2025/06/09 更新

お知らせ

 

写真a

ヤマグチ ムネオ
山口 宗男
YAMAGUCHI MUNEO
所属
九州大学病院 眼科 助教
医学部 医学科(併任)
職名
助教

研究分野

  • ライフサイエンス / 眼科学

学位

  • 博士 ( 2018年5月 九州大学 )

経歴

  • 九州大学 九州大学病院 眼科  助教 

    2025年4月 - 現在

論文

  • Heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation

    Yamaguchi M., Nakao S., Arima M., Little K., Singh A., Wada I., Kaizu Y., Zandi S., Garweg J.G., Matoba T., Shiraishi W., Yamasaki R., Shibata K., Go Y., Ishibashi T., Uemura A., Stitt A.W., Sonoda K.H.

    Diabetologia   67 ( 10 )   2329 - 2345   2024年10月   ISSN:0012186X

     詳細を見る

    出版者・発行元:Diabetologia  

    Aims/hypothesis: Diabetic retinopathy is characterised by neuroinflammation that drives neuronal and vascular degenerative pathology, which in many individuals can lead to retinal ischaemia and neovascularisation. Infiltrating macrophages and activated retina-resident microglia have been implicated in the progression of diabetic retinopathy, although the distinct roles of these immune cells remain ill-defined. Our aim was to clarify the distinct roles of macrophages/microglia in the pathogenesis of proliferative ischaemic retinopathies. Methods: Murine oxygen-induced retinopathy is commonly used as a model of ischaemia-induced proliferative diabetic retinopathy (PDR). We evaluated the phenotype macrophages/microglia by immunostaining, quantitative real-time RT-PCR (qRT-PCR), flow cytometry and scRNA-seq analysis. In clinical imaging studies of diabetic retinopathy, we used optical coherence tomography (OCT) and OCT angiography. Results: Immunostaining, qRT-PCR and flow cytometry showed expression levels of M1-like macrophages/microglia markers (CD80, CD68 and nitric oxide synthase 2) and M2-like macrophages/microglia markers (CD206, CD163 and macrophage scavenger receptor 1) were upregulated in areas of retinal ischaemia and around neo-vessels, respectively. scRNA-seq analysis of the ischaemic retina revealed distinct ischaemia-related clusters of macrophages/microglia that express M1 markers as well as C-C chemokine receptor 2. Inhibition of Rho-kinase (ROCK) suppressed CCL2 expression and reduced CCR2-positive M1-like macrophages/microglia in areas of ischaemia. Furthermore, the area of retinal ischaemia was reduced by suppressing blood macrophage infiltration not only by ROCK inhibitor and monocyte chemoattractant protein-1 antibody but also by GdCl3. Clinical imaging studies of diabetic retinopathy using OCT indicated potential involvement of macrophages/microglia represented by hyperreflective foci in areas of reduced perfusion. Conclusions/interpretation: These results collectively indicated that heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation in retinal vascular diseases including diabetic retinopathy. This adds important new information that could provide a basis for a more targeted, cell-specific therapeutic approach to prevent progression to sight-threatening PDR. Graphical Abstract: (Figure presented.).

    DOI: 10.1007/s00125-024-06215-3

    Scopus

  • Identifying Hyperreflective Foci in Diabetic Retinopathy via VEGF-Induced Local Self-Renewal of CX3CR1<sup>+</sup> Vitreous Resident Macrophages

    Yamaguchi M., Nakao S., Wada I., Matoba T., Arima M., Kaizu Y., Shirane M., Ishikawa K., Nakama T., Murakami Y., Mizuochi M., Shiraishi W., Yamasaki R., Hisatomi T., Ishibashi T., Shibuya M., Stitt A.W., Sonoda K.H.

