Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

Recently, Burgoyne and colleagues (8) proposed that the ONH is a biomechanical structure and suggested that the mechanisms of GON could be explained by biomechanical engineering concepts. This tenet is that connective tissue in the ONH is under IOP-related stress (force/cross sectional area) and strain (deformation), regardless of the IOP level. The stress and strain affect blood flow and three types of tissues; (i) the load-bearing connective tissues of the lamina cribrosa, peripapillary sclera, and scleral canal wall, (ii) RGC axons in the ONH, and (iii) cells comprising the ONH: astrocytes, glial, and vascular endothelial cells. This concept is valid because it explains not only the mechanism of high-tension glaucoma but also normal tension glaucoma, in which the connective tissue may be susceptible to damage even at normal levels of IOP. In this review, we discuss these concepts in more detail to explain the pathogenesis of GON and the pathophysiological changes in the ONH with emphasis on the biomechanical aspect of this structure.

HISTOLOGICAL CHANGE OF THE ONH IN GLAUCOMA

Optic Disc Cupping and Tissue Remodeling

Quigley and other researchers demonstrated that there is posterior deformation of the ONH surface and underlying lamina cribrosa after acute IOP elevation and that the architecture of the tissues’ return to the primary position after the IOP is lowered, indicating the presence of compliance in the connective tissues of these structures (9). This compliance was decreased in older human eyes (10) and in endstage pathology associated with glaucoma (11). In the enucleated eyes of humans with glaucoma and in those obtained from monkey glaucoma models, acute IOP elevation was shown to induce the backward bowing of the lamina cribrosa (12–14). The ONH surface also showed hyper-compliance (easily deformed by an applied load) under sustained IOP elevation for 4–8 weeks in monkey eyes (15). These studies indicate that the original compliance of the ONH connective tissues is damaged under IOP elevation. Finally, the ONH surface and the lamina cribrosa bows posteriorly, are sometimes compressed under Bruch’s membrane, and shows excavation (16). The backward bowing of lamina surface is usually followed by compression of successive lamina cribrosa sheets (17).

Regional Damage of Glaucomatous ONH

Clinically, damage to the superior and inferior quadrants of the optic disc and compatible visual field defect are the typical initial damage with IOP elevation (17). Histological studies indicate that larger pores with thinner connective tissue septae are arranged in the superior and inferior poles compared with those in the horizontal meridian (18). These thinner septae may be more susceptible to IOP-related stress and strain leading to axon damage. In both human and monkey studies of glaucoma, it is the large diameter nerve fibers that are preferentially damaged (19,20). Regional differences of the lamina cribrosa or distribution of neuronal types in this region may explain the initial specific damage of the ONH.

Disturbance of Axon Transport

Axonal transport is compromised at the level of the lamina cribrosa and is most likely because of the bent laminar trabeculae in this structure and loss of tissue compliance

after chronic stress and strain induced by elevated IOP (1,2,21,22). Obstruction of axonal transport induces disruption of mitochondrial function in the RGCs and reduces the expression of the neurotrophic factor, BDNF (23,24). These molecular events are considered to be some of the primary ones to induce apoptosis of RGC.

Changes in Blood Circulation

Early reports suggested that the blood flow of the ONH, retina, and choroids are affected by acute and chronic IOP elevation (25). However, there is no experimental evidence that selective loss of capillaries of the ONH precedes early events that trigger axonal loss. The reduction of choroidal blood flow by elevation of the IOP may be due, in part, to the fact that choroidal vessels have little or no autoregulatory mechanisms

(6). There is clinical evidence that flame-shaped disc hemorrhages are often associated with glaucoma, especially in normal tension glaucoma (26,27). Hayreh suggested that ocular perfusion pressure may play an important role in the development of GON and proposed nocturnal hypotension as one of the risk factors for this condition (28). The relatively higher prevalence of glaucoma in individuals with diabetes, hypertension, and migraine strongly suggests a correlation between abnormal blood circulation and glaucoma. Current methods of documenting ONH blood flow, however, are inadequate to confirm the role of blood flow in the mechanisms of GON, and further study is needed.

CELL-BIOLOGICAL CHANGES OF THE ONH IN GLAUCOMA

The Extracellular Matrix and Controlling Factors

Synthesis and remodeling of the extracellular matrix (ECM) is one of the earliest events of pathogenesis of GON (29). ECM remodeling in GON includes disruption of collagen fibrils, stiffness of elastic fibers, deposition of basement membrane components, changes in hydration levels and types of glycosaminoglycans (GAGs), and deposition of hyaluronic acid (30–38). In early glaucomatous changes in human and monkey eyes, disruption of both the collagen and elastin fibers in the laminar insertion sites of the ONH are evident (37). In mild cases of primary open angle glaucoma (POAG), tubular structure of elastic fibers and microfibrillar bundles are frequently lost, whereas in advanced POAG, other severe changes can be seen (31). Burgoyne has proposed that the disruption of collagen fibrils in the ECM is part of the mechanism of connective tissue damage associated with GON (8).

