Glaucoma is a progressive neurodegenerative disease that constitutes the main frequent cause of irreversible blindness. The number of people with glaucoma worldwide will increase from 76.5 million in 2020 to 111.8 million by 2040, mainly due to the aging of the population [1,2,3]. Glaucoma is characterized by loss of retinal ganglion cells (RGCs), thinning of the retinal nerve fiber layer, and cupping of the optic disc [4]. Glaucoma is a group of heterogeneous diseases characterized by varying clinical features. Aging, increased intraocular pressure (IOP), and genetic background are the main risk factors for glaucoma [4]. Primary open-angle glaucoma (POAG) is the main form in Western countries. Nevertheless, 30% of Caucasian patients with POAG, and a greater proportion of the Asian population show normal-tension glaucoma (NTG) [5]. The etiology of POAG is mainly described as mechanical and/or vascular processes. The mechanical process enhances compression of the axons due to elevation of IOP, whereas the vascular process highlights events in which blood flow and ocular perfusion pressure are diminished in the posterior pole [6,7]. Vascular or perfusion dysregulations in NTG present different clinical features, such as migraine headaches, Raynaud’s phenomenon or sleep apnea [8]. In high IOP glaucoma, both the anterior and posterior segments are damaged, and extensive affection is detectable in the trabecular meshwork (TM) and along the inner retina-central visual pathway [9].

 

In PAOG, the IOP increase leads to the TM occlusion induced by the iris tissue [9]. Chronic contact between the iris and the TM can lead to permanent damage to the TM. The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H₂O₂. The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].

During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNF-alpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB stimulation and the release of inflammatory markers [41,47].

These findings may suggest that the IOP elevation, which occurs in glaucoma, is associated with oxidative degenerative processes damaging the human TM endothelial cells (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal pathway responsible for autophagia [48], as well as cell senescence with an increase in senescence-associated-galactosidase [49]. OS induces a lysosomal dysregulation and the defective proteolytic stimulation of lysosomal enzymes with a subsequent decrease in autophagic flux and the promotion of cell senescence [9].

The IOP elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, leads to hypoperfusion and to reperfusion damages [50]. IOP elevation is considered as a cause of retinal ganglion cells (RGCs) damage, resulting in a retrograde transport blockade and the accumulation of neurotrophic factors at the lamina cribrosa instead of reaching the RGC soma [51]. The POAG etiology is still unclear but several risk factors have been observed as the causes of promoting its onset, such as elevated IOP, aging, gender, ethnicity, first-degree family history of glaucoma, oxidative stress, systemic and ocular vascular factors, and inflammation [52].