HSP90, a potential common therapeutic target for suppressing skin injury caused by exposure to chemically diverse classes of blistering agents
Vesicants such as arsenicals and mustards produce highly painful cutaneous inflammatory and blistering responses, hence, developed as chemical weapons during World War I/II. Here, using lewisite and sulfur mustard surrogates namely phenylarsine oxide (PAO) and 2-chloroethyl ethyl sulfide (CEES) respectively, we defined a common underlying mechanism of toxic action by these distinct classes of vesicants. Murine skin exposure to these chemicals causes skin inflammation and tissue destruction characterized by increase in skin bifold thickness, Draize score, infiltration of inflammatory cells and appearance of apoptotic epidermal and dermal cells. RNAseq analysis identified ~346 inflammatory genes that were commonly altered by both PAO and CEES along with identification of cytokine signaling activation as top canonical pathway. Activation of several of these inflammatory genes and pathways are associated with phosphorylation-dependent activation of heat shock protein 90 (pHSP90). Topical treatment with known HSP90 inhibitors, SNX-5422 and IPI-504 post PAO or CEES skin challenge significantly attenuates these chemical-induced skin damage (reduction in overall skin injury and clinical scores). In addition, highly upregulated inflammatory genes Saa3, Cxcl1, Ccl7, IL-6, Nlrp3, Csf3, Chil3 etc. by both PAO and CEES, significantly diminished by the treatment with these HSP90 inhibitors. These drugs not only reduced PAO or CEES-induced pHSP90 expression but also its client proteins NLRP3, pP38 and expression of their targeted inflammatory genes. These data confirm a critical role of HSP90 as a shared underlying molecular signaling of toxicity by these two distinct vesicants and provide effective and novel medical countermeasure to suppress vesicants pathogenesis. Overall design: Analysis of RNAseq data for mouse skin exposed with either vehicle (control) or chemicals phenylarsine oxide (PAO) or 2-chloroethyl ethyl sulfide (CEES). We also tested effects of SNX-5422, a HSP90 inhibitor on PAO or CEES-altered genes.