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M. M. Zhang, E. L. Liclican, S. B. Wang, A. J. Leedom, K. Gronert; Chronic Inflammatory Responses in the Cornea Exhibit Sex-Specific Differences. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1562.
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Chronic inflammation triggers pathological heme/lymph angiogenesis in the cornea, a key feature of many prominent ocular diseases. Sex-specific differences in the prevalence of ocular diseases are well documented and general sex-specific differences in inflammatory/immune responses have been reported. However, if chronic injury and the subsequent sequelae of inflammation and pathological angiogenesis exhibit sex-specific differences remains to be defined and was the aim of this study.
Chronic inflammation and neovascularization were induced by placing an 8-0 silk suture in the apex of the cornea of age-matched male and female Balb/c mice. Blood and lymph vessel formation were assessed by vital microscopy and immunofluorescence using CD31 (heme) and LYVE-1 (lymph) as specific markers of vascular and lymph endothelial cells, respectively. Myeloperoxidase (MPO) activity was selected as a quantitative marker for Polymorphonuclear leukocyte (PMN) infiltration. mRNA expression of key markers of corneal inflammation and angiogenesis (15-LOX, COX isoforms, HO-1 and selected receptors sFLT-1, FLT-4 and Fprl-1) was analyzed using RT-PCR.
Female and male mice developed similar degrees of heme angiogenesis and mRNA expression of key mediators of the VEGF circuit, VEGF-A and -C, and VEGF receptors (sFLT-1 and FLT-4) showed no sex-specific difference 7 days post suture placement. In contrast, marked differences were observed 48 hours post-suture injury. Males showed significantly higher PMN infiltration (2-fold) and expression of FLT-4 was markedly increased in females (1.5-fold). Females exhibited less lymph angiogenesis than males, correlating with a higher expression of 15-LOX in female than in male corneas (3-fold).
These results demonstrate for the first time sex-specific differences in the sequelae of chronic corneal injury and differential regulation of mediators of inflammation and angiogenesis. Specifically, regulation of the expression of the 15-LOX pathway, a resident protective pathway, may counter balance sex-specific upregulation of pro-inflammatory or pro-angiogenic circuits.
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