Skin disruption is associated with indomethacin‐induced small intestinal injury in mice

Abstract

One mechanism by which non-steroidal anti-inflammatory drugs (NSAIDs) cause intestinal injury is by inducing matrix metalloproteinases (MMPs) that degrade and remodel the extracellular matrix. In addition to the intestinal mucosa, MMPs are expressed in the skin and can be activated by mast cell-secreted tryptase. We therefore investigated whether intestinal injury resulting from treatment with the NSAID indomethacin induced MMPs in the skin of mice and caused an associated disruption of skin function. Hairless mice and mast cell-deficient mice were administered indomethacin, after which damage to the jejuna and skin was assessed with immunohistochemistry and Western blotting. The plasma concentration of inflammatory mediators was assessed to evaluate potential pathways for signalling skin disruption in response to intestinal injury. In hairless mice with intestinal injury, transepidermal water loss (TEWL) was higher and skin hydration was lower than in control mice. The expression levels of mast cells, tryptase, MMP-1 and MMP-9 were also increased, with concurrent degradation of types I and IV collagen. In contrast, no changes in skin TEWL or skin hydration were observed in mast cell-deficient mice with indomethacin-induced intestinal injury. In all mice evaluated, the plasma concentrations of IgE, IgA, histamine and TNF-α were increased in response to indomethacin treatment. Skin disruption was strongly associated with indomethacin-induced small intestinal injury, and the activation of mast cells and induction of tryptase, MMP-1 and MMP-9 are critical to this association.

Impaired Skin Barrier Function in Mice with Colon Carcinoma Induced by Azoxymethane and Dextran Sodium Sulfate

“…6,7) In a previous study, we have also reported that impaired skin barrier function was caused by mast cell degranulation in a mouse intestinal injury model. 2) In the present study, we confirmed that mast cells were present in the skin using toluidine blue staining, although no significant difference was observed between the mice that were treated with AOM+DSS and the control mice (data not shown). Therefore, it is necessary to clarify which causative molecular marker induces skin disruption in further studies.…”

“…2) Based on this finding, we postulated that other intestinal diseases might also influence skin barrier function, as there appears to be a close relationship between the skin and intestine. For example, inflammatory bowel disease involves several cutaneous manifestations, such as erythema nodosum and pyoderma gangrenosum.…”

Influence of Repeated Senna Laxative Use on Skin Barrier Function in Mice

“…TEWL and the skin hydration levels of the dorsal skin were respectively measured using a Tewameter® TM300 and Corneometer® CM825 (Courage+Khazaka Electronic GmbH, Cologne, Germany) on days zero, seven, 14, and 21, according to previously described methods7.…”

“…One of the major intestinal tract diseases is inflammatory bowel disease (IBD), which occasionally complicates skin disorders as extraintestinal manifestations6. Additionally, the skin barrier function was impaired via mast cells in a small intestine-injured mouse model7. Further, in mice with colitis or colon cancer, the impaired skin barrier function occurred with destruction of type I collagen89.…”

Atopic Dermatitis Deteriorates Dextran Sodium Sulfate-Induced Ulcerative Colitis via Thymic Stromal Lymphopoietin in Mice

“…We described the details of the staining method in our previous report [18]. Briefly, the specimens were incubated overnight at 4˚C with one of the following primary …”