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Comparison of the neuroinflammatory responses to selective retina therapy and continuous-wave laser photocoagulation in mouse eyes

  • Jung Woo Han
  • Juhye Choi
  • Young Shin Kim
  • Jina Kim
  • Ralf Brinkmann
  • Jungmook LyuEmail author
  • Tae Kwann ParkEmail author
Basic Science
  • 250 Downloads

Abstract

Purpose

This study investigated microglia and inflammatory cell responses after selective retina therapy (SRT) with microsecond-pulsed laser in comparison to continuous-wave laser photocoagulation (cwPC).

Methods

Healthy C57BL/6 J mice were treated with either a train of short pulses (SRT; 527-nm, Q-switched, 1.7-μs pulse) or a conventional thermal continuous-wave (532-nm, 100-ms pulse duration) laser. The mice were sacrificed and their eyes were enucleated 1, 3, 7, and 14 days after both laser treatments. Pattern of cell death on retinal section was evaluated by TUNEL assay, and the distribution of activated inflammatory cells and glial cells were observed under immunohistochemistry. Consecutive changes for the expression of cytokines such as IL-1β, TNF-α, and TGF-β were also examined using immunohistochemistry, and compared among each period after quantification by Western blotting.

Results

The numbers of TUNEL-positive cells in the retinal pigment epithelium (RPE) layer did not differ in SRT and cwPC lesions, but TUNEL-positive cells in neural retinas were significantly less on SRT. Vague glial cell activation was observed in SRT-treated lesions. The population of inflammatory cells was also significantly decreased after SRT, and the cells were located in the RPE layer and subretinal space. Proinflammatory cytokines, including IL-1β and TNF-α, showed significantly lower levels after SRT; conversely, the level of TGF-β was similar to the cwPC-treated lesion.

Conclusions

SRT resulted in selective RPE damage without collateral thermal injury to the neural retina, and apparently produced negligible glial activation. In addition, SRT showed a markedly less inflammatory response than cwPC, which may have important therapeutic implications for several macular diseases.

Keywords

Continuous-wave laser photocoagulation Inflammatory response Selective retina therapy Iba-1 CD11b F4/80 IL-1β TNF-α TGF-β 

Notes

Funding

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare (grant number: H I 17C0966, TK Park). This work was partially supported by the Soonchunhyang University Research Fund. The sponsor had no role in the design or conduct of this research.

Compliance with ethical standards

Conflict of interests

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Animal experiments

All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

Financial disclosure

None of the authors have any financial interests to disclose.

