Involvement of caspases and transmembrane metalloproteases in sulphur mustard-induced microvesication in adult human skin in organ culture: Directions for therapy

Mol, M.A.E.; Berg, R.M. van den; Benschop, H. P.

doi:10.1016/j.tox.2009.01.004

Cited by 34 publications

(26 citation statements)

References 48 publications

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“…laminin-5, collagen and other extracellular matrix proteins (ECM) after SM exposure (Hess and FitzGerald, 2007). These proteases are either secreted by neutrophils or are directly activated by SM at the time of injury, leading to blister formation (Chang et al, 2009; Mol et al, 2009; Ray et al, 2002; Sabourin et al, 2002). Similar to the microvesication observed following SM exposure as well as our previous studies with CEES and NM, in this study NM induced microvesication in WT mice in this study.…”

Section: Discussionmentioning

confidence: 99%

Myeloperoxidase deficiency attenuates nitrogen mustard-induced skin injuries

et al. 2014

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The pathologic mechanisms of skin injuries, following the acute inflammatory response induced by vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) exposure, are poorly understood. Neutrophils which accumulate at the site of injury, abundantly express myeloperoxidase (MPO), a heme protein that is implicated in oxidant-related antimicrobial and cytotoxic responses. Our previous studies have shown that exposure to SM analog 2-chloroethyl ethyl sulfide (CEES) or NM results in an inflammatory response including increased neutrophilic infiltration and MPO activity. To further define the role of neutrophil-derived MPO in NMinduced skin injury, here we used a genetic approach and examined the effect of NM exposure (12 h and 24 h) on previously established injury endpoints in C57BL/6J wild type (WT) and B6.129X1-MPOtm1Lus/J mice (MPO KO), homozygous null for MPO gene. NM exposure caused a significant increase in skin bi-fold thickness, epidermal thickness, microvesication, DNA damage and apoptosis in WT mice compared to MPO KO mice. MPO KO mice showed relatively insignificant effect. Similarly, NM-induced increases in the expression of inflammatory and proteolytic mediators, including COX-2, iNOS and MMP-9 in WT mice, while having a significantly lower effect in MPO KO mice. Collectively, these results show that MPO, which generates microbicidal oxidants, plays an important role in NM-induced skin injuries. This suggests the development of mechanism-based treatments against NM-and SM-induced skin injuries that inhibit MPO activity and attenuate MPO-derived oxidants.

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Section: Discussionmentioning

confidence: 99%

Myeloperoxidase deficiency attenuates nitrogen mustard-induced skin injuries

et al. 2014

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“…Recent findings (Ries et al, 2008;Mol et al, 2009) have shown that the release of matrix metalloproteinases (MMPs) is a critical element in the formation of SM-induced blisters. Further details of the molecular aspects of SM injury are discussed later in the issue .…”

Section: Discussionmentioning

confidence: 99%

Acute effects of sulfur mustard injury—Munich experiences

et al. 2009

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“…TACE is included in these experiments because it is an MMP family member that has been implicated in the corneal epithelial erosions that develop after exposure of eyes to mustard gas (Mol et al, 2009). After 60 minutes, extracts with no MMPs added showed a time-dependent reduction in the amount of full-length 4 integrin as a result of the action of endogenous proteases (Fig.…”

Section: Mmps and Tace Cleave 4 Integrin In Addition To A3 And 1 Inmentioning

confidence: 99%

MMP9 cleavage of the β4 integrin ectodomain leads to recurrent epithelial erosions in mice

Pal‐Ghosh

Blanco

Tadvalkar

et al. 2011

Journal of Cell Science

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Integrin α6β4 is an integral membrane protein within hemidesmosomes and it mediates adhesion of epithelial cells to their underlying basement membrane. During wound healing, disassembly of hemidesmosomes must occur for sheet movement-mediated cell migration. The mechanisms of disassembly and reassembly of hemidesmosomes are not fully understood. The current study was initiated to understand the underlying cause of recurrent corneal erosions in the mouse. Here, we show that in vivo: (1) MMP9 levels are elevated and β4 integrin is partially cleaved in epithelial cell extracts derived from debridement wounded corneas; (2) the β4 ectodomain is missing from sites where erosions develop; and (3) β4 cleavage can be reduced by inhibiting MMP activity. Although β4, α3 and β1 integrins were all cleaved by several MMPs, only MMP9 was elevated in cell extracts derived from corneas with erosions. Coimmunoprecipitation studies showed that β4 integrin associates with MMP9, and protein clustering during immunoprecipitation induced proteolytic cleavage of the β4 integrin extracellular domain, generating a 100 kDa β4 integrin cytoplasmic domain fragment. Confocal imaging with three-dimensional reconstruction showed that MMP9 localizes at erosion sites in vivo where the ectodomain of β4 integrin is reduced or absent. MMP activation experiments using cultured corneal and epidermal keratinocytes showed reduced levels of α6β4 and β1 integrins within 20 minutes of phorbol ester treatment. This report is the first to show that β4 integrin associates with MMP9 and that its ectodomain is a target for cleavage by MMP9 in vivo under pathological conditions.

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Involvement of caspases and transmembrane metalloproteases in sulphur mustard-induced microvesication in adult human skin in organ culture: Directions for therapy

Cited by 34 publications

References 48 publications

Myeloperoxidase deficiency attenuates nitrogen mustard-induced skin injuries

Myeloperoxidase deficiency attenuates nitrogen mustard-induced skin injuries

Acute effects of sulfur mustard injury—Munich experiences

MMP9 cleavage of the β4 integrin ectodomain leads to recurrent epithelial erosions in mice

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