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Morphine promotes neovascularizing retinopathy in sickle transgeneic mice.

ABSTRACT: Neovascularizing retinopathy is a significant complication of sickle cell disease (SCD), occurring more frequently in HbSC than HbSS disease. This risk difference is concordant with a divergence of angiogenesis risk, as identified by levels of pro- vs anti-angiogenic factors in the sickle patient's blood. Because our prior studies documented that morphine promotes angiogenesis in both malignancy and wound healing, we tested whether chronic opioid treatment would promote retinopathy in NY1DD sickle transgenic mice. After 10 to 15 months of treatment, sickle mice treated with morphine developed neovascularizing retinopathy to a far greater extent than either of the controls (sickle mice treated with saline and wild-type mice treated identically with morphine). Our dissection of the mechanistic linkage between morphine and retinopathy revealed a complex interplay among morphine engagement with its ? opioid receptor (MOR) on retinal endothelial cells (RECs); morphine-induced production of tumor necrosis factor ? and interleukin-6 (IL-6), causing increased expression of both MOR and vascular endothelial growth factor receptor 2 (VEGFR2) on RECs; morphine/MOR engagement transactivating VEGFR2; and convergence of MOR, VEGFR2, and IL-6 activation on JAK/STAT3-dependent REC proliferation and angiogenesis. In the NY1DD mice, the result was increased angiogenesis, seen as neovascularizing retinopathy, similar to the retinal pathology occurring in humans with SCD. Therefore, we conclude that chronic opioid exposure, superimposed on the already angiogenic sickle milieu, might enhance risk for retinopathy. These results provide an additional reason for development and application of opioid alternatives for pain control in SCD.

SUBMITTER: Gupta K

PROVIDER: S-EPMC6457224 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Morphine promotes neovascularizing retinopathy in sickle transgeneic mice.

Gupta Kalpna K Chen Chunsheng C Lutty Gerard A GA Hebbel Robert P RP

Blood advances 20190401 7

Neovascularizing retinopathy is a significant complication of sickle cell disease (SCD), occurring more frequently in HbSC than HbSS disease. This risk difference is concordant with a divergence of angiogenesis risk, as identified by levels of pro- vs anti-angiogenic factors in the sickle patient's blood. Because our prior studies documented that morphine promotes angiogenesis in both malignancy and wound healing, we tested whether chronic opioid treatment would promote retinopathy in NY1DD sick ...[more]

PMID: 30944099

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Project description:BackgroundSickle cell retinopathy (SCR) is one of the most important ocular manifestations of sickle cell disease (SCD). This study aims to assess the prevalence of SCR in SCD, identify risk factors for its development and progression to proliferative sickle cell retinopathy (PSCR), and evaluate the potential implications of these results on clinical practice.MethodsThis research is a secondary analysis of patients diagnosed with SCD from the epidemiological, multicenter Cooperative Study of Sickle Cell Disease (CSSCD). We included all patients who completed a full ophthalmic evaluation. We identified clinical and laboratory SCD characteristics associated with SCR using multivariate logistic regression models. Proliferative sickle cell retinopathy (PSCR) was diagnosed according to the Goldberg classification system.ResultsOf the 1904 study participants with SCD who met the inclusion criteria, 953 (50.1%) had retinopathy; of which 642 (67.3%) had bilateral disease. SCR was associated with older age (p < 0.001), history of smoking (p = 0.001), hematuria (p = 0.050), and a lower hemoglobin F (HbF) level (p < 0.001). PSCR risk increased with smoking (p = 0.005), older age (p < 0.001) higher hemoglobin level (p < 0.001) and higher white blood cell count (p = 0.011). Previous blood transfusion (p = 0.050), higher reticulocyte count (p = 0.019) and higher HbF level (p < 0.001) were protective factors against the development of PSCR. Ocular symptoms were associated with progression to PSCR in patients with SCR (p = 0.021).ConclusionIn this cohort of individuals with SCD, half of the participants had signs of SCR. Smoking and blood hemoglobin level were the two modifiable risk factors associated with increased retinopathy progression. Screening to identify the different stages of retinopathy, actively promoting smoking cessation, and optimizing the hematological profile of patients with SCD should guide treatment protocols designed to prevent the vision-threatening complications of the disease.

Dataset Information

Morphine promotes neovascularizing retinopathy in sickle transgeneic mice.

Publications

Morphine promotes neovascularizing retinopathy in sickle transgeneic mice.

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