Expression of cytokines and chemokines in mouse skin treated with sulfur mustard

Toxicol Appl Pharmacol. 2018 Sep 15;355:52-59. doi: 10.1016/j.taap.2018.06.008. Epub 2018 Jun 20.

Abstract

Sulfur mustard (2,2'-dichlorodiethyl sulfide, SM) is a chemical warfare agent that generates an inflammatory response in the skin and causes severe tissue damage and blistering. In earlier studies, we identified cutaneous damage induced by SM in mouse ear skin including edema, erythema, epidermal hyperplasia and microblistering. The present work was focused on determining if SM-induced injury was associated with alterations in mRNA and protein expression of specific cytokines and chemokines in the ear skin. We found that SM caused an accumulation of macrophages and neutrophils in the tissue within one day which persisted for at least 7 days. This was associated with a 2-15 fold increase in expression of the proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor α at time points up to 7 days post-SM exposure. Marked increases (20-1000 fold) in expression of chemokines associated with recruitment and activation of macrophages were also noted in the tissue including growth-regulated oncogene α (GROα/CXCL1), monocyte chemoattractant protein 1 (MCP-1/CCL2), granulocyte-colony stimulating factor (GCSF/CSF3), macrophage inflammatory protein 1α (MIP1α/CCL3), and IFN-γ-inducible protein 10 (IP10/CXCL10). The pattern of cytokines/chemokine expression was coordinate with expression of macrophage elastase/MMP12 and neutrophil collagenase/MMP8 suggesting that macrophages and neutrophils were, at least in part, a source of cytokines and chemokines. These data support the idea that inflammatory cell-derived mediators contribute to the pathogenesis of SM induced skin damage. Modulating the infiltration of inflammatory cells and reducing the expression of inflammatory mediators in the skin may be an important strategy for mitigating SM-induced cutaneous injury.

Keywords: Dermal toxicity; Immuno-multiplex assays; Inflammatory cells infiltration; Inflammatory mediators; Sulfur mustard; Vesicants.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chemical Warfare Agents / toxicity*
  • Chemokines / biosynthesis*
  • Cytokines / biosynthesis*
  • Ear, External / drug effects
  • Ear, External / metabolism
  • Ear, External / pathology
  • Immunohistochemistry
  • Inflammation / chemically induced
  • Inflammation / pathology
  • Inflammation Mediators / metabolism
  • Male
  • Matrix Metalloproteinase 12 / biosynthesis
  • Matrix Metalloproteinase 8 / biosynthesis
  • Mice
  • Mustard Gas / toxicity*
  • RNA / biosynthesis
  • RNA / genetics
  • Skin / drug effects*
  • Skin / metabolism*
  • Skin / pathology
  • Skin Diseases / chemically induced
  • Skin Diseases / metabolism

Substances

  • Chemical Warfare Agents
  • Chemokines
  • Cytokines
  • Inflammation Mediators
  • RNA
  • MMP8 protein, mouse
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase 12
  • matrix metallopeptidase 12, mouse
  • Mustard Gas