Unstable Oxygen Supply and Glaucoma

 

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Abstract

The pathogenesis of the glaucomatous optic neuropathy (GON) is an ongoing bone of contention. While the role of intraocular pressure (IOP) is well known, it is also clear that a variety of other factors, particularly those of a vascular nature, are involved as well. In contrast to other eye diseases, it is an unstable oxygen supply, as opposed to chronic hypoxia, that contributes to GON. The major cause of fluctuations in the local oxygen tension is an unstable ocular blood flow (OBF). OBF, in turn, fluctuates if the IOP spikes, blood pressure drops, or OBF autoregulation is defective. The main reason for disturbed autoregulation is a primary vascular dysregulation (PVD), particularly in the context of the so-called Flammer syndrome. Unstable oxygen tension leads to local oxidative stress with many detrimental effects, such as the activation of glial cells, which alters their morphology and gene expression. As a consequence, the local concentrations of nitric oxide and the metalloproteinases increase. The metalloproteinases digest extracellular matrix and thereby contribute to tissue remodelling. The short-lived nitric oxide easily diffuses into the neighbouring neuronal axons, allowing a fusion with the superoxide anion and thereby generating the cell-damaging peroxynitrite. Both this tissue remodelling and damage of the axons contribute to the development and progression of GON.

Zusammenfassung

Die Pathogenese der glaukomatösen Optikusneuropathie (GON) wird noch immer kontrovers diskutiert. Die Bedeutung des Augeninnendrucks für die Entstehung von GON ist unbestritten. Es ist aber ebenso unbestritten, dass auch andere Faktoren, insbesondere vaskuläre Faktoren, eine Rolle spielen. Entgegen älterer Auffassung ist es aber weniger die Hypoxie als vielmehr die instabile Sauerstoffversorgung, v. a. bedingt durch Schwankungen in der Augendurchblutung, die zur GON beiträgt. Schwankungen der Augendurchblutung wiederum gibt es bei Augendruckspitzen, Blutdruckabfällen und einer gestörten Autoregulation der okularen Zirkulation. Eine häufige Ursache der gestörten Autoregulation ist die vaskuläre Dysregulation im Rahmen eines Flammer-Syndroms. Eine schwankende Sauerstoffkonzentration führt zu lokalem oxidativen Stress. Im Auge betrifft das vor allem die Mitochondrien des Sehnervenkopfes. Denn dort haben wir nicht nur besonders viele Mitochondrien wegen der nicht myelinisierten Axone, sondern auch besonders häufig Schwankungen der Durchblutung. Die hypoxieresistenten Astrozyten werden aber sowohl durch mechanische Belastung wie auch durch oxidativen Stress aktiviert. Dadurch ändern sie nicht nur ihre Morphologie, sondern auch ihre Genexpression, was u. a. zur vermehrten Bildung von Stickstoffmonoxid und Metalloproteinasen führt. Letztere verdauen die extrazelluläre Matrix und tragen so zum Umbau des Sehnervenkopfs bei. Stickstoffmonoxid wiederum kann aus den Astrozyten in die neuronalen Axone diffundieren, wo es mit dem Hyperoxid-Anion fusioniert und dadurch das zelltoxische Peroxynitrit bildet. All diese Mechanismen tragen wesentlich zur Entstehung und Progression der GON bei.

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