Eyeworld

EW RETINA 52 April 2011 by Matt Young EyeWorld Contributing Editor Study of retinal complications in rodents may have implications for humans C ataract surgery in rodents has a major impact on pro-inflammatory gene and protein response in the posterior segment of the eye, new research has found. "A similar response in humans might explain the pathogenesis of cataract surgery-associated retinal complications such as cystoids mac- ular oedema," according to a report by Heping Xu, M.D., Centre for Vi- sion and Vascular Disease, Queen's University, Belfast, Ireland. The re- port was published online in August 2010 in Investigative Ophthalmology & Visual Science. The expression of pro-inflam- matory genes is "acute, if not instant," Dr. Xu noted. It predomi- nantly occurs in the neurosensory retina, he added. "Our study pro- vides the first experimental evidence that lens extraction induces a pro- inflammatory response in the retina," Dr. Xu reported. Monitoring the response Dr. Xu analyzed the effects of cataract surgery in 1 eye of 24 mice. The contralateral eye, as well as eyes from 9 unoperated animals, served as controls. "The neurosensory retina and retinal pigment epithelium (RPE)- choroid were collected post-opera- tively," Dr. Xu noted. "Expression of genes involved in the acute inflam- matory/injury response, including IL-1β [interleukin-1 beta], fibroblast growth factor, transforming growth factor b, chemokine CCL2, SDF-1 [stromal cell-derived factor-1], and complement [components] C3, C4, and factor B (CFB) were examined by real-time PCR [polymerase chain reaction] and, selectively, by im- munohistochemistry." Gene expression was analyzed first. These genes "might affect the BRB [blood-retinal barrier] including cytokine IL-1, chemokines CCL2 and SDF-1, and growth factors FGF [fibroblast growth factor] and VEGF in the retina and RPE/choroid." This could lead to complications such as macular edema. Dr. Xu found that 2 weeks post- op, the expression of IL-1β, CCL2, and FGF genes was "statistically sig- nificantly up-regulated in the neu- rosensory retina of eyes which had cataract extraction when compared with fellow unoperated eyes … as well as with eyes from normal, un- operated mice." IL-1β is an "important mediator of inflammatory response," Dr. Xu reported. Research has shown it to be involved in blood-retinal barrier breakdown, particularly related to diabetic retinopathy. Mice with IL- 1β overexpression also have more retinal VEGF expression, potentially promoting neovascularization, Dr. Xu noted. CCL2, meanwhile, is frequently coupled with IL-1β, "particularly during acute innate immune responses," Dr. Xu noted. A time-course study was con- ducted to determine how soon sur- gery could affect retina and RPE/ choroidal gene expression. The ex- pression of IL-1β and CCL2 genes was "massively upregulated" greater than 20-fold 30 minutes after lens extraction in the neurosensory retina of operated eyes compared with controls. The genes increased more than 50-fold by 24 hours post- op "and remained at high levels at 1 week post-surgery," Dr. Xu noted. When Dr. Xu analyzed the pro- tein expression of IL-1β and CCL2, strong immunostaining was found in the ganglion cell layer, inner nu- clear layer, and choroid of operated eyes. Dr. Xu concluded that lens ex- traction induces pro-inflammatory genes in the posterior segment. "The inflammatory/immune ac- tivation is manifested by the mas- sive production of inflammatory cytokine IL-1 and chemokine CCL2 and the activation of the comple- ment cascade," Dr. Xu reported. It is not known how lens re- moval causes retinal inflammation, Dr. Xu noted. It is possible that "in- flammation/cytokine gene expres- sion is induced in all structures of the eye and the low grade anterior segment inflammatory cell response is the maximal global response which will occur in the eye after lens extraction," Dr. Xu noted. "Related work in the field of wound healing and trauma has identified interest- ing novel mechanisms for the induc- tion of innate immune responses via 'danger signals' such as the release of uric acid form dying or injured cells or the accumulation of insoluble protein aggregates." This pro-inflammatory gene ex- pression has many clinical implica- tions, according to Dr. Xu. "The fact that lens extraction in- duces acute retinal immune/inflam- mation/cytokine gene activation may have important implications in cataract surgery-associated retinal complications including pseudopha- kic macular oedema, and especially so if there is co-existing pathology such as occurs in the progression of diabetic retinopathy/maculopathy and neovascular AMD, both of which are observed after this surgi- cal procedure," Dr. Xu concluded. Asked his opinion of the results, Francis S. Mah, M.D., co-medical director, Charles T. Campbell Oph- thalmic Microbiology Laboratory, University of Pittsburgh School of Medicine, noted that some patients without increased risk of problems after cataract surgery nonetheless de- velop cystoid macular edema. "Even if the surgery went per- fectly and the phaco time was low, some of these patients develop CME," Dr. Mah said. Meanwhile, he said, some re- search has shown that patients who have undergone phacoemulsifica- tion have a higher rate of AMD than those who have not had the surgery. Dr. Mah believes that sometimes there's a "retinal phenomenon that people can't explain" after cataract surgery. Possible causes include acute trauma, inflammation during surgery, or some problem related to the IOLs. "It's probably one of those— maybe a combination," he said. Anything surgeons can do to de- crease inflammation post-op, such as using strong steroids, is war- ranted, he said. EW Editors' note: Dr. Mah has no financial interests related to his comments. Dr. Xu has no financial interests related to this study. Contact information Mah: 412-647-2211, mahfs@upmc.edu Xu: heping.xu@qub.ac.uk Surveying continued from page 50 diabetics who did not. Dr. Zhang at- tributes this to the fact that, in such cases, the diabetes itself is more se- vere. In most cases, findings here were in line with other analysis. "Most of these things make sense and are pretty consistent with previ- ous findings and literature," Dr. Zhang said. "For example, we still have racial/ethnic risk factors— African Americans and Mexican Americans have a higher preva- lence." In non-Hispanic white indi- viduals, the rate of diabetic retinopathy among diabetics was 26.4% compared with 34% of Mexi- can Americans and 38.8% of non- Hispanic black individuals. Dr. Zhang sees such data as hav- ing important clinical implications. "It's important for physicians who have patients from a racial/ethnic minority to remind them that they may have a greater risk of complica- tions and that's why they need to get eye exams," Dr. Zhang said. "These things have some public health implications." He hopes that both physicians and patients come away from the study with more insight into dia- betic retinopathy. "I think that the message for physicians is that they will have a higher prevalence of dia- betic retinopathy among patients with diabetes, especially in racial/ ethnic minorities," Dr. Zhang said. "So there are some clinical implica- tions." He hopes that physicians don't lose sight of this and keep closer tabs on these individuals. Dia- betic patients need to keep their pre- disposition in mind. "They need to take control of their diabetes and get their eyes examined regularly," Dr. Zhang said. "Finding problems early and treating them right away can delay or prevent loss of vision." Going forward, Dr. Zhang hopes to look at the prevalence of retinopathy in non-diabetic individ- uals. "Even people without diabetes can have retinopathy caused by other conditions," he said. "We are doing some additional research on that as well." EW Editors' note: Dr. Zhang has no finan- cial interests related to his comments. Contact information Zhang: xzhang4@cdc.gov

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