房水流出阻力的动力学及相关形态学的研究
摘要
第一部分
房水流出阻力动力学及相关形态学在猴眼慢性青光眼模型中的研究
目的：通过研究房水流出阻力在猴眼慢性青光眼模型的Schlemm氏管(SC)内壁和邻管组织(JCT)的动力学和相关形态学改变，来理解房水流出阻力的产生机制。
方法：三只雌性短尾猴，每只猴用氩激光光凝一眼的小梁部，另一眼作为对照，随访15．96-69．96月(平均44．32±27．10月)。将眼球取出，在24小时内灌注示踪剂后固定。分别用共焦显微镜、光镜、电镜检查，观察Schlemm管及小梁组织。
结果：激光组的平均眼压是61．33±4．16mmHg(Mean±SD)，显著高于对照组(22．67±4．04mmHg，P=0．0003)，而房水流畅率(0．03±0．02μl／min／mmHg)显著低于对照组(0．39±0．17μl／min／mmHg，P＜0．001)。共焦显微镜检查发现激光眼的小梁组织中示踪剂呈节段性分布，而在对照眼中分布较为均匀，测量有效滤过长度百分比，对照眼(47．47±10．79％)是激光眼(8．40±4．81％)的6倍(P=0．013)。光镜和电镜检查发现，激光眼的小梁组织中大量色素沉着，疤痕形成，SC管壁塌陷，激光组的SC管内外壁间距离(4．57±3．25μm)显著窄于对照组(19．14±5．75μm，P＜0．0001)，部分SC内壁及JCT组织突入集液管(CC)入口，发生率明显高于对照组。
结论：激光破坏了小梁组织造成有效滤过面积减少可能是房水流出阻力增加的部分原因。
第二部分
猴眼中不同眼压下房水流出阻力的动力学和相关形态学的改变实验一实验造成急性高眼压眼和正常眼压眼中房水流出阻力的研究
目的：通过研究在不同眼压下房水流出阻力的动力学和相关形态学改变，来探索房水流出阻力产生的机制。
方法：6只离体猕猴眼分为两组，每组3只，分别在30mmHg和7mmHg下灌注，同时连续记录房水流畅率。在同样灌注压下灌注入示踪剂后固定眼球。在共焦显微镜下观察示踪剂的分布情况，测量示踪剂在SC内壁的分布长度及SC总长度，计算房水有效滤过长度百分比(PEFL)，将两组进行比较。在光镜下观察两组SC内壁及JCT组织的形态学改变及CC入口处的情况。
结果：灌注压在7mmHg时的房水流畅率(0．34±0．08μl／min／mmHg)是灌注压在30mmHg时(0．16±0．06μl／min／mmHg)的2．3倍(P=0．03)，平均房水滤过长度百分比(56．02±6．04％)是灌注压在30mmHg时的1．6倍(36．08±0．38％，P=0．03)。在30mmHg灌注压时，示踪剂的分布呈节段性，更趋于集中分布于CC入口处附近，并发现有SC管塌陷的情况。部分SC内壁及JCT组织突入CC入口处的发生率为79．04±20．50％，是灌注压在7mmHg时(26．14±20．81％)的3倍，差别有显著性意义(P=0．03)。
结论：急性眼压升高，房水流畅率下降伴房水有效滤过面积下降，房水流出受限，集中于CC入口处附近。房水流出的动力学改变受SC塌陷、部分SC内壁及JCT组织突入CC入口等形态学改变的影响。
实验二
实验造成急性高眼压后又降至正常眼中房水流出阻力的研究
目的：研究眼压下降后房水流出阻力的改变情况，并通过其动力学和形态学的改变来探索其发生机制。
方法：10只离体猕猴眼被分为三组，一组4只眼灌注压在30mmHg时灌入红色示踪剂，然后将灌注压下降到7mmHg后灌入等剂量的绿色示踪剂，同时记录房水流畅率。另两组每组3只猕猴眼，灌注压始终保持在30mmHg和7mmHg，同样灌入两种示踪剂。在共焦显微镜下观察两种示踪剂的分布情况并计算PEFL。在光镜下观察各组切片的组织形态学改变，部分SC内壁及JCT组织突入CC入口处的发生情况。另外2只离体人眼，用同样实验方法，一只灌注压从45mmHg下降至7mmHg，另一只对照眼灌注压始终保持在45mmHg。
结果：灌注压从30mmHg下降至7mmHg后房水流畅率从0．37±0．10μl／min／mmHg升高至0．48±0．21μl／min／mmHg(P=0．6)；灌注压从7mmHg至7mmHg后房水流畅率从0．38±0．22μl／min／mmHg变化至0．56±0．45μl／min／mmHg(P=0．6)；灌注压从30mmHg至30mmHg后房水流畅率从0．19±0．06μl／min／mmHg变化至0．32±0．10μl／min／mmHg(P=0．1)。随灌注压下降，PEFL增大，灌注压在30mmHg时为27．60±6．43％，当下降至7mmHg时，PEFL为45．78±7．37％，是灌注压在30mmHg时的1．7倍，差别有统计学意义(P=0．01)。而灌注压从7mmHg至7mmHg时，PEFL从56．02±6．05％变化至62．96±12．76％(P=0．44)，差别无统计学意义。灌注压从30mmHg至30mmHg时PEFL分别是36．08±0．38％和39．76±3．01％(P=0．17)，差别亦无统计学意义。光镜检查发现，在灌注压从30mmHg降至7mmHg的眼中，发生部分SC内壁及JCT突入CC入口的发生率和突入程度介于灌注压在30mmHg和7mmHg之间。它们的发生率分别是33．06±2．66％，26．14±20．81％和79．04±20．50％(P＞0．05)。在灌注压从45mmHg下降至7mmHg的人眼中也有同样发现。
