Fibrotic changes in the infrapatellar fat pad induce new vessel formation and sensory nerve fiber endings that associate prolonged pain

The infrapatellar fat pad (IFP) contains nerve fiber endings and is considered to play an important role in the perception of knee pain. However, it is unclear whether and to what degree prolonged pain influences the nociceptive role of the IFP. To answer this question, we established a novel rat model of knee pain in which inflammation is restricted to the IFP. Rats received a single intra-IFP injection of monoiodoacetic acid (MIA) (0.2 mg/10 µL or 1.0 mg/10 µL) in the left knee and a phosphate-buffered saline (10 µL) injection in the right knee as a control. Pain-avoidance behavior and histological changes of the knee joint were measured at multiple time points up to 28 days after MIA injection. Histological analysis showed a transient inflammatory response in the IFP body in the 0.2-mg model, whereas prolonged inflammation followed by fibrotic changes was observed in the 1.0-mg model. Subtle histological alterations were observed in the articular cartilage and IFP surface regardless of the dose. The pain-avoidance behavior test indicated the development of prolonged knee pain throughout the experimental period in the 1.0-mg group. Histological assessments showed a significant increase in calcitonin gene-related peptide (CGRP)-positive nerve fiber endings inside IFPs with fibrosis in newly vascularized surrounding regions. These data suggest that irreversible fibrotic changes in the IFP induce the formation of new vessels and CGRP-positive nerve fiber endings that associate prolonged pain in the joint.     

Punctate Inner Choroidopathy and Choroidal Neovascularization in Korean Patients

ABSTRACT

Purpose: To describe the clinical features and outcomes of punctate inner choroidopathy (PIC) in Korean patients

Methods: We retrospectively reviewed the medical records of patients with PIC between 2004 and 2015. The main outcome measures included best-corrected visual acuity (BCVA), presence of choroidal neovascularization (CNV), and optical coherence tomography findings. Patients with and without CNV were compared.

Results: Forty eyes of 26 patients were included. The final BCVA was better than 20/40 in 33 eyes (82.5%). CNV was initially present in 12 eyes (30.0%). The mean initial and final logMAR BCVA was poorer for eyes with CNV than for eyes without CNV. Eyes with CNV exhibited a larger myopic refractive error, inflammatory lesions confined within the posterior pole, and a decreased final subfoveal choroidal thickness compared with eyes without CNV.

Conclusion: PIC in the Korean population generally exhibits favorable visual outcomes, and eyes with CNV show more abnormalities and poorer outcomes.     

阿柏西普对碱烧伤大鼠角膜新生血管的抑制作用

目的　探讨阿柏西普对大鼠角膜碱烧伤后新生血管的抑制作用。方法　制备SD大鼠角膜碱烧伤动物模型,随机分成4组,每组各9只,A组、B组与C组分别给予20 g·L^-1、25 g·L^-1、30 g·L^-1的阿柏西普滴眼液,D组为生理盐水组（给予生理盐水）,每组每天2次滴眼治疗,共14 d。分别于碱烧伤后第3天、7天、14天,观察角膜新生血管（corneal neovascularization,CNV)情况并计算CNV面积。碱烧伤后第14天,处死全部小鼠,进行组织学和免疫组织化学检测各组CD34、VEGF蛋白表达情况。结果　碱烧伤后第 3天、7天和14天,A组、B组与C组的CNV面积均小于D组,差异均有统计学意义（均为P<0.05）;B组与C组在各时间点上CNV面积差异均无统计学意义（均为P>0.05）;但B组和C组与A组相比,差异均有统计学意义（均为P<0.05）。HE 染色及免疫组织化学染色结果显示:角膜碱烧伤后第14天,各组角膜CD34和VEGF蛋白表达增强,与A组、B组、C组比较,D组CNV旺盛致密,CD34和VEGF蛋白表达较强。A组CNV较B组和C组多,CD34和VEGF蛋白表达增强;B组和C组棕黄色颗粒分布无明显差异。碱烧伤后第14天,酶联免疫吸附试验测定结果显示:A组、B组和C组房水中TNF-α蛋白表达水平均低于D组,差异均有统计学意义（均为P<0.05）,B组、C组与A组比较,房水中TNF-α蛋白表达水平差异均有统计学意义（均为P<0.05）,但是B组和C组间差异无统计学意义（P>0.05）。结论　阿柏西普对碱烧伤后大鼠CNV形成具有抑制作用,且25 g·L^-1阿柏西普的治疗效果最佳。     