Astrocyte Involvement in Connective Tissue Remodeling

The connective tissue remodeling in GON is largely dependent on the distribution and cellular responses of reactive astrocytes (39–42). Although the chronology of various glaucomatous events in the ONH induced by IOP elevation is still unknown, resident astrocytes in the ONH may be activated at the primary stage of the disease process. The presence of reactive astrocytes in the ONH, responding to IOP elevation, is supported by clinical observations of enucleated human eyes with glaucoma and from experimental studies of organ and in vitro cell cultures (43–45). The role of the ONH astrocytes in axonal damage and ONH dysfunction has been confirmed by

observable pathological changes in the cell body and processes of astrocytes in the lamina cribrosa with increased IOP (42). There is also evidence that astrocyte activity is modulated by nitric oxide levels, and this can contribute to the health of RGCs in ocular hypertension. Glaucoma eyes or animal models of experimental glaucoma indicate that inducible nitric oxide synthase (iNOS) induced in astrocytes may be related to local blood flow or tissue damage (23,46–48). In addition, changes in gene expression in astrocytes such as the apparent upregulation of GFAP in moderate and advanced POAG patients or monkey (39) and HSP-27, one of the early intermediate genes, are associated with human glaucomatous ONH (49). Others molecules including cell surface adhesion molecules are shown to be upregulated in ONH (39,40). NCAM immunoreactivity is increased in most astrocytes in glaucoma. This is especially true for NCAM180, the predominant and more adhesive form of NCAM, which is expressed in glaucomatous ONH and interacts with cytoskeletal molecules (42,50,51). A number of integrins, which mediate cellular adhesion and ECM attachment, are also upregulated in glaucomatous eyes to increase signal transfer and mediate intracellular responses in the ONH (29). Extracellular signaling molecules for remodeling of ECM such as MMP, TIMP, and TGFbeta are also increased in the ONH and may contribute to tissue remodeling (29). Taken together, the clinical and experimental data strongly suggest that reactive astrocyte-mediated tissue remodeling of the structure of the lamina cribrosa is an important component in the pathophysiology of axonal function and the glaucomatous ONH.

Other Cell Types that May Contribute to the Pathophysiology of the ONH

IOP-related stress and strain affects not only astrocytes but also laminar capillary endothelial cells. Laminar deformation followed by collagen disruption enhances the thickening of basement membrane of these endothelial cells and the laminar trabecular basement membrane, a common occurrence in glaucomatous ONH (32,52).

ONH AS A BIOMECHANICAL STRUCTURE

The histopathological changes of the ONH in glaucoma described above have been interpreted from the point of view of both mechanical and vascular damage to axons coursing through the lamina cribrosa in the ONH. Recently, these histological changes have been assessed using biomechanical theory (15).

The biomechanical premise is that the lamina cribrosa is the primary pathological lesion site in GON and that IOP-related stress (force/cross sectional area) and strain (deformation) is the primary force to induce GON because the axons in this region are particularly vulnerable to compression of the lamina cribrosa. This is summarized in Fig. 1. The lamina cribrosa is always exposed to a hydrostatic pressure gradient between IOP and the retrolaminar tissue pressure (35). Thus, it should be noted that the ONH is always under the stress and strain by IOP, even when it is normal pressure.

Pressure gradient exerts stress to three tissues in ONH: (i) direct mechanical damage to the connective tissue, (ii) indirect stimulation of the constituent cells in the ONH, that is the astrocytes and vascular endothelial cells, through mechano-sensitive ion channels or membrane signaling, and (iii) direct or indirect damage to axons in the

Fig. 1. A representation of the stresses and responses found in the optic nerve head in glaucoma.

lamina cribrosa. The responses of each tissue may occur simultaneously and interact with each other to exacerbate deformation of the ONH in glaucoma. Load-bearing connective tissue in the lamina cribrosa is always under IOP-related strain. Even though the tissues are within the elastic levels, astrocytes are activated as described above, leading to tissue remodeling in the ONH, induction of stiffening of the connective tissue probably because of the change of collagen types and hydration levels, induction of basement membrane thickening, and diminished nutrient diffusion from the laminar capillaries, the latter a secondary occurrence elicited by the former two events. Once the load-bearing connective tissues are hyper-compliance, IOP-related strain and stress are integrated to damage tissues resulting in the compression of laminal layers. This connective tissue compression finally damages axons, collapses laminal capillaries, and reduces the diffusion of nutrients more extensively (8).