References

  1. 1.
    Brinkmann R, Roider J, Birngruber R (2006) Selective retina therapy (SRT): a review on methods, techniques, preclinical and first clinical results. Bull Soc Belge Ophtalmol (302):51–69Google Scholar
  2. 2.
    Brinkmann R, Huttmann G, Rogener J, Roider J, Birngruber R, Lin CP (2000) Origin of retinal pigment epithelium cell damage by pulsed laser irradiance in the nanosecond to microsecond time regimen. Lasers Surg Med 27(5):451–464CrossRefPubMedGoogle Scholar
  3. 3.
    Kim HD, Han JW, Ohn YH, Brinkmann R, Park TK (2014) Functional evaluation using multifocal electroretinogram after selective retina therapy with a microsecond-pulsed laser. Invest Ophthalmol Vis Sci 56(1):122–131CrossRefPubMedGoogle Scholar
  4. 4.
    Park YG, Seifert E, Roh YJ, Theisen-Kunde D, Kang S, Brinkmann R (2014) Tissue response of selective retina therapy by means of a feedback-controlled energy ramping mode. Clin Exp Ophthalmol 42(9):846–855CrossRefPubMedGoogle Scholar
  5. 5.
    Framme C, Walter A, Prahs P et al (2009) Structural changes of the retina after conventional laser photocoagulation and selective retina treatment (SRT) in spectral domain OCT. Curr Eye Res 34(7):568–579CrossRefPubMedGoogle Scholar
  6. 6.
    Framme C, Schuele G, Kobuch K, Flucke B, Birngruber R, Brinkmann R (2008) Investigation of selective retina treatment (SRT) by means of 8 ns laser pulses in a rabbit model. Lasers Surg Med 40(1):20–27CrossRefPubMedGoogle Scholar
  7. 7.
    Elsner H, Porksen E, Klatt C et al (2006) Selective retina therapy in patients with central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol 244(12):1638–1645CrossRefPubMedGoogle Scholar
  8. 8.
    Klatt C, Saeger M, Oppermann T et al (2011) Selective retina therapy for acute central serous chorioretinopathy. Br J Ophthalmol 95(1):83–88CrossRefPubMedGoogle Scholar
  9. 9.
    Koinzer S, Elsner H, Klatt C et al (2008) Selective retina therapy (SRT) of chronic subfoveal fluid after surgery of rhegmatogenous retinal detachment: three case reports. Graefes Arch Clin Exp Ophthalmol 246(10):1373–1378CrossRefPubMedGoogle Scholar
  10. 10.
    Prahs P, Walter A, Regler R et al (2010) Selective retina therapy (SRT) in patients with geographic atrophy due to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 248(5):651–658CrossRefPubMedGoogle Scholar
  11. 11.
    Roider J, Liew SH, Klatt C et al (2010) Selective retina therapy (SRT) for clinically significant diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 248(9):1263–1272CrossRefPubMedGoogle Scholar
  12. 12.
    Colome J, Ruiz-Moreno JM, Montero JA, Fernandez E (2007) Diode laser-induced mitosis in the rabbit retinal pigment epithelium. Ophthalmic Surg Lasers Imaging 38(6):484–490PubMedGoogle Scholar
  13. 13.
    Framme C, Kobuch K, Eckert E, Monzer J, Roider J (2002) RPE in perfusion tissue culture and its response to laser application. Preliminary report. Ophthalmologica 216(5):320–328CrossRefPubMedGoogle Scholar
  14. 14.
    Lee SH, Kim HD, Park YJ, Ohn YH, Park TK (2015) Time-dependent changes of cell proliferation after laser photocoagulation in mouse Chorioretinal tissue. Invest Ophthalmol Vis Sci 56(4):2696–2708CrossRefPubMedGoogle Scholar
  15. 15.
    Tababat-Khani P, Berglund LM, Agardh CD, Gomez MF, Agardh E (2013) Photocoagulation of human retinal pigment epithelial cells in vitro: evaluation of necrosis, apoptosis, cell migration, cell proliferation and expression of tissue repairing and cytoprotective genes. PLoS One 8(8):e70465CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chidlow G, Shibeeb O, Plunkett M, Casson RJ, Wood JP (2013) Glial cell and inflammatory responses to retinal laser treatment: comparison of a conventional photocoagulator and a novel, 3-nanosecond pulse laser. Invest Ophthalmol Vis Sci 54(3):2319–2332CrossRefPubMedGoogle Scholar
  17. 17.
    Lehnardt S (2010) Innate immunity and neuroinflammation in the CNS: the role of microglia in toll-like receptor-mediated neuronal injury. Glia 58(3):253–263PubMedGoogle Scholar
  18. 18.
    Mainster MA, White TJ, Tips JH, Wilson PW (1970) Retinal-temperature increases produced by intense light sources. J Opt Soc Am 60(2):264–270CrossRefPubMedGoogle Scholar
  19. 19.
    Wood JP, Shibeeb O, Plunkett M, Casson RJ, Chidlow G (2013) Retinal damage profiles and neuronal effects of laser treatment: comparison of a conventional photocoagulator and a novel 3-nanosecond pulse laser. Invest Ophthalmol Vis Sci 54(3):2305–2318CrossRefPubMedGoogle Scholar
  20. 20.
    Neumanna J, Brinkmann R (2008) Self-limited growth of laser-induced vapor bubbles around single microabsorbers. Am Inst Phys 93Google Scholar
  21. 21.
    Kim HD, Jang SY, Lee SH et al (2016) Retinal pigment epithelium responses to selective retina therapy in mouse eyes. Invest Ophthalmol Vis Sci 57(7):3486–3495CrossRefPubMedGoogle Scholar
  22. 22.
