a reduction in wound severity, improved closure and better overall appearance compared to WT controls, with increased decorin and improved overall collagen organization.
Conclusion: GzmB is elevated in PI, resulting in impaired healing through cleavage of key extracellular matrix components.