APPLICATION OF OCULAR HYPERTENSION ANIMAL MODELS FOR GON

During the last decade, several animal models including rat and mouse GON models have been generated to further elucidate the molecular mechanisms of GON development. Availability of transgenic animals, economical efficiency, easy handling, and availability of biological tools to study rodent genes and proteins strongly promote the use of rodents in GON studies. IOP levels can be elevated easily in rats using several standard methods, and optic nerve damage can be successfully induced in these animals

to analyze tissue responses to IOP elevation (53). The mouse model is especially attractive because of the availability of transgenic animals and the lack of a lamina cribrosa in these animals (54). Mabuchi et al. (55) reported that pressure-dependent optic nerve damage can be successfully induced in ocular hypertension mouse model or collagen I filament mutant mice despite the lack of a lamina cribrosa, the primary initial site of GON in human. Mimicking chronic ocular hypertension in experimental models and comparative analysis of GON among animals will contribute significantly to our understanding of the molecular and structural changes in the pathophysiology of ONH in glaucoma.

FUTURE DIRECTIONS

Numerous histological studies in human, primates, and rats, and recent biomechanical models of glaucoma have shed new light on the pathophysiology of GON. However, obtaining glaucoma tissue samples from humans has been a big challenge to study the initial events leading to glaucomatous optic nerve change. Development of better animals models, computerized analysis of glaucomatous ONH, and application of more sophisticated biological tool and techniques to analyze tissue or cellular function at the molecular and structural levels in the ONH will allow us to further understand the vulnerability of the lamina cribrosa to IOP and the dysfunction of the ONH in glaucoma.

REFERENCES

1.Anderson, D. R. & Hendrickson, A. (1974). Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve. Invest Ophthalmol 13, 771–83.

2.Minckler, D. S., Bunt, A. H. & Johanson, G. W. (1977). Orthograde and retrograde axoplasmic transport during acute ocular hypertension in the monkey. Invest Ophthalmol Vis Sci 16, 426–41.

3.Quigley, H. & Anderson, D. R. (1976). The dynamics and location of axonal transport blockade by acute intraocular pressure elevation in primate optic nerve. Invest Ophthalmol 15, 606–16.

4.Panda, S. & Jonas, J. B. (1992). Decreased photoreceptor count in human eyes with secondary angle-closure glaucoma. Invest Ophthalmol Vis Sci 33, 2532–6.

5.Yucel, Y. H., Zhang, Q., Gupta, N., Kaufman, P. L. & Weinreb, R. N. (2000). Loss of neurons in magnocellular and parvocellular layers of the lateral geniculate nucleus in glaucoma. Arch Ophthalmol 118, 378–84.

6.Fechtner, R. D. & Weinreb, R. N. (1994). Mechanisms of optic nerve damage in primary open angle glaucoma. Surv Ophthalmol 39, 23–42.

7.Yablonski, M. E. & Asamoto, A. (1993). Basic sciences in clinical glaucoma:hypothesis concerning the pathophysiology of optic nerve damage in open angle glaucoma. J Glaucoma 2, 119–27.

8.Burgoyne, C. F., Downs, J. C., Bellezza, A. J., Suh, J. K. & Hart, R. T. (2005). The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage. Prog Retin Eye Res 24, 39–73.

9.Quigley, H. A. (1977). The pathogenesis of reversible cupping in congenital glaucoma. Am J Ophthalmol 84, 358–70.

10.Albon, J., Purslow, P. P., Karwatowski, W. S. & Easty, D. L. (2000). Age related compliance of the lamina cribrosa in human eyes. Br J Ophthalmol 84, 318–23.

11.Zeimer, R. C. & Chen, K. (1987). Comparison of a noninvasive measurement of optic nervehead mechanical compliance with an invasive method. Invest Ophthalmol Vis Sci 28, 1735–9.

12.Levy, N. S. & Crapps, E. E. (1984). Displacement of optic nerve head in response to short-term intraocular pressure elevation in human eyes. Arch Ophthalmol 102, 782–6.

13.Radius, R. L. & Pederson, J. E. (1984). Laser-induced primate glaucoma. II. Histopathology.

Arch Ophthalmol 102, 1693–8.