结论：部分SC内壁及JCT突入CC入口的发生情况在眼压升高时明显增多，但随眼压下降，发生了逆转，突入数和程度减少，同时伴有效滤过面积和房水流畅率增高。
第三部分
猴眼洗脱现象中房水流出阻力的动力学及相关形态学的研究
目的：通过研究猴眼洗脱现象中房水流出阻力的动力学及相关形态学改变，来试图寻求促使人类青光眼眼压下降的方法。
方法：8只恒河猴离体眼，在恒定压力15mmHg下灌注葡萄糖磷酸缓冲液，将眼球分为两组，每组4只眼球，一组为实验组，灌注180分钟，另一组为对照组，灌注30分钟，连续记录房水流畅率。在两组眼中灌入同等剂量的荧光微球以标记房水流出道模式，然后在同样灌注压下灌入锇酸固定液固定眼球。分别在共焦显微镜、光镜和电镜下观察。测量SC管长度(TL)和示踪剂沿SC内壁分布的长度(L)后计算平均有效滤过长度百分比(PEFL=L／TL)。沿SC内壁测量发生分离的JCT组织的长度(SL)，并计算平均分离长度百分比(PLS=SL／TL)。
结果：灌注180分钟后房水流畅率(1．46±0．70μl／min／mmHg)比基线(0．58±0．20μl／min／mmHg)增长了150％，统计有显著性意义(P＜0．01)，并产生了洗脱现象；而对照组灌注30分钟后房水流畅率(0．44±0．16μl／min／mmHg)无显著增加(0．62±0．21μl／min／mmHg，P=0．46)；共焦显微镜检查发现示踪剂在实验眼的分布较对照组更加均匀，实验组的平均有效滤过长度百分比(83．37±4．13％)是对照组的3．4倍(24．19±8．42％，P＜0．001)。光镜和电镜检查发现实验眼JCT组织的结构发生改变，组织扩张变得疏松。JCT细胞间以及JCT细胞和间质间的连接被打破，发生分离。实验组的平均分离百分比(77．4±3．2％)是对照眼的2．3倍(33．5±5．3％，P＜0．001)。有效滤过长度百分比和分离长度百分比呈高度正相关(P=0．00002)。
结论：洗脱现象中出现邻管组织结构改变，JCT细胞间、细胞与基质间发生分离可能是房水流出阻力降低的原因。
PartⅠ
Hydrodynamic and Morphological Correlates in Monkey Eyeswith Laser Induced-Glaucoma
Purpose:To investigate the relationship between decreased outflow facility and thechanges in hydrodynamic aqueous outflow pattern and morphology after chronicelevated intraocular pressure (IOP)in laser-induced glaucoma of cynomolgusmonkey eyes.
Methods:Argon laser photocoagulation bums to the trabecular meshwork (TM)were made in one eye of each monkey (N=3),leaving the contralateral eye as anormotensive control.Between 16 and 70 months later (mean±STD=44.32±27.10),measurements were made of IOP by pneumatonometry and outflow facility byfluorophotometry.To label the hydrodymamic patterns of outflow,the eyes wereenucleated and perfused with fluorescent microspheres (0.5μm;0.002%)at the lastpressure measured before death minus 7mmHg.The eyes were perfusion-fixed withKarnovsky's fixative at the same pressure.Confocal images were taken along theinner wall (IW)of the Schlemm's canal (SC).The total length (TL)and the filtrationlength (FL)of the IW decorated by tracers were measured in frontal sections.Theaverage percent effective filtration length (PEFL=FL/TL)was calculated for eacheye.Sections exhibiting SC were then processed and examined under light andelectron microscopy.