PXN-pY31、PXN-pY118在小鼠角膜新生血管形成中的表达变化

目的　探讨Paxillin（PXN）-pY³¹、PXN-pY¹¹⁸在小鼠角膜碱烧伤后角膜新生血管形成过程中的表达变化。方法　取健康6~8周龄雄性C57BL6小鼠36只,均右眼建立角膜碱烧伤模型为实验组,左眼不作任何处理为对照组,观察碱烧伤后1 d、3 d、5 d、7 d、10 d、14 d 角膜新生血管情况,并行免疫组织化学染色;Western blot 检测实验组碱烧伤后1 d、3 d、5 d、7 d时PXN-pY³¹、PXN-pY¹¹⁸在角膜中的表达变化。结果　对照组角膜无新生血管生成,PXN-pY³¹、PXN-pY¹¹⁸在角膜中未见表达。实验组角膜新生血管长度、钟点数及面积随着碱烧伤后时间的延长均呈曲线样改变。免疫组织化学染色检测结果显示,实验组角膜中PXN-pY³¹、PXN-pY¹¹⁸的表达均较对照组增强,其动态过程与角膜新生血管的发展进程一致。Western blot检测结果示,实验组碱烧伤后3 d PXN-pY³¹,PXN-pY¹¹⁸的表达显著升高;碱烧伤后5 d,PXN-pY³¹、PXN-pY¹¹⁸的表达达到高峰;碱烧伤后7 d,PXN-pY³¹、PXN-pY¹¹⁸表达开始下降。碱烧伤后3 d、5 d、7 d时PXN-pY³¹、PXN-pY¹¹⁸的表达与碱烧伤后1 d相比,差异均有统计学意义（均为P<0.05）。结论　PXN-pY³¹、PXN-pY¹¹⁸在角膜损伤的病理机制中发挥作用,其表达变化与角膜新生血管的生长情况相关。     

康柏西普玻璃体内注射治疗特发性脉络膜新生血管

目的　探究康柏西普玻璃体内注射治疗特发性脉络膜新生血管（idiopathic choroidal neovascularization,ICNV）的疗效。方法　选择2016年1月至2018年1月我院眼科收治的ICNV患者146例（146眼）纳入研究,所有患者均行玻璃体内注射康柏西普治疗,测量治疗前后最佳矫正视力（BCVA）、眼压、黄斑中心凹脉络膜厚度（subfoveal choroidal thickness,SFCT）及上侧脉络膜厚度（superior choroidal thickness,SCT）、下侧脉络膜厚度（inferior choroidal thickness,ICT）、鼻侧脉络膜厚度（nasal choroidal thickness,NCT）、颞侧脉络膜厚度（temporal choroidal thickness,TCT）,观察并评价脉络膜新生血管（CNV）渗漏情况,比较患眼治疗前后BCVA、眼压及各区域脉络膜厚度,以及患眼及对侧眼脉络膜厚度差异。结果　与治疗前比较,患眼治疗后 1 d、1个月时BCVA均显著提高(均为P<0.05）。患眼治疗前后眼压比较差异均无统计学意义（均为P>0.05）。随访12个月时患眼渗漏区面积较治疗前均有下降,CNV渗漏治疗有效率为80.82%。治疗前患眼SFCT、NCT 2.2 mm、TCT 2.2 mm、TCT 3.45 mm均显著高于对侧眼（均为P<0.05）;治疗后12个月患眼各部位脉络膜厚度均较治疗前显著降低,差异均有统计学意义（均为P<0.05）。治疗过程中及治疗后均未见严重不良反应发生。结论　玻璃体内注射康柏西普可改善ICNV患者视力,减少视网膜渗漏症状,降低SFCT,效果较好。     