14.Yan, D. B., Coloma, F. M., Metheetrairut, A., Trope, G. E., Heathcote, J. G. & Ethier,

C.R. (1994). Deformation of the lamina cribrosa by elevated intraocular pressure. Br J Ophthalmol 78, 643–8.

15.Burgoyne, C. F., Quigley, H. A., Thompson, H. W., Vitale, S. & Varma, R. (1995). Early changes in optic disc compliance and surface position in experimental glaucoma.

Ophthalmology 102, 1800–9.

16.Quigley, H. A., Addicks, E. M., Green, W. R. & Maumenee, A. E. (1981). Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage. Arch Ophthalmol 99, 635–49.

17.Quigley, H. A., Hohman, R. M., Addicks, E. M., Massof, R. W. & Green, W. R. (1983). Morphologic changes in the lamina cribrosa correlated with neural loss in open-angle glaucoma. Am J Ophthalmol 95, 673–91.

18.Quigley, H. A. & Addicks, E. M. (1981). Regional differences in the structure of the lamina cribrosa and their relation to glaucomatous optic nerve damage. Arch Ophthalmol 99, 137–43.

19.Quigley, H. A., Dunkelberger, G. R. & Green, W. R. (1988). Chronic human glaucoma causing selectively greater loss of large optic nerve fibers. Ophthalmology 95, 357–63.

20.Quigley, H. A., Sanchez, R. M., Dunkelberger, G. R., L’Hernault, N. L. & Baginski, T. A. (1987). Chronic glaucoma selectively damages large optic nerve fibers. Invest Ophthalmol Vis Sci 28, 913–20.

21.Gaasterland, D., Tanishima, T. & Kuwabara, T. (1978). Axoplasmic flow during chronic experimental glaucoma. 1. Light and electron microscopic studies of the monkey optic nervehead during development of glaucomatous cupping. Invest Ophthalmol Vis Sci 17, 838–46.

22.Hayreh, S. S., March, W. & Anderson, D. R. (1979). Pathogenesis of block of rapid orthograde axonal transport by elevated intraocular pressure. Exp Eye Res 28, 515–23.

23.Pease, M. E., McKinnon, S. J., Quigley, H. A., Kerrigan-Baumrind, L. A. & Zack, D.

J.(2000). Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. Invest Ophthalmol Vis Sci 41, 764–74.

24.Quigley, H. A., McKinnon, S. J., Zack, D. J., Pease, M. E., Kerrigan-Baumrind, L. A., Kerrigan, D. F. & Mitchell, R. S. (2000). Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Invest Ophthalmol Vis Sci 41, 3460–6.

25.Alm, A. & Bill, A. (1970). Blood flow and oxygen extraction in the cat uvea at normal and high intraocular pressures. Acta Physiol Scand 80, 19–28.

26.Kitazawa, Y., Shirato, S. & Yamamoto, T. (1986). Optic disc hemorrhage in low-tension glaucoma. Ophthalmology 93, 853–7.

27.Krakau, T. (1989). Disc haemorrhages and the etiology of glaucoma. Acta Ophthalmol Suppl 191, 31–3.

28.Hayreh, S. S. & Baines, J. A. (1972). Occlusion of the posterior ciliary artery. 3. Effects on the optic nerve head. Br J Ophthalmol 56, 754–64.

29.Hernandez, M. R. (2000). The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res 19, 297–321.

30.Fukuchi, T., Sawaguchi, S., Hara, H., Shirakashi, M. & Iwata, K. (1992). Extracellular matrix changes of the optic nerve lamina cribrosa in monkey eyes with experimentally chronic glaucoma. Graefes Arch Clin Exp Ophthalmol 230, 421–7.

31.Hernandez, M. R. (1992). Ultrastructural immunocytochemical analysis of elastin in the human lamina cribrosa. Changes in elastic fibers in primary open-angle glaucoma. Invest Ophthalmol Vis Sci 33, 2891–903.

32.Hernandez, M. R., Andrzejewska, W. M. & Neufeld, A. H. (1990). Changes in the extracellular matrix of the human optic nerve head in primary open-angle glaucoma. Am J Ophthalmol 109, 180–8.

33.Hernandez, M. R., Pena, J. D., Selvidge, J. A., Salvador-Silva, M. & Yang, P. (2000). Hydrostatic pressure stimulates synthesis of elastin in cultured optic nerve head astrocytes. Glia 32, 122–36.

34.Hernandez, M. R., Ye, H. & Roy, S. (1994). Collagen type IV gene expression in human optic nerve heads with primary open angle glaucoma. Exp Eye Res 59, 41–51.