    Diabetes   71 ( 12 )   2685 - 2701   2022年12月   ISSN:00121797

     詳細を見る

    出版者・発行元:Diabetes  

    Intraretinal hyperreflective foci (HRF) are significant biomarkers for diabetic macular edema. However, HRF at the vitreoretinal interface (VRI) have not been exam-ined in diabetic retinopathy (DR). A prospective observational clinical study with 162 consecutive eyes using OCT imaging showed significantly increased HRF at the VRI during DR progression (P < 0.01), which was reversed by anti-vascular endothelial growth factor (VEGF) therapy. F4/80+ macrophages increased significantly at the VRI in Kimba (vegfa+/+) or Akimba (Akita × Kimba) mice (both P < 0.01), but not in diabetic Akita (Ins2+/2) mice, indicat-ing macrophage activation was modulated by elevated VEGF rather than the diabetic milieu. Macrophage depletion significantly reduced HRF at the VRI (P < 0.01). Fur-thermore, BrdU administration in Ccr2rfp/+Cx3cr1gfp/+ vegfa+/2 mice identified a significant contribution of M2-like tissue-resident macrophages (TRMs) at the VRI. Ki-67+ and CD11b+ cells were observed in preretinal tissues of DR patients, while exposure of vitreal macrophages to vitreous derived from PDR patients induced a significant proliferation response in vitro (P < 0.01). Taken to-gether, the evidence suggests that VEGF drives a local proliferation of vitreous resident macrophages (VRMs) at the VRI during DR. This phenomenon helps to explain the derivation and disease-relevance of the HRF lesions observed through OCT imaging in patients.

    DOI: 10.2337/db21-0247

    Scopus

  • Morphology and fluorescein leakage in diabetic retinal microaneurysms: a study using multiple en face OCT angiography image averaging

    Fukuda Y., Nakao S., Kaizu Y., Arima M., Shimokawa S., Wada I., Yamaguchi M., Takeda A., Sonoda K.H.

    Graefe's Archive for Clinical and Experimental Ophthalmology   260 ( 11 )   3517 - 3523   2022年11月   ISSN:0721832X

     詳細を見る

    出版者・発行元:Graefe's Archive for Clinical and Experimental Ophthalmology  

    Purpose: To investigate the relevance of microaneurysm morphology in optical coherence tomography angiography (OCTA) image averaging and fluorescein leakage in diabetic retinopathy (DR). Methods: In 38 consecutive patients with DR, ten consecutive 3- × 3-mm fovea-centered OCTA (HS100, Canon Inc., Tokyo, Japan) and fluorescein angiography (FA) were performed, and averaged OCTA images were created based on the 10 images. After detecting all microaneurysms in FA images, the morphology was classified into four types (focal bulge, saccular/pedunculated, fusiform, and mixed) using averaged OCTA images. The correlation between microaneurysm leakage in FA, retinopathy stage, and microaneurysm morphology was estimated. Results: Thirty-eight eyes (50.0%) of the 33 patients were available for analysis, and 370 (63.5%) of the 583 FA-detected microaneurysms were morphologically classifiable (focal bulge, 46; saccular/pedunculated, 143; fusiform, 29; and mixed, 152) in OCTA. There was a significant correlation between stage and percentage of microaneurysm morphology and between morphology and the presence of leakage (P < 0.0001 and P < 0.01, respectively). The proportion of focal bulges decreased with stage progression, while the other three types increased with stage progression. The percentage of FA leakage for focal bulge, saccular/pedunculated, fusiform, and mixed was 41.3%, 66.4%, 82.8%, and 66.4%, respectively, and the fusiform type showed significant FA leakage. Conclusion: Microaneurysm morphology is correlated with the DR stage and FA leakage. Microaneurysm morphology recognition using OCTA image averaging may be useful for the clinical evaluation of DR. [Figure not available: see fulltext.]

    DOI: 10.1007/s00417-022-05713-7

    Scopus

  • Longer Interscan Times in OCT Angiography Detect Slower Capillary Flow in Diabetic Retinopathy

    Kaizu Y., Nakao S., Soda T., Horie J., Wada I., Yamaguchi M., Takeda A., Sonoda K.H.

