A rapid increase in the global prevalence of skin inflammatory diseases like psoriasis cannot be attributed to genetics alone. Environmental factors including major ubiquitous organic pollutants like polycyclic aromatic hydrocarbons (PAHs) could contribute to their pathophysiology. Benzo[a]pyrene (BaP) is one of the PAH that is generated mainly from cigarette smoke, wood‐burning, automobile exhaust etc. The molecular mechanisms that lead to inflammatory skin diseases following exposure to BaP are not well elucidated, though there are suggestions that these responses could be mediated by aryl hydrocarbon receptor (AhR), a xenobiotic sensor. To investigate the effect of BaP exposure on skin inflammation in a mouse psoriatic model, the dorsal skin of naïve C57BL/6 mice was shaved (48h prior to exposure) and exposed to 62.5mg of 5% imiquimod (IMQ) cream once daily for five days. For assessing the initiation or exacerbation of psoriasis from exposure to BaP, mice were exposed 64μg BaP in 50μl acetone for five days before IMQ application [BaP+IMQ] or for five days together with the IMQ [(BaP+IMQ)] application. Following the analysis and scoring of clinical lesions, mice were sacrificed, and skin sections were analyzed for inflammation‐related histopathological and molecular changes. BaP exposure together with IMQ exacerbated IMQ‐induced psoriatic inflammatory lesions including the skin bi‐fold thickness, epidermal and dermal thickness, hyperkeratosis, dermal fibrosis, neutrophil infiltration, neutrophil degeneration and mast cell degranulation. Molecular analysis on the skin samples to further elucidate the effect BaP on IMQ‐induced inflammatory markers such as neutrophil infiltration, macrophages, inflammatory cytokines that could exacerbate psoriasis is being carried out. In other studies, defining the role of AhR in BaP‐induced biological, molecular, and metabolic alterations in mouse skin, concomitant treatment with AhR antagonist CH‐223191 was given before BaP+IMQ treatment. The antagonist treatment before the (BaP+IMQ) treatment abrogated the BaP‐caused increase in epidermal and dermal thickness in psoriatic mice. The effect of the AhR inhibitor on other biological and molecular psoriatic parameters that are exacerbated on exposure to BaP are also being analyzed to decipher the role of AhR in BaP‐induced and/or exacerbation in inflammatory skin diseases like psoriasis. Support or Funding Information Skaggs Scholars Program Grant, University of Colorado Denver and Start‐up Fund to Neera Tewari‐Singh, Michigan State University
Nitrogen mustard (NM), a structural analog of warfare agent sulfur mustard (SM), is a chemical vesicant that causes blistering of skin and damage to mucus membranes. NM is a strong alkylating and DNA damaging agent. Currently, we lack effective therapies to rescue skin injuries by NM and SM. The insight into the mechanisms of NM and SM‐induced skin injuries is crucial for the development of effective targeted therapies. Our lab’s previous studies suggest that skin toxicity from NM exposure can cause macromolecular damage and activation of signaling pathways, especially those related to inflammation, oxidative stress, and DNA damage. Therefore, targeting anti‐oxidative stress and anti‐inflammatory pathways such as the nuclear factor erythroid 2‐related (Nrf2) pathway can be essential to treat epidermal injuries from this vesicant exposure. Nrf2 is a key transcription factor that controls the basal and induced expression of an array of antioxidant response element–dependent genes to provide anti‐inflammatory and cytoprotective effects to cells. Thus, activating the Nrf2 pathway can be a targeted approach for the treatment of NM skin toxicity. To study the role of the Nrf2 pathway in NM‐induced toxicity, we used mouse skin epidermal JB6 cells. The JB6 cells were treated with 75µM of NM for 2, 6, 12 or 24 hours where approximately 50% of cell viability was achieved (MTT assay and trypan blue cell counting). Using qPCR analysis, we further studied the RNA expression of the Nrf2 pathway and its targeted genes including heme oxygenase‐1 (HO‐1), NADPH Quinone oxidoreductase enzyme (NQO‐1), Glutamate‐Cysteine Ligase Modifier Subunit (GCLM), Glutamate‐Cysteine Ligase Catalytic Subunit (GCLC) and Catalase. Our results showed an upregulation in RNA expression for HO‐1 at 2 and 6 hours post NM exposure, and a downregulation in Nrf2, NQO‐1, Catalase, GCLM, and GCLC. There was also an upregulation for HO‐1 and NQO‐1 at 12 hours post NM exposure. However, there was a downregulation in RNA expression for all these markers at 24 hours post NM exposure. To induce the activation of Nrf2 pathway and its targeted genes, we want to treat the cells with synthetic oleanane triterpenoid derivatives of 2‐cyano‐3,12‐dioxooleana‐1,9(11)‐dien‐28‐oic acid (CDDO), which are among the most potent Nrf2 activators. These results will help us further investigate in in vivo studies if triterpenoids via cytoprotective and antioxidant effects could be used for the treatment of acute as well as long‐term skin toxicity from NM exposure.
Emerging evidence suggests that environmental chemicals, mainly the organic pollutants like polycyclic hydrocarbons (PAHs), could contribute to the pathophysiology of several chronic inflammatory skin diseases like atopic dermatitis and psoriasis. Benzo[a]pyrene (BaP), the main source of atmospheric PAH, is generated mainly from cigarette smoke, wood‐burning and automobile exhaust. Several reports suggest that the inflammatory effects exerted by BaP could be mediated via the aryl hydrocarbon receptor (AhR) signaling pathway. AhR ligands exert the antioxidative pathway triggered by injury and inflammation, and could activate the nuclear factor‐erythroid 2‐related factor‐2 (NRF2). Pathology of Psoriasis includes acanthosis, hyperkeratosis, and parakeratosis of the epidermis, invasion of neutrophils into the epidermis as well as an inflammatory response. BaP exposure could exacerbate the inflammatory pathology of psoriasis; however, comprehensive studies to assess this and decipher the molecular mechanisms involved, remain elusive. In the present study, we evaluated the effect of BaP on mouse skin psoriasis. For generating psoriasis, the dorsal skin of C57BL/6 male and female mice was shaved and exposed to 62.5mg of 5% imiquimod (IMQ) cream once daily for five days. To study the effect of BaP in the exacerbation of IMQ‐ induced psoriasis, mice were exposed to 64µg BaP in 50µl acetone for five days before IMQ application [BaP+IMQ] or for five days together with the IMQ [(BaP+IMQ)] application. Histopathological analysis showed that BaP exposure together with IMQ exacerbated IMQ‐induced psoriatic inflammatory lesions including the skin bi‐fold thickness, epidermal and dermal thickness, acanthosis, hyperkeratosis, dermal fibrosis and neutrophil infiltration. Our ongoing molecular studies show that the exposure of BaP in IMQ‐induced psoriatic mice elevated the expression of inflammatory markers like COX‐2, MMP9, myeloperoxidase (maker of neutrophil infiltration) and NRF2. Increased expression of these markers suggests that BaP could activate inflammatory pathways and further elevate the skin inflammation in IMQ induced psoriasis. Further mechanistic studies are underway to evaluate the pathways involved in BaP‐induced exacerbation of psoriasis.
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