Results:The average IOP in laser-treated eyes was 61.33±4.16 mmHg,which wassignificantly higher than that of controls (22.67±4.04 mmHg,P=0.0003).Theaverage outflow facility (0.03±0.02μl/min/mmHg)was 13-fold lower inlaser-treated eyes than that of controls (0.39±0.17μl/min/mmHg,P=0.02).Byconfocal microscopy,in control eyes,SC was open and a segmental distribution ofmicrospheres was found with a greater concentration in the juxtacanalicularconnective tissue (JCT)region near the collector channel (CC)ostia.Much lesstracer labeling along SC in laser-treated eyes was seen than that in controls.Theaverage PEFL in controls (47.47±10.79%)was 6-fold larger than in laser-treatedeyes (8.40±4.81%,P=0.013).By light microscopy,there was extensivepigmentation throughout the TM,denser extracellular matrix in the JCT region,andmost of the SC collapsed with focal herniations of the IW and JCT protruding into the CC ostia in laser-treated eyes.The mean width of SC in control eyes(19.14±5.75μm)was 4-fold wider than in laser-treated eyes (4.57±3.25μm,p＜0.0001).In the laser-treated eyes,16 CC ostia were examined,herniations werefound in 14 CC ostia (88%),while herniations were found in 4 CC ostia of 23 CCostia examined in control eyes (17%,p＜0.0001).By electron microscopy,few or nomicrospheres were observed in laser-treated areas.However,in non-lasered areas,numerous microspheres were observed near the CC ostia area compared withcontrols.
Conclusions:In laser-induced glaucoma model,laser damage results in areduction in the available area for outflow across the IW of SC which contributes tothe decrease in outflow facility and thus elevation of the IOP Collapse of SC,causedby chronic elevation of IOP,further decreases in the available area for outflow in avicious cycle.This study suggests that available area for aqueous outflow play animportant role in regulating outflow resistance.
PartⅡ
Morphological and Hydrodynamic Correlates for ChangingAqueous Humor Outflow Resistance with different IOP
ExperimentⅠ
Purpose:To understand how hydrodynamic and morphologic changes in theaqueous humor outflow pathway contribute to decreased aqueous humor outflowfacility following acute elevation of intraocular pressure (IOP)in monkey eyes.
Methods:Enucleated monkey eyes were perfused at two different pressures30mmHg and 7 mmHg,while outflow facility was continuously recorded.Dulbecco's PBS + 5.5 mM glucose containing fluorescent microspheres (0.5μm,0.002% v/v)was perfused to outline aqueous outflow patterns followed byperfusion-flxation.Confocal images were taken along the inner wall (IW)of the SCin radial and frontal sections.Percent effective filtration length (PEFL=IW lengthexhibiting tracer labeling/total length of IW)was measured.Herniations of IW intocollector channel (CC)ostia were examined and graded for each eye by lightmicroscopy.
Results:Increasing IOP from 7 to 30 mmHg coincided with a 2.3-fold decrease inoutflow facility,from 0.34±0.08μl/min/mmHg at 7 mmHg to0.16±0.06μl/min/mmHg at 30 mmHg (P=0.03),a 1.6-fold decrease in PEFL withtracer more confined to the vicinity of CC ostia,from 56.02±6.04% at 7 mmHg to36.08±0.38% at 30 mmHg (P=0.03).Progressive collapse of the SC and increasingpercentage of CC ostia exhibiting herniations at 30 mmHg under light microscopy.
Conclusions:Decreasing outflow facility during acute IOP elevation coincides witha reduction in available area for aqueous humor outflow and confinement of outflowto the vicinity of CC ostia.These hydrodynamic changes are likely driven bymorphologic changes associated with SC collapse and herniation of IW of SC intoCC ostia.
ExperimentⅡ
Purpose:To determine whether the filtration area for aqueous outflow increaseswhen IOP is decreased from 30mmHg to 7mmHg or from 45mmHg to 7mmHgwithin the same eye.
