June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Ischemia-reperfusion injury as a model of activation and resolution of retinal neuroinflammation and vascular permeability
Author Affiliations & Notes
  • Steven F Abcouwer
    Ophthalmology & Visual Science, Univ of Michigan Kellog Eye Ctr, Ann Arbor, MI
  • Sumathi Shanmugam
    Ophthalmology & Visual Science, Univ of Michigan Kellog Eye Ctr, Ann Arbor, MI
  • Cheng-mao Lin
    Ophthalmology & Visual Science, Univ of Michigan Kellog Eye Ctr, Ann Arbor, MI
  • Heather Lindner
    Ophthalmology & Visual Science, Univ of Michigan Kellog Eye Ctr, Ann Arbor, MI
  • Dolly Ann Padovani-Claudio
    Ophthalmology & Visual Science, Univ of Michigan Kellog Eye Ctr, Ann Arbor, MI
  • Prathiba Jayaguru
    Ophthalmology & Visual Science, Univ of Michigan Kellog Eye Ctr, Ann Arbor, MI
  • Arivalagan Muthusamy
    Ophthalmology & Visual Science, Univ of Michigan Kellog Eye Ctr, Ann Arbor, MI
  • David A Antonetti
    Ophthalmology & Visual Science, Univ of Michigan Kellog Eye Ctr, Ann Arbor, MI
  • Footnotes
    Commercial Relationships Steven Abcouwer, None; Sumathi Shanmugam, None; Cheng-mao Lin, None; Heather Lindner, None; Dolly Padovani-Claudio, None; Prathiba Jayaguru, None; Arivalagan Muthusamy, None; David Antonetti, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 3101. doi:
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      Steven F Abcouwer, Sumathi Shanmugam, Cheng-mao Lin, Heather Lindner, Dolly Ann Padovani-Claudio, Prathiba Jayaguru, Arivalagan Muthusamy, David A Antonetti; Ischemia-reperfusion injury as a model of activation and resolution of retinal neuroinflammation and vascular permeability. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3101.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: The retina is often considered an immune privileged tissue with vascular endothelial tight junctions (TJ) that restrict leukocyte trafficking. Despite the broad use of ischemia reperfusion (IR) injury to investigate neuronal damage, little is known about the neuroinflammatory and vascular responses in this model of sterile retinal damage. We hypothesized that IR induces a neuroinflammatory and vascular permeability response with subsequent resolution.

Methods: Ischemia was induced in C57BL/6 mice for 90 min followed by natural reperfusion. The effect of IR on neurodegeneration, vascular permeability and neuroinflammation over 4 weeks was examined using measures of retinal cell death by DNA fragmentation; integrity of the blood-retinal barrier (BRB) by FITC-BSA leakage; the disassembly of endothelial TJ complexes by immunofluorescence (IF); retinal edema and retinal layer thinning in situ by optical coherence tomography (OCT); and luminal leukostasis and tissue infiltration of leukocyte subsets by IF and flow cytometry examining leukocyte, myeloid and granulocyte markers

Results: The IR model exhibited rapid neuronal cell death, BRB permeability and neuroinflammation that was sustained for 2 weeks and resolved by 4 weeks. OCT demonstrated a transient edema followed by layer thinning up to 2 weeks. A dramatic increase in leukostasis occurred at day 1, consisting of both lymphocytes and myeloid leukocytes, composed primarily of Ly6C(hi) inflammatory monocytes and Ly6G(+) granulocytes. A transition to leukocyte infiltration occurred between days 1 and 4, continued for 2 weeks and was fully resolved at 4 weeks. As myeloid inflammation progressed toward resolution, granulocytes were replaced by Ly6C(neg) reparative patrolling monocytes.

Conclusions: The mouse retinal IR-injury represents a model of prolonged but self-limiting neuroinflammation and vascular permeability that can be used to study mechanisms of resolution of cellular inflammation and restoration of the BRB.

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