Sulfur mustard (SM), the most widely used chemical warfare agent, and nitrogen mustard (NM) are strong alkylating agents causing DNA damage as well as oxidative damage leading to the activation of several molecular pathways. After a latent period, their effect is an inflammatory response, epidermal cell death and excruciating vesication and ulcerations in the skin tissue, which is the main target organ. Based on the exposure dose and duration, these effects can lead to long-term skin complications like xerosis, erythema and pigmentation changes with a long wound healing tenure causing medical burden and affecting the life quality. There is plethora of information available on the skin pathology following exposure to vesicating agents; however, the complex molecular mechanisms that lead to chronic skin lesions from acute exposures are still debatable. Our completed studies in SKH-1 hairless mice have shown that acute cutaneous vesicant exposure can lead to oxidative stress, DNA damage, activation of signaling pathways, and expression of inflammatory and proteolytic mediators including cytokines, contributing to the skin inflammation, blister formation, and delayed wound healing. Furthermore, we also found that NM-induced changes in MMP-9, inflammatory cytokines like FGF2, TNF-? and IL-1? and VEGF in mouse skin were accompanied with alterations in micro- RNAs miR-155, miR-203a and miR-21. Notably, these mi-RNAs are connected to chronic skin inflammation, immune response and fibrosis (miR-155), cytokine signaling by targeting genes encoding pro-inflammatory cytokines like TNF-? in the skin tissue (miR-203a) and skin wound healing and collagen deposition (miR-21). This application is built upon these preliminary findings, and will investigate in detail the effect of SM and NM exposure on miRNA changes in the skin tissue. Our hypothesis is that altered miRNAs related to inflammation, wound healing and fibrosis could target the gene expression directing molecular pathway alterations to cause chronic skin injury from vesicating agents? exposure. Employing both NM- and SM-induced skin tissues with chronic lesions in established mouse skin injury models, specific aims are: 1) to determine miRNAs associated with inflammation, wound healing and fibrosis, and analyze miRNA targets as well as related molecular pathways via miRNA target and pathway analysis programs; and 2) to confirm the identified miRNA target molecules most relevant to vesicant-induced skin injury, and compare the outcomes between both the NM- and SM-induced skin injuries. Completion of the proposed studies is anticipated to identify unique miRNAs driving the molecular pathway alterations observed in SKH-1 hairless mice following both SM- and NM-exposures. Outcomes are anticipated to establish miRNA signatures, which can serve as novel diagnostic biomarkers and open a new avenue of miRNA-targeted treatment of skin complications following SM and NM exposure.

R21AR074929

2019-07-08

2021-04-30