Discussion
inflammation, skin injury, sunburn
ADVERSE EFFECTS, INFLAMMATION, INFLAMMATORY RESPONSE
In the control phase of this study, we analyzed the protein expression profile of untreated NM skin injury and identified 22 protein markers of untreated NM injury. In the intervention phase, we repeated the NM exposure, after which participants were randomized to receive placebo or a single 200,000 IU dose of oral VitD. Oral VitD was selected over topical for more precise dosing and direct systemic effects, and its use was justified based on a previous dosage study demonstrating its efficacy in reducing expression of proinflammatory mediators after sunburn (Our study confirms that NM injury markers previously only identified in animal models and in vitro human keratinocyte studies (CCL2, CCL3, CXCL1, CXCL10, CCL19, OSM, PLAU, and CXCL8) are translatable to in vivo human work (The intervention-independent divergence in severity of inflammatory response observed in this study is consistent with the variable response to topical chemotherapeutics observed in clinical practice, in which some patients tolerate repeat exposures while others experience treatment-limiting adverse effects (Since topical chemotherapy regimens require repeated applications in the clinical setting, we propose that a panel identifying the combined upregulation of these 3 markers after a patient’s initial NM exposure may have clinical utility for predicting which patients may develop the exaggerated response phenotype with continued use. Early identification of at-risk patients would allow clinicians to make treatment adjustments or prophylactically provide stronger supportive therapies. Recent advances in noninvasive protein collection, such as tape stripping, increase the practicality of such a panel.The 3-marker Severe response signature may provide insight into the mechanisms underlying the exaggerated-response phenotype. Previously, acute NM-associated inflammation was assumed to be mediated primarily by innate immunity. However, all 3 Severe response markers function in bridging innate and adaptive immunity, including IL-17 signaling, which has been identified in previous mouse lung studies as a driving pathway of chronic SM inflammation (Regardless of whether an exaggerated response to topical chemotherapy occurs, our results suggest that systemic VitD is an effective immunomodulatory intervention. Protein, pathway-enrichment data, and serum VitD metabolite levels provide evidence that VitD metabolism and antiinflammatory properties differ depending on the underlying inflammatory status of the patient. During a mild inflammatory response, VitD is metabolized within reference-range levels and suppresses the primarily neutrophilic cytokines CXCL5, CXCL6, and CXCL8, which may suppress inflammatory feedback cycles (While this study was not designed to evaluate the mechanisms of VitD metabolism, the upregulation of promonocytic DEPs and CBC changes observed in Severe participants may suggest that the metabolic differences in VitD are mediated in part by an increase in activated macrophages, which are well known to conduct extrarenal hydroxylation of 25(OH)DIn conclusion, we provide proof-of-concept evidence that a single administration of high-dose oral VitD safely and durably suppresses clinical and biological markers of postinjury inflammation. We identified participants experiencing an exaggerated inflammatory response to chemical injury and used exploratory outcomes and post hoc analysis to associate this phenotype with IL-17 signaling and a potentially predictive biomarker signature. Additional studies investigating the mechanisms of the observed divergent response to injury, optimal dosing regimens, and adjuvant treatment potential for VitD therapies are essential next steps.