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Terry Singhapricha, Una Kelly, Michael Landowski, Marybeth Groelle, Peter Saloupis, Catherine Bowes Rickman; Oxidative Stress Significantly Increases Expression of Inflammatory and Antioxidant Markers in Complement Factor H Deficient Mice Compared to Wild-Type Mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):364. doi: https://doi.org/.
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Age-related macular degeneration (AMD) is the leading cause of blindness in the United States in people over 65 years of age. Studies have shown polymorphisms in the complement factor H (CFH) gene, which encodes an alternative complement pathway inhibitor, as the strongest genetic factor associated with AMD risk. A recent study has shown that CFH may protect against the inflammatory response by binding to lipid peroxidation products such as malondialdehyde. The aim of this study was to compare the response to oxidative stress in CFH deficient mice (cfh-/-) and wild-type mice in vivo.
cfh-/- mice aged 64-68 weeks and age-matched wild-type controls were divided into two groups per genotype based on oxidative stress exposure. The mice were injected subconjunctivally with the oxidative stressor hydroquinone (HQ), and the retinal pigmented epithelium and choroid were harvested. The inflammatory response was queried through pathway focused PCR arrays. The gene expression levels were normalized to housekeeping genes and data was calculated using ΔΔCt method and shown as fold changes.
The PCR results showed significant increases in fold regulation for acute inflammatory markers such as Cxcl1 and IL6 as well as in antioxidant markers after HQ injection in both groups, with cfh-/- mice showing greater increase in expression than wild type. In addition, only the cfh-/- mice showed significant increased expression of other cytokines that regulate acute inflammatory processes such as prostaglandin synthesis and leukocyte chemotaxis.
cfh-/- mice expressed significantly higher levels of both antioxidant markers and acute inflammatory markers such as IL6 and Cxcl1/KC compared to wild type mice after acute oxidative stress. Additionally, only the cfh-/- group showed significantly higher expression levels of other acute inflammatory cytokines such as Ptgs2, Cxcl2, and Cxcl5. The comparative increase in these markers provide evidence that complement dysregulation leads to an inflammatory response in the posterior eye in response to oxidative stress.
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