Role of emmprin/CD147 in tissue remodeling.

Emmprin/CD147 is a cell membrane glycoprotein that belongs to the Ig superfamily and is involved in numerous physiological and pathological systems. Through its ability to interact with multiple partners within the cell surface and its potential to regulate the expression of several targets within the cell, emmprin may have different functions depending on the cell or tissue type. However, its role in tissue remodeling remains the most clearly demonstrated. Emmprin is able to induce, in the same cellular model, both the matrix metalloproteinases and the serine protease urokinase plasminogen activator, whose concerted action in the breakdown of the extracellular matrix (ECM) during various physiopathological situations has been reported. In addition, emmprin also promotes myofibroblasts' differentiation and tissue contraction through the induction of alpha smooth muscle actin, thus expanding on the mechanism by which emmprin remodels ECM

Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions

Tear hyperosmolarity plays an essential role in the initiation and progression of dry-eye disease. Under a hyperosmotic environment, corneal epithelial cells experience perturbations in endoplasmic reticulum function that can lead to proinflammatory signaling and apoptosis. In this study, we investigated the effect of tauroursodeoxycholic acid (TUDCA), a chemical chaperone known to protect against endoplasmic reticulum stress, on corneal epithelial cells exposed to hyperosmotic conditions. We found that the expression of the genes involved in the activation of the unfolded protein response and the pro-apoptotic transcription factor DDIT3 were markedly upregulated in patients with Sjögren’s dry-eye disease and in a human model of corneal epithelial differentiation following treatment with hyperosmotic saline. Experiments in vitro demonstrated that TUDCA prevented hyperosmotically induced cell death by reducing nuclear DNA fragmentation and caspase-3 activation. TUDCA supplementation also led to the transcriptional repression of CXCL8 and IL5, two inflammatory mediators associated with dry-eye pathogenesis. These studies highlight the role of hyperosmotic conditions in promoting endoplasmic reticulum stress in the cornea and identify TUDCA as a potential therapeutic agent for the treatment of dry-eye disease

Glycogene Expression Profile of Human Limbal Epithelial Cells with Distinct Clonogenic Potential

Glycans function as valuable markers of stem cells but also regulate the ability of these cells to self-renew and differentiate. Approximately 2% of the human genome encodes for proteins that are involved in the biosynthesis and recognition of glycans. In the present study, we evaluated the expression of a small subset of glycogenes in human limbal epithelial cells with distinct clonogenic potential. Individual clones were classified as abortive or clonogenic, based on the fraction of the terminal colonies produced; clones leading exclusively to terminal colonies were referred to as abortive while those with half or fewer terminal colonies were referred to as clonogenic. An analysis of glycogene expression in clonogenic cultures revealed a high content of transcripts regulating the galactose and mannose metabolic pathways. Abortive clones were characterized by increased levels of GCNT4 and FUCA2, genes that are responsible for the branching of mucin-type O-glycans and the hydrolysis of fucose residues on N-glycans, respectively. The expansion of primary cultures of human limbal epithelial cells for 10 days resulted in stratification and a concomitant increase in MUC16, GCNT4 and FUCA2 expression. These data indicate that the clonogenic potential of human limbal epithelial cells is associated with specific glycosylation pathways. Mucin-type O-glycan branching and increased fucose metabolism are linked to limbal epithelial cell differentiation

Long-term visual outcome of childhood blepharokeratoconjunctivitis.

PURPOSE: To assess the visual outcome of childhood blepharokeratoconjunctivitis. DESIGN: Retrospective noncomparative case series. METHODS: We reviewed visual acuity and corneal examination results for 23 patients (mean age 19 +/- 4 years, range, 11 to 26 years) who had healed more than three years previously (up to 15 years). RESULTS: The disease involved 29 eyes and was unilateral in 17 children. Corneal sequelae (neovascularization or scars) involved 18 eyes (62%) of 15 children (65%). Mean best-corrected visual acuity was 20/25 (range, 20/100 to 20/20). Best-corrected visual acuity was no more than 20/30 in seven eyes (24%) of seven children (30%). Fifteen eyes (52%) of 13 children (45%) had astigmatisms of at least 0.75 diopters attributable to corneal scars. CONCLUSIONS: Corneal and visual sequelae are frequent in childhood blepharokeratoconjunctivitis. Early diagnosis and specific treatment are mandatory

Archipelago keratitis: a clinical variant of recurrent herpetic keratitis?

OBJECTIVE: To describe archipelago keratitis, a presumed clinical variant of herpetic epithelial keratitis. DESIGN: Case series. PARTICIPANTS: A series of 6 patients with an unusual form of superficial keratitis. METHODS: History, including age, gender, clinical evolution, and treatment; slit-lamp biomicroscopy findings; in vivo confocal microscopy findings; and corneal epithelial scrapings were analyzed. MAIN OUTCOME MEASURES: Clinical ocular examination, a diagnostic workup including corneal scraping for herpesvirus polymerase chain reaction, in vivo confocal microscopy, and therapeutic outcome. RESULTS: The authors describe a series of 6 patients with keratitis consisting of foci of epithelial erosions associated with subepithelial nummular inflammatory infiltrates and disposed in a radial, centripetal, archipelagolike pattern originating from the limbus. All the patients had a past history of herpetic epithelial keratitis, herpetic vesicles on the ipsilateral lid, or both. Polymerase chain reaction-based screening for herpes simplex virus 1 and 2 in corneal scrapings demonstrated positive results in 2 patients. In vivo corneal confocal microscopy revealed focal areas of hyperreflective epithelial cells and hyperreflective subepithelial dendritic structures overlying activated keratocytes. All the patients improved with oral valacyclovir treatment followed by topical steroid therapy. CONCLUSIONS: Archipelago keratitis may be a new clinical variant of herpetic keratitis, reflecting herpetic dissemination from the limbus to the center of the cornea

Extracellular matrix metalloproteinase inducer up-regulates the urokinase-type plasminogen activator system promoting tumor cell invasion.

Extracellular matrix metalloproteinase inducer (EMMPRIN) is a membrane glycoprotein overexpressed in many cancer tissues and is known for its ability to stimulate MMP expression. In this work, we show that EMMPRIN is also a regulator of the urokinase-type plasminogen activation (uPA) system of serine proteases, thus participating to the increase of the overall proteolytic function of the cancer cells. Enhanced EMMPRIN expression in a tumorigenic breast epithelial cell line NS2T2A increased the levels of uPA, uPA receptor, and the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1), as measured by quantitative reverse transcription-PCR, Western blot, and plasminogen-casein zymography. This response was down-regulated by either EMMPRIN small interfering RNA or a blocking antibody to EMMPRIN. EMMPRIN-containing purified membrane fraction from Chinese hamster ovary cells when added exogenously to NS2T2A cells induced a similar activation of the uPA/PAI-1 system. Additionally, overexpression of EMMPRIN in NS2T2A cells increased uPA levels in cocultured endothelial cells, showing a paracrine regulation loop involving a tumor-stroma interaction. EMMPRIN-expressing cells also exhibited enhanced invasive potential in vitro, and the use of amiloride (uPA inhibitor) and marimastat (MMP inhibitor) showed that the two proteolytic systems reduced alone and in combination the invasive potential mediated through EMMPRIN. These data show a novel regulatory pathway for uPA activity and suggest that EMMPRIN is involved in uPA dysregulation observed in cancer