Local Ischemia and Increased Expression of Vascular Endothelial Growth Factor Following Ocular Dissemination of Mycobacterium tuberculosis

Abstract

The pathogenesis of intraocular tuberculosis remains poorly understood partly due to the lack of adequate animal models that accurately simulate human disease. Using a recently developed model of ocular tuberculosis following aerosol infection of guinea pigs with Mycobacterium tuberculosis, we studied the microbiological, histological, and clinical features of intraocular tuberculosis infection. Viable tubercle bacilli were cultivated from all eyes by Day 56 after aerosol delivery of ∼200 bacilli to guinea pig lungs. Choroidal tuberculous granulomas showed reduced oxygen tension, as evidenced by staining with the hypoxia-specific probe pimonidazole, and expression of vascular endothelial growth factor (VEGF) was detected in the retinal pigment epithelium (RPE) and photoreceptors. Fundoscopic examination of M. tuberculosis-infected guinea pig eyes revealed altered vascular architecture and chorioretinal hemorrhage by Day 56 after infection. This model may be useful in further elucidating the pathogenesis of ocular tuberculosis, as well as in developing tools for diagnosis and assessment of antituberculosis treatment responses in the eye.

Rapidly blinding posterior tubercular uveitis

“…This maybe secondary to the fact that ocular hypoxia sets in very fast in eyes with inflammation of the choroid secondary to mycobacterium tuberculosis [4-6]. This causes decreased choroidal circulation, and this may reduce the penetration of the drugs of ATT into the eye.…”

Intravitreal bevacizumab as an adjunct in the management of a vascular choroidal granuloma

“…While attempts are being made to elucidate the pathogenesis of intraocular tuberculosis (TB), reduced oxygen tension in choroidal granulomas and increased expression of vascular endothelial growth factor (VEGF) in the retinal pigment epithelium and photoreceptors have been demonstrated in animal models of ocular TB 2. Also, in pulmonary TB, localised tissue hypoxia in necrotic granulomas has been demonstrated in animal models 3.…”

Leukocyte-endothelial interactions within the ocular microcirculation in inflammation and infection

“…Other adhesion molecules, like platelet endothelial cell adhesion molecule-1 and intercellular adhesion molecule (ICAM)-1 were also found to increase on the vascular endothelium of animals after Pseudomonas ocular infection [47]. Increased expression of multiple adhesion molecules, including ICAM-1, VCAM-1 and/or LFA-1, was seen in the corneal and/or uveal endothelium in animals with experimental melanin-induced uveitis [22] and endotoxin-induced uveitis [125], and on the iris biopsy specimens from patients with uveitis [49], or on TNF-stimulated human iris endothelial cells [107]. These findings support the involvement of certain chemokine receptors and adhesion molecules in leukocyte infiltration, although whether they are specifically required for intraocular tissue recruitment of leukocytes has not been definitively shown.…”

“…For instance, when a more prolonged infection is established, a chronic inflammatory response is induced and granulomas (collection of activated macrophages and activated T cells) are formed, as shown in the choroid on day 56 post-mycobacterial infection in guinea pigs [93,125], or in the retina on day 21 post-HSV-1 infection in mice [3]. Further, in a model of allergic conjunctivitis, the conjunctival infiltrates were shown to include not only macrophages and T cells, but also eosinophils [36].…”