    Tackenberg MA, Tucker BA, Swift JS et al (2009) Muller cell activation, proliferation and migration following laser injury. Mol Vis 15:1886–1896PubMedPubMedCentralGoogle Scholar
  23. 23.
    Krady JK, Basu A, Allen CM et al (2005) Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 54(5):1559–1565CrossRefPubMedGoogle Scholar
  24. 24.
    BenEzra D, Hemo I, Maftzir G (1990) In vivo angiogenic activity of interleukins. Arch Ophthalmol 108(4):573–576CrossRefPubMedGoogle Scholar
  25. 25.
    Shimura M, Yasuda K, Nakazawa T et al (2009) Panretinal photocoagulation induces pro-inflammatory cytokines and macular thickening in high-risk proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 247(12):1617–1624CrossRefPubMedGoogle Scholar
  26. 26.
    Carmi Y, Voronov E, Dotan S et al (2009) The role of macrophage-derived IL-1 in induction and maintenance of angiogenesis. J Immunol 183(7):4705–4714CrossRefPubMedGoogle Scholar
  27. 27.
    Lavalette S, Raoul W, Houssier M et al (2011) Interleukin-1beta inhibition prevents choroidal neovascularization and does not exacerbate photoreceptor degeneration. Am J Pathol 178(5):2416–2423CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Nelson CM, Ackerman KM, O’Hayer P, Bailey TJ, Gorsuch RA, Hyde DR (2013) Tumor necrosis factor-alpha is produced by dying retinal neurons and is required for Muller glia proliferation during zebrafish retinal regeneration. J Neurosci 33(15):6524–6539CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Oliveira RG, Ferreira AP, Cortes AJ, Aarestrup BJ, Andrade LC, Aarestrup FM (2013) Low-level laser reduces the production of TNF-alpha, IFN-gamma, and IL-10 induced by OVA. Lasers Med Sci 28(6):1519–1525CrossRefPubMedGoogle Scholar
  30. 30.
    Shi X, Semkova I, Muther PS, Dell S, Kociok N, Joussen AM (2006) Inhibition of TNF-alpha reduces laser-induced choroidal neovascularization. Exp Eye Res 83(6):1325–1334CrossRefPubMedGoogle Scholar
  31. 31.
    Lee J, Choi JH, Joo CK (2013) TGF-beta1 regulates cell fate during epithelial-mesenchymal transition by upregulating survivin. Cell Death Dis 4:e714CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ie D, Gordon LW, Glaser BM, Pena RA (1994) Transforming growth factor-beta 2 levels increase following retinal laser photocoagulation. Curr Eye Res 13(10):743–746CrossRefPubMedGoogle Scholar
  33. 33.
    Yamamoto C, Ogata N, Yi X et al (1998) Immunolocalization of transforming growth factor beta during wound repair in rat retina after laser photocoagulation. Graefes Arch Clin Exp Ophthalmol 236(1):41–46CrossRefPubMedGoogle Scholar
  34. 34.
    Ishida K, Yoshimura N, Yoshida M, Honda Y (1998) Upregulation of transforming growth factor-beta after panretinal photocoagulation. Invest Ophthalmol Vis Sci 39(5):801–807PubMedGoogle Scholar
  35. 35.
    Ito A, Hirano Y, Nozaki M, Ashikari M, Sugitani K, Ogura Y (2015) Short pulse laser induces less inflammatory cytokines in the murine retina after laser photocoagulation. Ophthalmic Res 53(2):65–73CrossRefPubMedGoogle Scholar
  36. 36.
    Ogata N, Ando A, Uyama M, Matsumura M (2001) Expression of cytokines and transcription factors in photocoagulated human retinal pigment epithelial cells. Graefes Arch Clin Exp Ophthalmol 239(2):87–95CrossRefPubMedGoogle Scholar
  37. 37.
    Er H, Doganay S, Turkoz Y et al (2000) The levels of cytokines and nitric oxide in rabbit vitreous humor after retinal laser photocoagulation. Ophthalmic Surg Lasers 31(6):479–483PubMedGoogle Scholar
  38. 38.
    Jobling AI, Guymer RH, Vessey KA et al (2015) Nanosecond laser therapy reverses pathologic and molecular changes in age-related macular degeneration without retinal damage. FASEB J 29(2):696–710CrossRefPubMedGoogle Scholar
  39. 39.
    Schuele G, Rumohr M, Huettmann G, Brinkmann R (2005) RPE damage thresholds and mechanisms for laser exposure in the microsecond-to-millisecond time regimen. Invest Ophthalmol Vis Sci 46(2):714–719CrossRefPubMedGoogle Scholar
  40. 40.
    Kelly MW (1997) Intracellular cavitation as a mechanism of short-pulse laser injury to the retinal pigment epithelium. PhD thesis. Tufts University. 231Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Jung Woo Han
    • 1
  • Juhye Choi
    • 2
  • Young Shin Kim
    • 1
  • Jina Kim
    • 1
  • Ralf Brinkmann
    • 3
  • Jungmook Lyu
    • 2
    Email author
  • Tae Kwann Park
    • 1
    • 4
    • 5
    Email author
  1. 1.Department of Ophthalmology, College of MedicineSoonchunhyang UniversityBucheonSouth Korea
  2. 2.Department of Medical ScienceKonyang UniversityDaejeonRepublic of Korea
  3. 3.Institute of Biomedical OpticsUniversity of Lübeck and Medizinisches Laserzentrum Lübeck GmbHLübeckGermany
  4. 4.Laboratory for Translational Research on Retinal Macular Degeneration, College of MedicineSoonchunhyang UniversityBucheonSouth Korea
  5. 5.Department of OphthalmologySoonchunhyang University College of Medicine, Soonchunhyang University Bucheon HospitalBucheon-siSouth Korea

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