Aqueous humor outflow system Anatomy & physiology 녹내장 컨퍼런스 Aqueous humor outflow system Anatomy & physiology R4정영권

90% : 10 %(5~30%)

Convential outflow pathway Trabecular meshwork – Schlemm’s canal

Band or ropelike trabeculae 1. The uveal meshwork innermost portion Band or ropelike trabeculae extend from the root of the iris to pph cornea Irregular openings : 25~75 um Uveal meshwork는 다각형 소공이고 방수가 아무 저항없이 통과할수 있다. 섬유주층이 깊어질수록 소공의 크기는 작아집니다. 서로 다른 층에 있는 소공끼리는 직접 마주 보지 않으므로 방수는 훨씬 먼거리를 우회하여 흐르고 있다.

2. The corneoscleral meshwork Extends from the scleral spur to Schwalbe line Elliptical opening : smaller 5~50um Ant. Tendon of longitudinal m.  Sclera spur Mechanical role : cholinergic agent Cornealsclera meshwor은 포도막섬유주보다 작고 원공에 가깝다. Juxtacanalicular meshwork는 섬유주의 바깥층으로 각공막섬유주의 내피세포와 쉘렘관 내벽의 내피세포층 사이에 끼여있는 결합조직층으로 섬유주판과 같은 판상 구조는 없습니다. 이곳이 가장 촘촘하며 방수유출경로중 가장 저항이 쎕니다.

Cholinergic agent : pilocarpine decrease IOP widening of JXT and TM but decrease Uveoscleral outflow AC Before pilocarpine treatment Increase size of schlemm’s canal Administration of pilocarpine contracts the ciliary muscle - Pull SS posteriorly and internally AC Enlargement of intertrabecular spaces

2. The corneoscleral meshwork Four concentric layer Inner connective tissue core - typical collagen fiber 640Å Elastic fiber - typical collagen, spiraling pattern 1000Å Glassy membrane : basement Outer endothelial cells - gap junction, desmosomes - phagocytosis - cytoplasmic process Structure of corneoscleral lamellae of the trabecular meshwork. BM, basement membrane (thickened); C, collagenous fibers; CC, central core of trabecular lamella; D, desmosome; EL, elastic-like fibers; TC, trabecular cells. 4 3 1 2 Microfilament Cell contraction, motility, phagocytosis, pinocytosis, cell adhesion

Schlemm’s canal endothelium : Basement membrane(-) Trabecullar lamellar endothelial cell process Limit distention Countering tension  schlemm’s endo. Schlemm’s canal endothelium Juxtacanalicular cell Deformation as IOP △ Giant vacuoles △

3. juxtacanalicular(JXT) meshwork Differs from other parts Pore tissue, cribriform layer, endothelial meshwork Three layer Innermost portion – continuous corneoscleral meshwork Juxtacanalicular cell : loosely arranged - cell process - sustain cellular stress - distribute IOP induced stress across the entire trabecular lamellae system Schlemm’s canal endothelium Cornealsclera meshwor은 포도막섬유주보다 작고 원공에 가깝다. Juxtacanalicular meshwork는 섬유주의 바깥층으로 각공막섬유주의 내피세포와 쉘렘관 내벽의 내피세포층 사이에 끼여있는 결합조직층으로 섬유주판과 같은 판상 구조는 없습니다. 이곳이 가장 촘촘하며 방수유출경로중 가장 저항이 쎕니다.

Schlemm’s canal endothelium Monolayer Tight junction – physiologic barrier Giant vacuole Cellular distention & invagination as IOP△ Surrounded by cell body Cornealsclera meshwor은 포도막섬유주보다 작고 원공에 가깝다. Juxtacanalicular meshwork는 섬유주의 바깥층으로 각공막섬유주의 내피세포와 쉘렘관 내벽의 내피세포층 사이에 끼여있는 결합조직층으로 섬유주판과 같은 판상 구조는 없습니다. 이곳이 가장 촘촘하며 방수유출경로중 가장 저항이 쎕니다.

transcellular? or pressure induced distention? Giant vacuole : transcellular? or pressure induced distention? Passive transport (Pressure-dependent) Resistance estimated basis of the Size, total number of pores, giant vacuoles Small fraction of the total outflow resistance Possible mechanism : transient transcellular pores - active transport, actin filament Paracellular ? Cornealsclera meshwor은 포도막섬유주보다 작고 원공에 가깝다. Juxtacanalicular meshwork는 섬유주의 바깥층으로 각공막섬유주의 내피세포와 쉘렘관 내벽의 내피세포층 사이에 끼여있는 결합조직층으로 섬유주판과 같은 판상 구조는 없습니다. 이곳이 가장 촘촘하며 방수유출경로중 가장 저항이 쎕니다.

