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Yong Yuan, Chia-Yang Liu, Jeffrey J. Miller, Hongshan Liu, Osamu Yamanaka, William D. Hardie, Winston W. Kao; Doxycycline Induction of TGF-α Overexpression in Adult Mice Corneal Epithelium Causes Cornea Inflammation and Plateau Iris. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1836.
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TGF-α transduces signal through EGF receptor and is required for corneal epithelium homeostasis. Topical application of TGF-α promotes wound healing. Inflammation in cornea has been reported in TGF-α null mice, possibly due to trauma and inefficient healing. Here we examine if conditional overexpression of TGF-α could help maintain or cause corneal pathogenesis in adult mice.
A tet-ON binary transgenic Krt12rtTA/tet-O-TGF-α mouse strain was generated by breeding of Krt12rtTA knock-in mice with tet-O-TGF-α transgenic mice. The binary transgenic mice were subjected to doxycycline (Dox) induction to overexpress TGF-α in corneal epithelium. Intraocular pressure was measured by non-invasive tonometer TonoLab. The enucleated eyes of the experimental mice were analyzed by histopathology, biochemistry, and immunohistochemistry.
Induction of excess TGF-α in adult mice resulted in inflammation and angiogenesis; leading to corneal opacification. Histological examinations showed that induction of TGF-α caused lymphocyte infiltration into corneal stroma. It also caused the closing of the anterior chamber angle secondary to an anteriorly positioned ciliary body, a situation similar to plateau iris in human. Within ten days of doxycycline induction, intraocular pressure (IOP) increased to above 20 mmHg while IOP of control mice remained around 15 mmHg. Quantitative real-time RT-PCR revealed that many cytokines and chemokines were up-regulated in TGF-α expressing cornea, including IL-1β, IL-10, IL-12α, IL-12β, IL-6, IFN-α1, IFN-α2, IFN-γ and CCL2. Innate immune response genes, toll like receptors 1, 6, 7, 8, were also up-regulated by TGF-α.
Our data suggests that the levels of biologically active TGF-α in the aqueous humor must be under tight control to maintain proper corneal homeostasis. Overexpression of TGF-α in corneal epithelial induces inflammation and causes anterior chamber angle closure which resembles to plateau iris in human, mimicking close angle glaucoma in human. Our results also raise the question if TGF-α is suitable to treat corneal wound. Given the fact that plateau iris is one of the most common angle-closure glaucomas in younger patients, EGF receptor signal pathway may play important role in the pathogenesis of this disease.
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