Defining the timing of 25(OH)D rescue following nitrogen mustard exposure

Abstract

Objective Mass exposure to alkylating agents such as nitrogen mustard (NM), whether accidental or intentional as during warfare, are known to cause systemic toxicity and severe blistering from cutaneous exposure. Thus, establishing the timing and appropriate dose of any potential drug designed to reverse or impede these toxicities is critical for wound repair and survival. Our previous data demonstrates that a single intraperitoneal injection of low-dose 25-hydroxyvitamin D3 (25(OH)D) given as early as 1 h following NM exposure is sufficient to rescue mice from pancytopenia and death. However, the duration of time following exposure where intervention is still effective as a countermeasure is unknown. In this study, we sought to assess the maximal time permissible following NM exposure where 25(OH)D still affords protection against NM-induced cutaneous injury. Additionally, we determined if a higher dose of 25(OH)D would be more efficacious at time interval where low dose 25(OH)D is no longer effective. Methods Low (5 ng) and high (50 ng) doses of 25(OH)D were administered intraperitoneally to mice following exposure to topical NM to assess wound resolution and survival. Mice were imaged and weighed daily to measure wound healing and to monitor systemic toxicity. Results We demonstrated that 5 ng 25(OH)D administered as early as 1 h and as late as 24 h post-NM exposure is able to achieve 100% recovery in mice. In contrast, intervention at and beyond 48 h of NM exposure failed to achieve full recovery and resulted in ≥60% death between days 6 and 12, demonstrating the critical nature of timely intervention with 25(OH)D at each respective dose. In order to circumvent the observed failure at >48 h exposure, we provided two consecutive doses of 5 ng or 50 ng of 25(OH)D at 48 h and 72 h post-NM exposure. Repeat dosing with 25(OH)D at 48 h and beyond led to marked improvement of lesion size with 75% recovery from mortality. Conclusions The opportunity to use 25(OH)D as a medical countermeasure for NM-induced toxicity has a finite of window for intervention. However, modifications such as repeat dosing can be an effective strategy to extend the intervention potential of 25(OH)D.

MG53 Mitigates Nitrogen Mustard-Induced Skin Injury

“…These injury processes are associated with the alkylating properties and/or thiol-depleting functions of SM and NM [5,9,[16][17][18][19][20][21]. Oxidative stress and cell membrane damage caused by SM and NM are major factors contributing to the development of debilitating conditions such as blistering, chronic inflammation, and ulceration [16,19,20,[22][23][24]. Due to their lipophilic nature, SM/NM can penetrate deep into the epidermal layer and cause damage to keratinocytes and hair follicles [25].…”

A novel treatment for skin repair using a combination of spironolactone and vitamin D3

“…Our laboratory has previously shown that treatment with vitamin D (VD) significantly decreases skin inflammation caused by exposure to NM or ultraviolet (UV) radiation. [7][8][9][10][11] Vitamin D3 (VD3), the predominant form of VD in humans, can be produced in the skin after UV exposure or be derived from animal-based foods. Activation of VD is tightly regulated and requires two separate enzymatic reactions, first by the liver to produce 25-hydroxyvitamin D (25(OH)D) and the second by the kidney to produce 1,25dihydroxycholecalciferol (1,25(OH) 2 D or calcitriol), the biologically active form of VD.…”

“…Our laboratory has previously shown that treatment with vitamin D (VD) significantly decreases skin inflammation caused by exposure to NM or ultraviolet (UV) radiation 7–11 . Vitamin D3 (VD3), the predominant form of VD in humans, can be produced in the skin after UV exposure or be derived from animal‐based foods.…”