    Ophthalmology Science   2 ( 3 )   2022年9月

     詳細を見る

    出版者・発行元:Ophthalmology Science  

    Purpose: To investigate the detection of slower retinal capillary blood flow using commercial OCT angiography (OCTA) with a longer interscan time in diabetic retinopathy (DR). Design: Observational, prospective, cross-sectional study. Participants: A total of 62 eyes from 39 subjects with diabetes mellitus and 10 eyes from 9 healthy subjects. Methods: Commercial spectral domain-OCT was used to obtain 3 × 3-mm fovea-centered OCTA images of all eyes with 3 different interscan times (4.3, 5.7, and 8.6 ms). For each interscan time, OCTA imaging was performed 5 consecutive times, and a ×5 averaged image was obtained. Capillary flow density and visualization of retinal capillaries in the superficial and deep capillary plexuses (SCPs and DCPs, respectively) were compared between the 3 averaged images from the 3 different interscan times. Main Outcome Measures: Capillary flow density and visualization of foveal capillaries in 3 images with different interscan times. Results: Forty-five eyes of 34 patients were analyzed. There was no significant difference in the flow density of the SCP and DCP between the 3 images with different interscan times in all the DR stages. Some capillaries including microaneurysms that could not be observed at 4.3 ms could be observed at 5.7 or 8.6 ms. There were significantly more capillaries with difference points between the 3 images in the group with DR than in the group without DR (P < 0.01). The morphology of some microaneurysms also changed with longer interscan times. Conclusions: OCTA with longer interscan times revealed slower flow points in capillaries and more accurate visualization and morphology of microaneurysms in DR.

    DOI: 10.1016/j.xops.2022.100181

    Scopus

  • Hyperreflective Membrane at the Vitreoretinal Interface in Diabetic Macular Edema: A Finding in Ultra-High-Resolution Optical Coherence Tomography

    Wada I., Nakao S., Arima M., Ishikawa K., Yamaguchi M., Kaizu Y., Sekiryu H., Mori K., Kiyohara K., Takeda A., Ishibashi T., Sadda S.R., Sonoda K.H.

    Translational Vision Science and Technology   11 ( 9 )   2022年9月

     詳細を見る

    出版者・発行元:Translational Vision Science and Technology  

    Purpose: Detecting subtle vitreoretinal interface (VRI) findings, such as a posterior hyaloid membrane, is difficult with conventional retinal imaging. We compared ultra-high-resolution spectral domain optical coherence tomography (UHR-SD-OCT) with standard-resolution OCT (SD-OCT) for the imaging of VRI abnormalities in diabetic retinopathy (DR). Methods: This prospective cross-sectional study included 113 consecutive patients (91 patients with diabetes and 22 healthy controls). The VRI was evaluated, and the results were compared between the conventional SD-OCT and UHR-SD-OCT images. VRI findings were also investigated before and after internal limiting membrane peeling during vitrectomy for proliferative DR. Results: A total of 159 eyes (87.4%) of 91 patients with diabetes were analyzed. UHR-SD-OCT could detect a hyperreflective layer at the VRI, in which en face OCT showed a membrane-like structure, termed the hyperreflective membrane (HRMe). The preop-erative HRMe could not be detected in all patients with proliferative DR who under-went internal limiting membrane peeling during vitrectomy. Although the HRMe did not correlate with the DR stage, eyes with diabetic macular edema (DME) (64.5%) showed a significant HRMe with UHR-SD-OCT more frequently than those without DME (35.8%) (P = 0.005). Conclusions: UHR-SD-OCT can detect the HRMe at the VRI in DR eyes, particularly in eyes with DME. The HRMe may present a thickened posterior hyaloid membrane that contributes to DME development. Translational Relevance: UHR-SD-OCT detects slight changes in the VRI in DR eyes. In the future, it may help to elucidate the mechanism of DME formation.