抗血管内皮生长因子药物治疗渗出型老年性黄斑变性的局限性研究现状

渗出型老年性黄斑变性(wAMD)是由于脉络膜新生毛细血管通过破裂的Bruch膜到达RPE层和光感受器细胞层形成脉络膜新生血管(CNV),继而导致新生血管出血、渗漏以及瘢痕形成。鉴于VEGF在CNV发生发展过程中具有重要作用,各种眼内抗VEGF药物靶向治疗是目前wAMD治疗的一线选择。但抗VEGF药物治疗wAMD的疗效受多种因素影响,仍有部分患者存在治疗无应答、药物耐受、需要长期反复注射以及严重副作用等问题。深入探究wAMD发病的生理病理过程,寻找导致CNV形成的最根本原因,从病因出发探寻更优的治疗方案是未来研究的方向。     

FOXC2 controls Ang-2 expression and modulates angiogenesis, vascular patterning, remodeling, and functions in adipose tissue

Adipogenesis is spatiotemporally coupled to angiogenesis throughout adult life, and the interplay between these two processes is communicated by multiple factors. Here we show that in a transgenic mouse model, increased expression of forkhead box C2 (FOXC2) in the adipose tissue affects angiogenesis, vascular patterning, and functions. White and brown adipose tissues contain a considerably high density of microvessels appearing as vascular plexuses, which show redistribution of vascular smooth muscle cells and pericytes. Dysfunction of these primitive vessels is reflected by impairment of skin wound healing. We further provide a mechanistic insight of the vascular phenotype by showing that FOXC2 controls Ang-2 expression by direct activation of its promoter in adipocytes. Remarkably, an Ang-2-specific antagonist almost completely reverses this vascular phenotype. Thus, the FOXC2-Ang-2 signaling system is crucial for controlling adipose vascular function, which is part of an adaptation to increased adipose tissue metabolism.     

Müller glial cells inhibit proliferation of retinal endothelial cells via TGF‐β2 and Smad signaling

Neovascularization is a sight‐threatening complication of ischemic proliferative retinopathies. Transforming growth factor (TGF)‐β, a cytokine with multiple functions in the retina, participates in the control of pathological angiogenesis and neovascularization. Retinal glial (Müller) cells produce TGF‐β2 under physiological and post‐ischemic conditions. To characterize glial cell‐derived mediators of angiogenesis regulation in glial‐endothelial interactions in the retina, we co‐cultured primary Müller cells and bovine microvascular retinal endothelial cells (BRECs). Müller cell‐derived TGF‐β2 was bound by the BRECs, which were found to express serine/threonine kinase TGF‐β receptors, and stimulated TGF‐β‐dependent anti‐proliferative signaling pathways. The proliferation of BRECs was attenuated by exogenous TGF‐β2 as well as by the presence of Müller cell culture media. The following intracellular signaling mechanisms were found to be involved in the anti‐angiogenic action of Müller cell‐derived TGF‐β2: (i) binding of TGF‐β2 to BRECs is mediated by the type‐II TGF‐β receptor, leading to (ii) activation and phosphorylation of receptor‐activated Smads; (iii) Müller cell‐derived TGF‐β2 activates Smad2 and Smad3 to (iv) attenuate the phosphorylation state of the MAP kinases, extracellular signal‐regulated kinase (ERK)‐1/‐2. Neutralizing TGF‐β or TGF‐β type‐II receptor or blocking the activation of Smads partially abrogated the effect of Müller cell‐conditioned media on BRECs. Together, our data suggest that Müller cells release TGF‐β2, inhibiting the proliferation of retinal endothelial cells via activation of Smad2/Smad3 and attenuation of ERK signaling. Given the context‐dependent action of TGF‐β2 on angiogenesis, our results may have implications for understanding the pathogenesis of retinal angiopathies, such as diabetic retinopathy, and the anti‐angiogenic role of TGF‐β therein. GLIA 2014;62:1476–1485