Methods:We used two tracers with different excitation and emission spectra inorder to label the outflow patterns before and after reducing the perfusion pressure.Ten freshly enucleated monkey eyes were perfused at 30 mmHg (n=4)with 0.3 mlof red fluorescent microspheres (0.5μm,0.002% v/v),followed by an anteriorchamber exchange to remove the red tracer.A perfusion was continued at 7 mmHgwith a green tracer (0.3ml),followed by a pefusion with Karnovsky's fixative(0.3ml).The control eyes were perfused with only red tracer (0.3ml)at either 30mmHg (n=3)or 7 mmHg (n=3).Sections were cut radially and tangentially to thelimbus in all four quadrants and counter-stained for laser confocal.The pattern offluorescent tracer distribution was visualized in the trabecular meshwork,SC andCC ostia.Outflow facility and effective filtration area were measured at 30mmHgand 7mmHg in separate eyes (control)as well as within the same eye in which thepressure was decreased (experimental).Sections displaying the SC and CC ostiawere then processed for light micrscopy to analyze and grade the numbers of CCostia obstructed by herniated IW and JCT.Two human eyes were perfused with twodifferent tracer in the same way,one was kept the IOP at 45mmHg as control,theother is from 45mmHg to 7mmHg,then observed under confocal and lightmicroscopy.
Results:As the perfusion pressure decreased from high to normal within the sameeye the herniations were found to be either partially or completely reversible,andcorrelate with an increase in facility as well as an increase in the area available foroutflow either in monkey eyes or in human eyes.The average facility ofexperimental eyes perfused at 30mmHg was 0.37±0.10μl/min/mmHg which waslower than the average facility measured after the perfusion pressure was dropped to7 mmHg (0.48±0.21μl/min/mmHg,P=0.6).The percent of ostia obstructed byherniated tissue in eyes that had an acute IOP decrease (from 30 mmHg to 7 mmHg,33.06±2.66%)and was lower than eyes perfused at a constant 30 mrnHg(79.04±20.50%,P=0.06)but not as low as in eyes that were perfused at a constant 7mmHg (P=0.6).
Conclusions:We found that the herniations occurring in eyes that underwent anacute IOP increase are partially reversible and correlate with an increase in effectivefiltration area in the outflow pathway,as well as outflow facility.These studies pointto the importance of effective filtration length and the presence or absence ofhemiations as important factors in outflow resistance.
PartⅢ
Hydrodynamic and Morphological Changes during Washout inMonkey Eyes
Purpose:To better understand the physiology of the washout effect in monkey eyesin order to exploit it as a means of reducing IOP in human eyes with glaucoma.
Methods:Eight enucleated monkey eyes were used in this study.Within 24 hourspostmortem,eyes were perfused with Dulbecco's PBS containing 5.5mM glucose at15mmHg for long-duration (180 minutes)or short-duration (30 minutes,n=4 foreach group).The eyes were perfused with red fluorescent microspheres (0.5μm;0.002% v/v)to trace the hydrodynamic patterns of outflow,and then wereperfusion-fixed with Karnovsky's fixative at the same pressure.Radial and frontalsections in all quadrants were prepared and confocal irnages were taken along theinner wall (IW)of the Schlemm's canal (SC).The total length (TL)and thetracer-decorated length (L)of IW were measured in＞16 images/eye,and theaverage percent effective filtration length (PEFL=L/TL)was calculated for each eye.The sections with SC were processed and examined under light and electronmicroscopy.The TL of IW and the length exhibiting separation (SL)injuxtacanalicular connective tissue (JCT)were measured.The average percentseparation length (PLS=SL/TL)was calculated.
Results:Outflow facility increased 150% [1.46±0.70μl/min/mmHg (mean±SE),p＜0.01] from baseline facility (0.58±0.20μl/min/mmHg)after 180 minutesperfusion to induce washout.No significant increases were found in outflow facilityafter 30 minutes perfusion (0.44±0.16μl/min/mmHg)compared to baseline(0.62±0.21μl/min/mmHg,P=0.46).A more uniform tracer pattern was seen inlong-duration perfusion eyes than in short-duration perfusion eyes.The averagePEFL in long-duration eyes (83.37±4.13%)was 3.4-fold larger than inshort-duration eyes (24.19±8.42%,P＜0.001).The JCT region appeared distended inlong-duration eyes compared with short-duration eyes.The connections betweenJCT cells and between JCT cell and matrix were lost in expansion regions.The PLSin JCT region was 2.3-fold larger in long-duration eyes (77.4±3.2%)than that inshort-duration eyes (33.5±5.3%,p＜0.001).A significant positive correlation wasfound between PEFL and PSL (P=0.00002)suggesting that as connectivity betweenthe JCT and IW decreases the available area for aqueous humor drainage increasesalong the SC.
Conclusions:Increasing outflow facility during washout coincides with an increasein available area for aqueous humor outflow.These hydrodynamic changes arelikely driven by morphologic changes associated with a decrease in cell-cell and cell-matrix connections in the JCT region.
