The glaucoma is a progressive, multifactorial neurodegenerative disease that is the most frequent cause of irreversible blindness. It was recently estimated that the number of people suffering from glaucoma worldwide will increase from 76.5 million in 2020 to 111.8 million by 2040, mainly due to an ageing population. The term glaucoma actually encompasses several conditions. Primary open-angle glaucoma (POAG) is the most common form in Western countries. The aetiology of POAG is generally mechanical, when intraocular pressure leads to compression of axons, or vascular, when blood flow and ocular perfusion pressure are reduced.
The role of inflammation in glaucoma
The onset of glaucoma is related to various risk factors, which include advanced age, increased intraocular pressure (IOP) and genetic background. Oxidative stress, mitochondrial dysfunction and cellular senescence tend to be increased in the ageing retina and are considered among the main factors increasing the risk of glaucoma. When the retina ages, in fact, oxidative stress and lipid peroxidation are considered the main causes of tissue stress, which leads to the activation of local parainflammation of varying degrees.
Para-inflammation is defined as an adaptive tissue response to harmful stimuli, stress or malfunction, and has characteristics that are considered to be intermediate between the normal basal tissue state and the inflammatory state. A physiological level of parainflammation is necessary to maintain tissue homeostasis and restore function, but when tissue is exposed to stress and/or malfunction for a prolonged period, inflammation can play a deleterious role and be implicated in both the onset of glaucoma and its progression. In fact, excessive parainflammation can produce inflammatory responses with a marked release of cytokines and chemokines, which cause irreparable damage to the neuroretina.
Inflammation can also have a detrimental effect on conjunctival and corneal barrier functions and cause activation of the immune system. Consequently, glaucoma appears as a disease in which inflammatory processes may be present to varying degrees throughout the entire structure of the eye.
The inflammation in retinal and optic nerve head degeneration
Glaucomatous degenerative disease is characterised by a progressive loss of retinal ganglion cells (RGCs), thinning of the retinal nerve fibre layer and cupping of the optic nerve head (ONH). Various stimuli, including chronic mechanical stress induced by elevated IOP, hypoxia/ischemia and oxidative stress, together with deprivation of neurotrophic factors, can cause RGC dysfunction and death. Furthermore, it has been suggested that increased stress over a prolonged period may lead to a failure in the regulation of the local protective immune response mediated by glial cells and the complement system, leading to a process of neuroinflammatory degeneration, which contributes to disease progression.
Neuroinflammatory mechanisms in glaucoma
Some studies have proposed a number of molecular and signalling pathways that are regulators of neuroinflammation in the aetiology of glaucoma. These are complex mechanisms involving a close interaction between glial cells, immune cells, endothelial cells and RGCs via autocrine/paracrine pathways. One pathogenetic hypothesis is based on vascular stress at the level of the ONH and retina, which leads to a persistent inflammatory phenotype, with increased oxidative stress and cellular ageing/senescence, associated with a loss of neuroprotection and remodelling of glial cells, release of apoptotic signals, degeneration of RGCs, disruption of the blood-retinal barrier and tissue damage in the ONH.
Inflammation and trabecular meshwork in glaucoma
Upstream of the degeneration of ONH and the loss of RGC characteristic of neuropathy due to glaucoma, as seen, increased IOP plays an important role. Studies have shown that local parainflammation may play a regulatory role in the outflow of aqueous humour from the trabecular meshwork. Several histological studies, in fact, have shown over-regulation of inflammation-associated genes in the trabecular meshwork, which may be involved in the onset or progression of glaucoma.
Inflammation of the ocular surface in glaucoma
The most visible manifestations of inflammation in glaucoma are those occurring at the ocular surface. Ocular surface disease (OSD) is therefore very common in these patients, who often complain of a foreign body sensation in the eye, redness, itching, pain and photosensitivity. Superficial changes also include effects that are not clinically visible, such as the infiltration of inflammatory cells, a significant decrease in the number and density of central corneal sub-basal nerve fibres, and a reduction in corneal sensitivity.
Modulation of inflammation in glaucoma: perspectives and future directions
We examined how the balance of inflammatory mechanisms is necessary to maintain healthy ocular structures. In fact, parainflammation can quickly go from being a physiological process to becoming a factor contributing to ocular tissue degeneration.
There is evidence that stimuli causing cellular stress, including increased intraocular pressure or decreased blood flow, associated with chronic oxidative stress, may tip the balance from beneficial parainflammation towards toxic levels, participating in the pathogenesis and progression of glaucoma. To date, various therapeutic approaches have been proposed to prevent or modulate excessive inflammatory reactions in glaucoma, but extensive clinical studies will be needed to investigate their safety and efficacy.
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