Serine protease signaling of epidermal permeability barrier homeostasis

Evidence is growing that protease-activated receptor-2 (PAR-2) plays a key role in epithelial inflammation. We hypothesized here that PAR-2 plays a central role in epidermal permeability barrier homeostasis by mediating signaling from serine proteases (SP) in the stratum corneum (SC). Since the SC contains tryptic- and chymotryptic-like activity, we assessed the influence of SP activation/inhibition on barrier function. Acute barrier disruption increases SP activity and blockade by topical SP inhibitors (SPI) accelerates barrier recovery after acute abrogation. This improvement in barrier function is due to accelerated lamellar body (LB) secretion. Since tryptic SP signal certain downstream responses through PAR-2, we assessed its potential role in mediating the negative effects of SP on permeability barrier. Firstly, PAR-2 is expressed in the outer nucleated layers of the epidermis and most specifically under basal condition to the lipid raft (LR) domains. Secondly, tape stripping-induced barrier abrogation provokes PAR-2 activation, as shown by receptor internalization (i.e. receptor movement from LR to cytolpasmic domains). Thirdly, topical applications of PAR-2 agonist peptide, SLIGRL, delay permeability barrier recovery and inhibit LB secretion, while, conversely, PAR-2 knockout mice display accelerated barrier recovery kinetics and enhanced LB secretion, paralleled by increased LR formation and caveolin-1 expression. These results demonstrate first, the importance of SP/SPI balance for normal permeability barrier homeostasis, and second, they identify PAR-2 as a novel signaling mechanism of permeability barrier, that is, of response linked to LB secretion.     

Expression of cyclooxygenase-2 in cholangiocarcinoma: correlation with clinicopathological features and prognosis

BACKGROUND AND AIMS: No information is available on the nature of the correlation between cyclooxygenase-2 (COX-2) expression and the clinicopathological features and prognosis of cholangiocarcinoma (CC). The goal of the present study was to determine the possible roles and clinical significance of COX-2 expression in CC. METHODS: We investigated the immunohistochemical expression of COX-2 in 102 patients with CC with respect to clinicopathological characteristics, namely evidence of Clonorchis sinensis infection, proliferation index (PI, assessed by Ki-67 expression), apoptotic index (AI, assessed by TUNEL stain), and microvessel density (MVD, assessed by CD34 expression). Evidence of C. sinensis infection was assessed by the microscopic examination of stools for C. sinensis ova, serological testing (ELISA), and the detection of peripheral bile duct dilations by imaging studies. RESULTS: An immunohistochemical investigation demonstrated the immunolabeling of tumor cells, mainly in the cytoplasmic and perinuclear regions, in 53 (52%) of the 102 patients with CC. No significant differences were found in terms of age, sex, tumor differentiation, involvement of the resection margin, presence of lymph nodes or liver metastases, or in pTNM stage between COX-2 positive and COX-2 negative patients. However, evidence of C. sinensis infection was more common in COX-2 positive patients (P < 0.05). No significant differences were found for PI, AI, MVD, or cumulative survival between COX-2 positive and COX-2 negative patients. CONCLUSION: Clonorchis sinensis infection is related to aberrant COX-2 expression in patients with CC. However, COX-2 expression is not related to clinical outcome in CC patients.     

A Case of Primary Cutaneous Mucinous Carcinoma with Neuroendocrine Differentiation

Primary cutaneous mucinous carcinoma is a rare malignant tumor that originates from the deepest portion of the eccrine sweat duct. Common sites of involvement are the face and scalp. Biopsy shows dermal epithelial cell islands embedded in mucin pools separated by fibrous septae. It is difficult to differentiate this tumor histologically from metastatic adenocarcinoma. Recurrence after excision is common but metastases are rare. We report a primary cutaneous mucinous carcinoma with neuroendocrine differentiation on the right cheek of a 63-year-old man.