房水流出阻力动力学及相关形态学在猴眼慢性青光眼模型中的研究
目的：通过研究房水流出阻力在猴眼慢性青光眼模型的Schlemm氏管(SC)内壁和邻管组织(JCT)的动力学和相关形态学改变，来理解房水流出阻力的产生机制。
方法：三只雌性短尾猴，每只猴用氩激光光凝一眼的小梁部，另一眼作为对照，随访15．96-69．96月(平均44．32±27．10月)。将眼球取出，在24小时内灌注示踪剂后固定。分别用共焦显微镜、光镜、电镜检查，观察Schlemm管及小梁组织。
结果：激光组的平均眼压是61．33±4．16mmHg(Mean±SD)，显著高于对照组(22．67±4．04mmHg，P=0．0003)，而房水流畅率(0．03±0．02μl／min／mmHg)显著低于对照组(0．39±0．17μl／min／mmHg，P＜0．001)。共焦显微镜检查发现激光眼的小梁组织中示踪剂呈节段性分布，而在对照眼中分布较为均匀，测量有效滤过长度百分比，对照眼(47．47±10．79％)是激光眼(8．40±4．81％)的6倍(P=0．013)。光镜和电镜检查发现，激光眼的小梁组织中大量色素沉着，疤痕形成，SC管壁塌陷，激光组的SC管内外壁间距离(4．57±3．25μm)显著窄于对照组(19．14±5．75μm，P＜0．0001)，部分SC内壁及JCT组织突入集液管(CC)入口，发生率明显高于对照组。
结论：激光破坏了小梁组织造成有效滤过面积减少可能是房水流出阻力增加的部分原因。
第二部分
猴眼中不同眼压下房水流出阻力的动力学和相关形态学的改变实验一实验造成急性高眼压眼和正常眼压眼中房水流出阻力的研究
目的：通过研究在不同眼压下房水流出阻力的动力学和相关形态学改变，来探索房水流出阻力产生的机制。
方法：6只离体猕猴眼分为两组，每组3只，分别在30mmHg和7mmHg下灌注，同时连续记录房水流畅率。在同样灌注压下灌注入示踪剂后固定眼球。在共焦显微镜下观察示踪剂的分布情况，测量示踪剂在SC内壁的分布长度及SC总长度，计算房水有效滤过长度百分比(PEFL)，将两组进行比较。在光镜下观察两组SC内壁及JCT组织的形态学改变及CC入口处的情况。
结果：灌注压在7mmHg时的房水流畅率(0．34±0．08μl／min／mmHg)是灌注压在30mmHg时(0．16±0．06μl／min／mmHg)的2．3倍(P=0．03)，平均房水滤过长度百分比(56．02±6．04％)是灌注压在30mmHg时的1．6倍(36．08±0．38％，P=0．03)。在30mmHg灌注压时，示踪剂的分布呈节段性，更趋于集中分布于CC入口处附近，并发现有SC管塌陷的情况。部分SC内壁及JCT组织突入CC入口处的发生率为79．04±20．50％，是灌注压在7mmHg时(26．14±20．81％)的3倍，差别有显著性意义(P=0．03)。
结论：急性眼压升高，房水流畅率下降伴房水有效滤过面积下降，房水流出受限，集中于CC入口处附近。房水流出的动力学改变受SC塌陷、部分SC内壁及JCT组织突入CC入口等形态学改变的影响。
实验二
实验造成急性高眼压后又降至正常眼中房水流出阻力的研究
目的：研究眼压下降后房水流出阻力的改变情况，并通过其动力学和形态学的改变来探索其发生机制。
方法：10只离体猕猴眼被分为三组，一组4只眼灌注压在30mmHg时灌入红色示踪剂，然后将灌注压下降到7mmHg后灌入等剂量的绿色示踪剂，同时记录房水流畅率。另两组每组3只猕猴眼，灌注压始终保持在30mmHg和7mmHg，同样灌入两种示踪剂。在共焦显微镜下观察两种示踪剂的分布情况并计算PEFL。在光镜下观察各组切片的组织形态学改变，部分SC内壁及JCT组织突入CC入口处的发生情况。另外2只离体人眼，用同样实验方法，一只灌注压从45mmHg下降至7mmHg，另一只对照眼灌注压始终保持在45mmHg。
结果：灌注压从30mmHg下降至7mmHg后房水流畅率从0．37±0．10μl／min／mmHg升高至0．48±0．21μl／min／mmHg(P=0．6)；灌注压从7mmHg至7mmHg后房水流畅率从0．38±0．22μl／min／mmHg变化至0．56±0．45μl／min／mmHg(P=0．6)；灌注压从30mmHg至30mmHg后房水流畅率从0．19±0．06μl／min／mmHg变化至0．32±0．10μl／min／mmHg(P=0．1)。随灌注压下降，PEFL增大，灌注压在30mmHg时为27．60±6．43％，当下降至7mmHg时，PEFL为45．78±7．37％，是灌注压在30mmHg时的1．7倍，差别有统计学意义(P=0．01)。而灌注压从7mmHg至7mmHg时，PEFL从56．02±6．05％变化至62．96±12．76％(P=0．44)，差别无统计学意义。灌注压从30mmHg至30mmHg时PEFL分别是36．08±0．38％和39．76±3．01％(P=0．17)，差别亦无统计学意义。光镜检查发现，在灌注压从30mmHg降至7mmHg的眼中，发生部分SC内壁及JCT突入CC入口的发生率和突入程度介于灌注压在30mmHg和7mmHg之间。它们的发生率分别是33．06±2．66％，26．14±20．81％和79．04±20．50％(P＞0．05)。在灌注压从45mmHg下降至7mmHg的人眼中也有同样发现。
