A slit-lamp examination is an indispensable and essential clinical evaluation method in ophthalmology, but, it is qualitative subjective. To complement its weaknesses in making a quantitative evaluation of flare intensity and number of cells in the aqueous humor in the eye, we invented the laser flare-cell photometer in 1988. The instrument enables a non-invasive quantitative evaluation of flare intensity and number of cells in the aqueous with good accuracy and repeatability as well as maneuverability equal to slit-lamp microscopy. The instrument can elucidate the pathophysiology in the blood-aqueous barrier (BAB) function in a variety of ocular disorders. The accuracy of the instrument makes it possible to investigate not only the pathophysiology of intraocular disorders but also the effects of various drugs and surgical procedures in BAB. The instrument does not only lighten the burden on patients in clinical examinations and study but it also helps minimize the sacrifice of experimental animals and improves the reliability of the results by minimizing inter-individual variations through its good repeatability. Here I shall relate how the instrument has been applied to clinical and basic studies in ophthalmology and what novel knowledge its application contributed to pathophysiology in ophthalmology.
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases with the potential to degrade all types of extracellular matrix. The ADAM (a disintegrin and metalloproteinase) family of peptidases was recently identified as cleaving the extracellular domain of transmembrane proteins. This was termed ectodomain shedding. We investigated the MMP expression in patients with corneal diseases and the potential role of ADAMs in corneal pathophysiology. We detected upregulation of the active form of MMP-2 and MMP-9 in the tear fluid from patients with corneal melting or recurrent corneal erosion. Using human corneal epithelial cells, we observed ADAM17-dependent ectodomain shedding of soluble tumor necrosis factor receptor 1 and soluble interleukin-6 (IL-6) receptor (sIL-6R). The production of sIL-6R was also induced by messenger RNA splicing in the human corneal epithelial cells. IL-6/sIL-6R-induced signal transducer and activator of transcription 3 phosphorylation was observed in cultured human corneal fibroblasts, suggesting that IL-6 trans-signaling induced inflammatory cellular signaling in the human corneal fibroblasts. We demonstrated that MMPs are significantly upregulated in collagen-destructive disorders of the cornea. Additionally, we observed that ectodomain shedding by ADAMs in corneal epithelial cells mediated the production of soluble cytokine receptors. Trans-signaling of IL-6 can induce an inflammatory response in corneal stroma, indicating the significance of IL-6 trans-signaling in ocular surface inflammation. Thus, MMPs and ADAMs play an important role in the pathophysiology of corneal diseases.
The present study demonstrated the presence of crucial cytokines, soluble cytokine receptors, and chemokines in tears of patients with VKC and GPC. In particular, IL-6sR increased significantly in both the VKC and GPC groups, whereas eotaxin-2 increased significantly only in the VKC group. Thus, IL-6sR may play an important pathophysiological role in giant papillary proliferation in VKC and GPC, and eotaxin-2 may play an important role in eosinophilic inflammation in VKC.
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