Intrascleral, episcleral, subconjunctival venous plexus Schlemm’s canal 360-degree, endothelial-lined channel averages 190 to 370 mm in diameter plexus-like system continuous with the inner wall endothelium smoother surface Larger Less numerous cells no pores numerous, large outlet channels Collector channel Intrascleral, episcleral, subconjunctival venous plexus Direct channel(Aqueous vein) Indirect channel

Schlemm’s canal valve low high High Low Schlemm canal의 collapse시 유출 증가 Low lumen of the valves is compressed between the walls of Schlemm's canal at a relatively low IOP of 25 mmHg

Unconventional outflow Uveoscleral outflow - anterior uvea at the iris root  supraciliary & supra choroidal space Ciliary m. contraction  ▽ Uveovortex outflow into the iris vessels and vortex vein Blood aqueous barrier, high vessel pressure

Outflow physiology

Conventional Outflow

Perfusion study Elevating IOP -> - Collapse of Schlemm canal - distention of TM Increase in endothelial vacuoles with ballooning of the inner wall endothelial cells into canal  increased resistance to Aqueous humor outflow

Perfusion study Expanding Schlemm’s canal -> resistance ▼ Post depression of the lens, tension on the choroid  Widening of the schlemm’s canal, increase inner wall porosity

Morphology changes Age Long, wedge shape  shorter, rhomboidal form Sclera spur  prominent Uveal meshwork  more compact TM beam thicken Intertrabecular space  narrow Extracellular material increase Endothelial cellularity decline 0.58%/yr Giant vacuoles in Schlemm’s canal▽

Acceleration of normal aging process? OAG Obstruction by Foreign material(pigment, RBC, GAG..) Loss of trabecular endothelial cell Reduction in pore density & size in shlemm’s endothelium Loss of giant vacuoles(number, size) in schlemm’s endothelium  resistance △ Loss of phagocytic activity(FB△, cell death△) Disturbance of neurologic feedback mechanism (slow down Aqueous formation, speed outflow)  Alterations in trabecular beams Thickened basement membrane Narrowed intertrabecular space Fusion Collector channel narrowing Closure of schlemm’s canal Thickened scleral spur Acceleration of normal aging process? Normal trabecular meshwork, × 3.0K. Each cylindrical uveal trabecular beam is distinct, with generally smooth endothelial surfaces, and some cellular borders visible (thin arrows). Large intertrabecular spaces are present. Melanin granules, (thick arrow), can be seen on the cells and within the spaces. POAG eye × 3.0K; 67-year-old male, highest baseline IOP 28 mmHg. There are flat and widened uveal trabeculae, beneath which corneoscleral trabeculae and spaces are seen. Fewer spaces are visible cf control eyes. Fused trabeculae can be seen (thick arrow). RBC (thin arrow), melanin granules and debris are seen on the surface

Steroid induced glaucoma ECM accumulation △ Fine fibrillar material increase, in Subendothelial region of the schlemm’s canal Intercellular space ▽ ECM △

Glucocorticoid mechanisms Steroid  Lysosomal membrane reinforce, hyaluronidase release▽ Polymerized glycosaminoglycan hydration  obstr. Inhibit the synthesis of endogenous prostaglandins inhibition of phagocytosis. Direct ostr. by steroid particle Mutation of gene (TIGR : trabecular meshwork-inducible glucocorticoid response) Production of abnormal glucocorticoid inducible stress response protein(myocilin) in TM Juvenile glaucoma : Dexa  myocilin expression increased in TM But, Steroid induced glaucoma : myocilin mutation(-) Steorid 가 PG의 antagonist 안압을 높인다. Hyaluronan non sulfated linear GAG HMW-HA (~106Da) is first degraded by hyaluronidase 2 (HYAL2) into smaller 104Da sized fragments before it is taken up by a cell. The cell can either utilize surface HA receptors for receptor mediated endocytosis or macropinocytosis. Once internalized the HA is degraded by hyaluronidase 1 (HYAL1) into small 102Da fragments and then exocytosed.

Extracellular matrix Connetive tissue core, basement membrane TM endothelium surface ★ Play important role in regulating IOP Fibrillar and nonfibrillar collagens Elastin containing microfibrils Matricellular and structural organizing proteins Glycosaminoglycans, proteoglycans Constant turnover, remodeling Response to mechanically induced IOP stretching through cell adhesion protein, cell surface receptor, associated binding protein, certain cytokines, growth factors, drugs

Extracellular matrix Glycosaminoglycan(GAG) Component, ECM Disrupting GAG biosynthesis  1.5-fold outflow facility increase Fibrinolysis Protective mechanism : fibrin, platelet tPA Influence resistance to outflow Altering glycoprotein content of ECM

Cellular and Cytoskeletal Mechanism TM endothelial cell - Phagocytize, degrade foreign material Engulf debris, detach from trabecular core, leave in Schlemm’s canal Damaged protein accumulation with age d/t - oxidative stress Decline in the cellular proteolytic machinery that eliminate misfolded and damaged proteins Alteration Cytoskeleton. Cytochalasins, EDTA, H-7 : disrupt microfilaments - Reduce resistance, alteration in TM, inner wall of schlemm

Cellular and Cytoskeletal Mechanism Sulfhydryl : iodoacetamide, nethylmaleimide, ethracrynic acid Alteration of cell membrane sulfhydryl groups at multiple sites in the endothelial lining of schlemm’s canal  outflow increase 2. Modulate aqueous humor hydrogen peroxide ▽ (reduce outflow through oxidative damage of TM)

Unconventional Outflow

Unconventional, Uveoscleral outflow Uveoscleral pathway : “pressure independent” Ciliary muscle tension - Reduced by cholinergic agonist Decrease with aging - thickening of elastic fibers in ciliary m. Pilocarpine  reduce outflow Atropine  increase outflow Uveitis  reduce outflow PG(low dose) ECM remodelling, widening intermuscular spaces  increase outflow Inflammation break BAB iop상승 Inflammation mimicking effect

Episcleral venous pressure Complex, only partially understood Commonly venous pressure 1mmHg,  IOP 1mmHg IOP increase > Venous pressure increase? Normal episcleral venous pressure 8~11 mmHg

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