结论：部分SC内壁及JCT突入CC入口的发生情况在眼压升高时明显增多，但随眼压下降，发生了逆转，突入数和程度减少，同时伴有效滤过面积和房水流畅率增高。
第三部分
猴眼洗脱现象中房水流出阻力的动力学及相关形态学的研究
目的：通过研究猴眼洗脱现象中房水流出阻力的动力学及相关形态学改变，来试图寻求促使人类青光眼眼压下降的方法。
方法：8只恒河猴离体眼，在恒定压力15mmHg下灌注葡萄糖磷酸缓冲液，将眼球分为两组，每组4只眼球，一组为实验组，灌注180分钟，另一组为对照组，灌注30分钟，连续记录房水流畅率。在两组眼中灌入同等剂量的荧光微球以标记房水流出道模式，然后在同样灌注压下灌入锇酸固定液固定眼球。分别在共焦显微镜、光镜和电镜下观察。测量SC管长度(TL)和示踪剂沿SC内壁分布的长度(L)后计算平均有效滤过长度百分比(PEFL=L／TL)。沿SC内壁测量发生分离的JCT组织的长度(SL)，并计算平均分离长度百分比(PLS=SL／TL)。
结果：灌注180分钟后房水流畅率(1．46±0．70μl／min／mmHg)比基线(0．58±0．20μl／min／mmHg)增长了150％，统计有显著性意义(P＜0．01)，并产生了洗脱现象；而对照组灌注30分钟后房水流畅率(0．44±0．16μl／min／mmHg)无显著增加(0．62±0．21μl／min／mmHg，P=0．46)；共焦显微镜检查发现示踪剂在实验眼的分布较对照组更加均匀，实验组的平均有效滤过长度百分比(83．37±4．13％)是对照组的3．4倍(24．19±8．42％，P＜0．001)。光镜和电镜检查发现实验眼JCT组织的结构发生改变，组织扩张变得疏松。JCT细胞间以及JCT细胞和间质间的连接被打破，发生分离。实验组的平均分离百分比(77．4±3．2％)是对照眼的2．3倍(33．5±5．3％，P＜0．001)。有效滤过长度百分比和分离长度百分比呈高度正相关(P=0．00002)。
结论：洗脱现象中出现邻管组织结构改变，JCT细胞间、细胞与基质间发生分离可能是房水流出阻力降低的原因。
PartⅠ
Hydrodynamic and Morphological Correlates in Monkey Eyeswith Laser Induced-Glaucoma
Purpose:To investigate the relationship between decreased outflow facility and thechanges in hydrodynamic aqueous outflow pattern and morphology after chronicelevated intraocular pressure (IOP)in laser-induced glaucoma of cynomolgusmonkey eyes.
Methods:Argon laser photocoagulation bums to the trabecular meshwork (TM)were made in one eye of each monkey (N=3),leaving the contralateral eye as anormotensive control.Between 16 and 70 months later (mean±STD=44.32±27.10),measurements were made of IOP by pneumatonometry and outflow facility byfluorophotometry.To label the hydrodymamic patterns of outflow,the eyes wereenucleated and perfused with fluorescent microspheres (0.5μm;0.002%)at the lastpressure measured before death minus 7mmHg.The eyes were perfusion-fixed withKarnovsky's fixative at the same pressure.Confocal images were taken along theinner wall (IW)of the Schlemm's canal (SC).The total length (TL)and the filtrationlength (FL)of the IW decorated by tracers were measured in frontal sections.Theaverage percent effective filtration length (PEFL=FL/TL)was calculated for eacheye.Sections exhibiting SC were then processed and examined under light andelectron microscopy.