35.Morgan, J. E., Jeffery, G. & Foss, A. J. (1998). Axon deviation in the human lamina cribrosa. Br J Ophthalmol 82, 680–3.

36.Pena, J. D., Netland, P. A., Vidal, I., Dorr, D. A., Rasky, A. & Hernandez, M. R. (1998). Elastosis of the lamina cribrosa in glaucomatous optic neuropathy. Exp Eye Res 67, 517–24.

37.Quigley, H. A., Brown, A. & Dorman-Pease, M. E. (1991). Alterations in elastin of the optic nerve head in human and experimental glaucoma. Br J Ophthalmol 75, 552–7.

38.Quigley, H. A., Dorman-Pease, M. E. & Brown, A. E. (1991). Quantitative study of collagen and elastin of the optic nerve head and sclera in human and experimental monkey glaucoma. Curr Eye Res 10, 877–88.

39.Hernandez, M. R. & Pena, J. D. (1997). The optic nerve head in glaucomatous optic neuropathy. Arch Ophthalmol 115, 389–95.

40.Morgan, J. E. (2000). Optic nerve head structure in glaucoma: astrocytes as mediators of axonal damage. Eye 14 (Pt 3B), 437–44.

41.Trivino, A., Ramirez, J. M., Salazar, J. J., Ramirez, A. I. & Garcia-Sanchez, J. (1996). Immunohistochemical study of human optic nerve head astroglia. Vision Res 36, 2015–28.

42.Varela, H. J. & Hernandez, M. R. (1997). Astrocyte responses in human optic nerve head with primary open-angle glaucoma. J Glaucoma 6, 303–13.

43.Pena, J. D., Agapova, O., Gabelt, B. T., Levin, L. A., Lucarelli, M. J., Kaufman, P. L. & Hernandez, M. R. (2001). Increased elastin expression in astrocytes of the lamina cribrosa in response to elevated intraocular pressure. Invest Ophthalmol Vis Sci 42, 2303–14.

44.Pena, J. D., Varela, H. J., Ricard, C. S. & Hernandez, M. R. (1999). Enhanced tenascin expression associated with reactive astrocytes in human optic nerve heads with primary open angle glaucoma. Exp Eye Res 68, 29–40.

45.Tezel, G., Hernandez, M. R. & Wax, M. B. (2001). In vitro evaluation of reactive astrocyte migration, a component of tissue remodeling in glaucomatous optic nerve head. Glia 34, 178–89.

46.Liu, B. & Neufeld, A. H. (2000). Expression of nitric oxide synthase-2 (NOS-2) in reactive astrocytes of the human glaucomatous optic nerve head. Glia 30, 178–86.

47.Neufeld, A. H. (1999). Nitric oxide: a potential mediator of retinal ganglion cell damage in glaucoma. Surv Ophthalmol 43 Suppl 1, S129–35.

48.Neufeld, A. H., Hernandez, M. R. & Gonzalez, M. (1997). Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol 115, 497–503.

49.Tezel, G., Hernandez, R. & Wax, M. B. (2000). Immunostaining of heat shock proteins in the retina and optic nerve head of normal and glaucomatous eyes. Arch Ophthalmol 118, 511–8.

50.Ricard, C. S., Kobayashi, S., Pena, J. D., Salvador-Silva, M., Agapova, O. & Hernandez, M. R. (2000). Selective expression of neural cell adhesion molecule (NCAM)-180 in optic

nerve head astrocytes exposed to elevated hydrostatic pressure in vitro. Brain Res Mol Brain Res 81, 62–79.

51.Ricard, C. S., Pena, J. D. & Hernandez, M. R. (1999). Differential expression of neural cell adhesion molecule isoforms in normal and glaucomatous human optic nerve heads. Brain Res Mol Brain Res 74, 69–82.

52.Morrison, J. C., Dorman-Pease, M. E., Dunkelberger, G. R. & Quigley, H. A. (1990). Optic nerve head extracellular matrix in primary optic atrophy and experimental glaucoma. Arch Ophthalmol 108, 1020–4.

53.Morrison, J. C., Johnson, E. C., Cepurna, W. & Jia, L. (2005). Understanding mechanisms of pressure-induced optic nerve damage. Prog Retin Eye Res 24, 217–40.

54.May, C. A. & Lutjen-Drecoll, E. (2002). Morphology of the murine optic nerve. Invest Ophthalmol Vis Sci 43, 2206–12.

55.Mabuchi, F., Aihara, M., Mackey, M. R., Lindsey, J. D. & Weinreb, R. N. (2004). Regional optic nerve damage in experimental mouse glaucoma. Invest Ophthalmol Vis Sci 45, 4352–8.