    DOI: 10.1167/tvst.11.9.21

    Scopus

  • A Case of Bullous Central Serous Chorioretinopathy Treated with Surgical Removal of Submacular Fibrin and Subsequent Photodynamic Therapy under Silicone Oil

    Notomi S., Shiose S., Kohno R.I., Shimokawa S., Ishikawa K., Kano K., Mori K., Wada I., Fukuda Y., Nakatake S., Yamaguchi M., Sonoda K.H.

    Case Reports in Ophthalmology   13 ( 2 )   385 - 392   2022年5月

     詳細を見る

    出版者・発行元:Case Reports in Ophthalmology  

    Bullous retinal detachment is a rare complication in the chronic phase of central serous chorioretinopathy (CSC). Only a small subset of eyes with chronic CSC develops into the bullous variant of CSC (bCSC). In patients with bCSC, the elevated concentration of fibrin in the subretinal space leads to persistent retinal detachment and eventually, severe vision loss. We experienced a case of unilateral bCSC with a massive accumulation of subretinal fibrin. Multiple leakage points and dilated choroidal veins were also observed. The patient underwent surgical removal of subretinal fibrin and silicone oil injection followed by photodynamic therapy (PDT). After this treatment, the retina was successfully reattached, and the affected eye was free from recurrent exudative changes for more than 18 months. Massive subretinal fibrin could be surgically removed to prevent the formation of subretinal fibrosis and retinal fold, and PDT under silicone oil can control the underlying exudative changes in bCSC.

    DOI: 10.1159/000524515

    Scopus

▼全件表示

講演・口頭発表等

MISC

共同研究・競争的資金等の研究課題

  • 糖尿病網膜症におけるマイクログリア・マクロファージを標的とした神経保護治療

    研究課題/領域番号:21K16897  2021年 - 2022年

    日本学術振興会  科学研究費助成事業  若手研究

    山口 宗男

      詳細を見る

    担当区分:研究代表者  資金種別:科研費

    抗VEGF療法等により、糖尿病網膜症(DR)の本態である血管病変の沈静化は得られるようになった。しかし、しばしば血管病変は沈静化していても視力不良な症例を認める。網膜イメージング機器の解像度が上がったことにより、そのような症例では網膜視細胞の障害が示唆されるようになったが、現在治療法はない。神経障害に炎症細胞の関与を考え、神経保護治療の標的として解析を行う。

    CiNii Research

  • シングルセルレベルでの眼内増殖組織の活動性バイオマーカー検索

    研究課題/領域番号:20K09829  2020年4月 - 2023年3月

    科学研究費助成事業  基盤研究(C)

    中尾 新太郎, 石川 桂二郎, 山口 宗男, 有馬 充, 澤 新一郎

      詳細を見る

    資金種別:科研費

    網膜増殖性疾患は外科的手術が唯一の治療法であるが、侵襲性があり度重なる手術が必要となる場合ある。現在、有効な薬物治療はなく開発困難な理由として、増殖組織が多様な細胞の集合体であり、細胞の相互作用と環境への反応が存在することが考えられる。今回増殖糖尿病網膜症にフォーカスし、増殖組織のシングルセルRNAシークエンスにより、眼内増殖組織に含まれる細胞群とその遺伝子発現を同定する。シングルセルレベルでの遺伝子ライブラリーを作成し、今後の基盤研究とする。将来的に臨床データ(眼底所見・光干渉断層像・蛍光造影検査・再発など)との相関により分子病態層別化・精密医療実現・分子標的薬創生に貢献できると考える。

    CiNii Research

専門診療領域

  • 生物系/医歯薬学/外科系臨床医学/眼科学

臨床医資格

  • 専門医

    日本眼科学会

医師免許取得年

  • 2009年