Results:The average IOP in laser-treated eyes was 61.33±4.16 mmHg,which wassignificantly higher than that of controls (22.67±4.04 mmHg,P=0.0003).Theaverage outflow facility (0.03±0.02μl/min/mmHg)was 13-fold lower inlaser-treated eyes than that of controls (0.39±0.17μl/min/mmHg,P=0.02).Byconfocal microscopy,in control eyes,SC was open and a segmental distribution ofmicrospheres was found with a greater concentration in the juxtacanalicularconnective tissue (JCT)region near the collector channel (CC)ostia.Much lesstracer labeling along SC in laser-treated eyes was seen than that in controls.Theaverage PEFL in controls (47.47±10.79%)was 6-fold larger than in laser-treatedeyes (8.40±4.81%,P=0.013).By light microscopy,there was extensivepigmentation throughout the TM,denser extracellular matrix in the JCT region,andmost of the SC collapsed with focal herniations of the IW and JCT protruding into the CC ostia in laser-treated eyes.The mean width of SC in control eyes(19.14±5.75μm)was 4-fold wider than in laser-treated eyes (4.57±3.25μm,p＜0.0001).In the laser-treated eyes,16 CC ostia were examined,herniations werefound in 14 CC ostia (88%),while herniations were found in 4 CC ostia of 23 CCostia examined in control eyes (17%,p＜0.0001).By electron microscopy,few or nomicrospheres were observed in laser-treated areas.However,in non-lasered areas,numerous microspheres were observed near the CC ostia area compared withcontrols.
Conclusions:In laser-induced glaucoma model,laser damage results in areduction in the available area for outflow across the IW of SC which contributes tothe decrease in outflow facility and thus elevation of the IOP Collapse of SC,causedby chronic elevation of IOP,further decreases in the available area for outflow in avicious cycle.This study suggests that available area for aqueous outflow play animportant role in regulating outflow resistance.
PartⅡ
Morphological and Hydrodynamic Correlates for ChangingAqueous Humor Outflow Resistance with different IOP
ExperimentⅠ
Purpose:To understand how hydrodynamic and morphologic changes in theaqueous humor outflow pathway contribute to decreased aqueous humor outflowfacility following acute elevation of intraocular pressure (IOP)in monkey eyes.
Methods:Enucleated monkey eyes were perfused at two different pressures30mmHg and 7 mmHg,while outflow facility was continuously recorded.Dulbecco's PBS + 5.5 mM glucose containing fluorescent microspheres (0.5μm,0.002% v/v)was perfused to outline aqueous outflow patterns followed byperfusion-flxation.Confocal images were taken along the inner wall (IW)of the SCin radial and frontal sections.Percent effective filtration length (PEFL=IW lengthexhibiting tracer labeling/total length of IW)was measured.Herniations of IW intocollector channel (CC)ostia were examined and graded for each eye by lightmicroscopy.
Results:Increasing IOP from 7 to 30 mmHg coincided with a 2.3-fold decrease inoutflow facility,from 0.34±0.08μl/min/mmHg at 7 mmHg to0.16±0.06μl/min/mmHg at 30 mmHg (P=0.03),a 1.6-fold decrease in PEFL withtracer more confined to the vicinity of CC ostia,from 56.02±6.04% at 7 mmHg to36.08±0.38% at 30 mmHg (P=0.03).Progressive collapse of the SC and increasingpercentage of CC ostia exhibiting herniations at 30 mmHg under light microscopy.
Conclusions:Decreasing outflow facility during acute IOP elevation coincides witha reduction in available area for aqueous humor outflow and confinement of outflowto the vicinity of CC ostia.These hydrodynamic changes are likely driven bymorphologic changes associated with SC collapse and herniation of IW of SC intoCC ostia.
ExperimentⅡ
Purpose:To determine whether the filtration area for aqueous outflow increaseswhen IOP is decreased from 30mmHg to 7mmHg or from 45mmHg to 7mmHgwithin the same eye.
