title: Absence of a p53 allele delays nitrogen mustard-induced early apoptosis and inflammation of murine skin.
abstract: Bifunctional alkylating agent sulfur mustard (SM) and its analog nitrogen mustard (NM) cause DNA damage leading to cell death, and potentially activating inflammation. Transcription factor p53 plays a critical role in DNA damage by regulating cell cycle progression and apoptosis. Earlier studies by our laboratory demonstrated phosphorylation of p53 at Ser15 and an increase in total p53 in epidermal cells both in vitro and in vivo following NM exposure. To elucidate the role of p53 in NM-induced skin toxicity, we employed SKH-1 hairless mice harboring wild type (WT) or heterozygous p53 (p53+/-). Exposure to NM (3.2mg) caused a more profound increase in epidermal thickness and apoptotic cell death in WT relative to p53+/- mice at 24h. However, by 72h after exposure, there was a comparable increase in NM-induced epidermal cell death in both WT and p53+/- mice. Myeloperoxidase activity data showed that neutrophil infiltration was strongly enhanced in NM-exposed WT mice at 24h persisting through 72h of exposure. Conversely, robust NM-induced neutrophil infiltration (comparable to WT mice) was seen only at 72h after exposure in p53+/- mice. Similarly, NM-exposure strongly induced macrophage and mast cell infiltration in WT, but not p53+/- mice. Together, these data indicate that early apoptosis and inflammation induced by NM in mouse skin are p53-dependent. Thus, targeting this pathway could be a novel strategy for developing countermeasures against vesicants-induced skin injury.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 12850 E. Montview Blvd, Aurora, CO 80045, USA. Swetha.Inturi@ucdenver.edu
authors.forename: Swetha
authors.initials: S
authors.lastname: Inturi
authors.forename: Neera
authors.initials: N
authors.lastname: Tewari-Singh
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jain
authors.forename: Srirupa
authors.initials: S
authors.lastname: Roy
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity*; D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003877:Dermatitis, Contact / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008466:Mechlorethamine / Q000633:toxicity*; D051379:Mice; D008812:Mice, Hairless; D009195:Peroxidase / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: D000477:Alkylating Agents; D016159:Tumor Suppressor Protein p53; D008466:Mechlorethamine; D009195:Peroxidase
keywords: 2-chloroethyl ethyl sulfide; ATM; ATR; Ataxia telangiectasia mutated; Ataxia telangiectasia-Rad3-related; CEES; GSH; Glutathione; MPO; Myeloperoxidase; NM; Nitrogen mustard; PARP; Poly (ADP-ribose) polymerase; SM; Skin apoptosis; Skin inflammation; Skin p53; Sulfur mustard; TUNEL; TdT-mediated dUTP Nick-End Labeling; WT; p53 heterozygous; p53 knock out; p53 wild type; p53+/−; p53−/−