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E. Carlson, M. Lin, C.–Y. Liu, W.W. Y. Kao, E. Pearlman; Alterations in Extracelluar Matrix Gene Expression Due to Corneal Inflammation . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4356.
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The early events in an inflammatory response dictate the duration, intensity and impact upon the host. A severe corneal inflammatory response may result in vision loss due to stromal opacity or scarring. Previous reports show that proteoglycans are key in maintaining the integrity and transparency of the cornea through their interactions with collagen fibrils. The goal of this study is to determine the impact of inflammation upon proteoglycan expression and the clinical manifestations which may result.
Corneal inflammation was induced by intrastromal injection of lipopolysaccharide into the corneal stroma of mice using phosphate–buffered saline as a control. Early in the inflammatory response, 6 and 24 hours following induction, corneas were excised and quantitative RT–PCR and/or western blot analysis was performed for lumican and keratocan. LPS–keratitis was also induced in lumican–null mice and the enucleated eyes were frozen, sectioned and stained for NIMP–R14. Keratitis was also induced using microfilaria in GFP chimeric mice and imaged using confocal micrographs reconstructed into 3–dimensional movie files, respectively. Furthermore, a mRNA microarray was performed in microfilaria–induced keratitis.
Lumican mRNA expression decreased within 6 hours of an inflammatory stimulus. Compared to keratocan, lumican expression showed a larger decrease at 6 hours, but keratocan was significantly lower at 24 hours. These decreases were not due to keratocyte apoptosis. Microarray analysis also demonstrated a significant decrease of both proteoglycans in a microfilaria–induced keratitis model. Keratocan protein levels were significantly decreased 24 hrs after the inflammatory stimulus in both in vivo models of keratitis; whereas, explanted corneas did not show a decrease in keratocan protein expression. Keratocan–null mice demonstrated a more robust inflammatory response at 24 hours as compared to wild–type controls with respect to the kinetics of infiltrating cells and overall corneal opacity as analyzed by biomicroscopy. However, lumican–null mice showed an impaired neutrophil infiltration in response to an LPS stimulus.
The orchestration of corneal transparency and inflammatory responses in cornea is dictated by a host of signalling mechanisms. Lumican and keratocan were both down–regulated transcriptionally in corneal inflammation which may result in loss of stromal matrix regulation leading to long–term opacity.
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