Methods:We used two tracers with different excitation and emission spectra inorder to label the outflow patterns before and after reducing the perfusion pressure.Ten freshly enucleated monkey eyes were perfused at 30 mmHg (n=4)with 0.3 mlof red fluorescent microspheres (0.5μm,0.002% v/v),followed by an anteriorchamber exchange to remove the red tracer.A perfusion was continued at 7 mmHgwith a green tracer (0.3ml),followed by a pefusion with Karnovsky's fixative(0.3ml).The control eyes were perfused with only red tracer (0.3ml)at either 30mmHg (n=3)or 7 mmHg (n=3).Sections were cut radially and tangentially to thelimbus in all four quadrants and counter-stained for laser confocal.The pattern offluorescent tracer distribution was visualized in the trabecular meshwork,SC andCC ostia.Outflow facility and effective filtration area were measured at 30mmHgand 7mmHg in separate eyes (control)as well as within the same eye in which thepressure was decreased (experimental).Sections displaying the SC and CC ostiawere then processed for light micrscopy to analyze and grade the numbers of CCostia obstructed by herniated IW and JCT.Two human eyes were perfused with twodifferent tracer in the same way,one was kept the IOP at 45mmHg as control,theother is from 45mmHg to 7mmHg,then observed under confocal and lightmicroscopy.
Results:As the perfusion pressure decreased from high to normal within the sameeye the herniations were found to be either partially or completely reversible,andcorrelate with an increase in facility as well as an increase in the area available foroutflow either in monkey eyes or in human eyes.The average facility ofexperimental eyes perfused at 30mmHg was 0.37±0.10μl/min/mmHg which waslower than the average facility measured after the perfusion pressure was dropped to7 mmHg (0.48±0.21μl/min/mmHg,P=0.6).The percent of ostia obstructed byherniated tissue in eyes that had an acute IOP decrease (from 30 mmHg to 7 mmHg,33.06±2.66%)and was lower than eyes perfused at a constant 30 mrnHg(79.04±20.50%,P=0.06)but not as low as in eyes that were perfused at a constant 7mmHg (P=0.6).
Conclusions:We found that the herniations occurring in eyes that underwent anacute IOP increase are partially reversible and correlate with an increase in effectivefiltration area in the outflow pathway,as well as outflow facility.These studies pointto the importance of effective filtration length and the presence or absence ofhemiations as important factors in outflow resistance.
PartⅢ
Hydrodynamic and Morphological Changes during Washout inMonkey Eyes
Purpose:To better understand the physiology of the washout effect in monkey eyesin order to exploit it as a means of reducing IOP in human eyes with glaucoma.
Methods:Eight enucleated monkey eyes were used in this study.Within 24 hourspostmortem,eyes were perfused with Dulbecco's PBS containing 5.5mM glucose at15mmHg for long-duration (180 minutes)or short-duration (30 minutes,n=4 foreach group).The eyes were perfused with red fluorescent microspheres (0.5μm;0.002% v/v)to trace the hydrodynamic patterns of outflow,and then wereperfusion-fixed with Karnovsky's fixative at the same pressure.Radial and frontalsections in all quadrants were prepared and confocal irnages were taken along theinner wall (IW)of the Schlemm's canal (SC).The total length (TL)and thetracer-decorated length (L)of IW were measured in＞16 images/eye,and theaverage percent effective filtration length (PEFL=L/TL)was calculated for each eye.The sections with SC were processed and examined under light and electronmicroscopy.The TL of IW and the length exhibiting separation (SL)injuxtacanalicular connective tissue (JCT)were measured.The average percentseparation length (PLS=SL/TL)was calculated.
Results:Outflow facility increased 150% [1.46±0.70μl/min/mmHg (mean±SE),p＜0.01] from baseline facility (0.58±0.20μl/min/mmHg)after 180 minutesperfusion to induce washout.No significant increases were found in outflow facilityafter 30 minutes perfusion (0.44±0.16μl/min/mmHg)compared to baseline(0.62±0.21μl/min/mmHg,P=0.46).A more uniform tracer pattern was seen inlong-duration perfusion eyes than in short-duration perfusion eyes.The averagePEFL in long-duration eyes (83.37±4.13%)was 3.4-fold larger than inshort-duration eyes (24.19±8.42%,P＜0.001).The JCT region appeared distended inlong-duration eyes compared with short-duration eyes.The connections betweenJCT cells and between JCT cell and matrix were lost in expansion regions.The PLSin JCT region was 2.3-fold larger in long-duration eyes (77.4±3.2%)than that inshort-duration eyes (33.5±5.3%,p＜0.001).A significant positive correlation wasfound between PEFL and PSL (P=0.00002)suggesting that as connectivity betweenthe JCT and IW decreases the available area for aqueous humor drainage increasesalong the SC.
Conclusions:Increasing outflow facility during washout coincides with an increasein available area for aqueous humor outflow.These hydrodynamic changes arelikely driven by morphologic changes associated with a decrease in cell-cell and cell-matrix connections in the JCT region.
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