Abstract
Collagenases are useful in enzymatic wound debridement. Clostridial collagenase, marketed as Collagenase Santyl Ointment (CSO), is FDA approved for such use. Building on the scientific premise that collagenases as well as collagen degradation products may regulate immune cell function, we sought to investigate the potential role of CSO in wound inflammation. We tested the hypothesis that in addition to enacting debridement, CSO contributes to the resolution of persistent wound inflammation. Wound macrophages were isolated from PVA sponges loaded with CSO or petrolatum and implanted in mice. Significant increase in pro-reparative and decrease in pro-inflammatory polarization was noted in macrophages of acute as well as diabetic wounds. Wound macrophages from CSO-treated group displayed increased production of anti-inflammatory cytokines IL-10 and TGF-β, and decreased levels of pro-inflammatory cytokines TNF-α and IL-1β. The active ingredient of CSO, CS-API, induced the expression of mϕheal /M(IL-4) polarization markers ex vivo. CS-API treatment attenuated transactivation of NF-κB and significantly induced STAT6 phosphorylation. A significant role of a novel PGE2-EP4 pathway in CS-API induced STAT6 activation and the mϕheal /M(IL-4) polarization was identified. Taken together, findings of this work reposition CSO as a potential agent that may be effective in resolving wound inflammation, including diabetic wounds.
Highlights
Chronic wounds are a major socioeconomic threat costing billions of dollars annually to the US healthcare system[1]
Treatment of bone marrow derived macrophages (BMDM) with recombinant IL-10 significantly inhibited LPS-induced TNF-α release (Fig. 1F) suggesting that increased IL-10 in response to Collagenase Santyl Ointment (CSO) may be implicated in lowering of LPS-induced TNF-α release
This study provides maiden evidence demonstrating that a commonly used enzymatic wound debridement agent CSO that contains clostridial collagenases as the active ingredient is a powerful inducer of mφheal functional state in acute and chronic diabetic wounds
Summary
Chronic wounds are a major socioeconomic threat costing billions of dollars annually to the US healthcare system[1]. Collagenase Santyl Ointment (CSO) is an FDA-approved clostridial collagenase based prescription ointment for effective enzymatic debridement of chronic wounds and burns[3]. Whether CSO activity at the wound site may modify the function of wound resident and immune cells remains unknown. Given the current ambiguity in macrophage nomenclature for tissue macrophages[18,19], and proposed misfit of wound macrophage (wmφ) with the M1/M2 nomenclature[16,20,21], for this work we classify in vivo wmφ based on the pro-inflammatory (mφinf) or pro-resolution/healing (mφheal) polarization states. We sought to understand whether clostridial collagenase, the enzyme used as the wound debridement agent in CSO, may influence the fate of wound inflammation by inducing mφ polarization
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