A type IV collagenase inhibitor, N-hydroxy-3-phenyl-2-(4-phenylbenzenesulfonamido) propanamide (BiPS), suppresses skin injury induced by sulfur mustard

Toxicol Appl Pharmacol. 2020 Aug 15;401:115078. doi: 10.1016/j.taap.2020.115078. Epub 2020 May 29.

Abstract

Sulfur mustard (SM) is a highly toxic blistering agent thought to mediate its action, in part, by activating matrix metalloproteinases (MMPs) in the skin and disrupting components of the basement membrane zone (BMZ). Type IV collagenases (MMP-9) degrade type IV collagen in the skin, a major component of the BMZ at the dermal-epidermal junction. In the present studies, a type IV collagenase inhibitor, N-hydroxy-3-phenyl-2-(4-phenylbenzenesulfonamido) propanamide (BiPS), was tested for its ability to protect the skin against injury induced by SM in the mouse ear vesicant model. SM induced inflammation, epidermal hyperplasia and microblistering at the dermal/epidermal junction of mouse ears 24-168 h post-exposure. This was associated with upregulation of MMP-9 mRNA and protein in the skin. Dual immunofluorescence labeling showed increases in MMP-9 in the epidermis and in the adjacent dermal matrix of the SM injured skin, as well as breakdown of type IV collagen in the basement membrane. Pretreatment of the skin with BiPS reduced signs of SM-induced cutaneous toxicity; expression of MMP-9 mRNA and protein was also downregulated in the skin by BiPS. Following BiPS pretreatment, type IV collagen appeared intact and was similar to control skin. These results demonstrate that inhibiting type IV collagenases in the skin improves basement membrane integrity after exposure to SM. BiPS may hold promise as a potential protective agent to mitigate SM induced skin injury.

Keywords: Basement Membrane; MMP-9; Matrix Metalloproteinase Inhibitor; Sulfur Mustard; Type IV Collagen.

Publication types

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

MeSH terms

  • Animals
  • Benzopyrans / pharmacology
  • Benzopyrans / therapeutic use*
  • Chemical Warfare Agents / toxicity*
  • Collagen Type IV / antagonists & inhibitors*
  • Collagen Type IV / metabolism
  • Epidermis / drug effects
  • Epidermis / pathology
  • Male
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Matrix Metalloproteinase Inhibitors / therapeutic use*
  • Mice
  • Mustard Gas / toxicity*
  • Skin Diseases / chemically induced
  • Skin Diseases / drug therapy*
  • Skin Diseases / metabolism
  • Skin Diseases / pathology

Substances

  • 1',3-dihydro-1'-(2-carboxyethyl)-3,3-dimethyl-6-nitrospiro-(2H-1-benzopyran-2,2'-(2H)-indoline)
  • Benzopyrans
  • Chemical Warfare Agents
  • Collagen Type IV
  • Matrix Metalloproteinase Inhibitors
  • Mustard Gas