Proteolytic Degradation and Inflammation Play Critical Roles in Polypoidal Choroidal Vasculopathy.

Polypoidal choroidal vasculopathy (PCV) is a common subtype of wet age-related macular degeneration in Asian populations, whereas choroidal neovascularization is the typical subtype in Western populations. The cause of PCV is unknown. By comparing the phenotype of a PCV mouse model expressing protease high temperature requirement factor A1 (HTRA1) in retinal pigment epithelium with transgenic mice expressing the inactive HTRA1S328A, we showed that HTRA1-mediated degradation of elastin in choroidal vessels is critical for the development of PCV, which exhibited destructive extracellular matrix remodeling and vascular smooth muscle cell loss. Compared with weak PCV, severe PCV exhibited prominent immune complex deposition, complement activation, and infiltration of inflammatory cells, suggesting inflammation plays a key role in PCV progression. More important, we validated these findings in human PCV specimens. Intravitreal delivery of an HTRA1 inhibitor (DPMFKLboroV) was effective (36% lesion reduction; P = 0.009) in preventing PCV initiation but ineffective in treating existing lesions. Anti-inflammatory glucocorticoid was effective in preventing PCV progression but ineffective in preventing PCV initiation. These results suggest that PCV pathogenesis occurs through two stages. The initiation stage is mediated by proteolytic degradation of extracellular matrix proteins attributable to increased HTRA1 activity, whereas the progression stage is driven by inflammatory cascades. This study provides a basis for understanding the differences between PCV and choroidal neovascularization, and helps guide the design of effective therapies for PCV.

Chloroquine Ingestion to Prevent SARS-CoV-2 Infection: A Report of Two Cases.

INTRODUCTION: Amid the global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), chloroquine and hydroxychloroquine were being studied as agents to prevent and treat coronavirus disease 2019. Information about these agents and their effects circulated throughout the general public media, raising the concern for self-directed consumption of both pharmaceutical and non-pharmaceutical products. CASE REPORT: We present two cases of chloroquine toxicity that occurred after ingestion of an aquarium disinfectant that contained chloroquine phosphate in a misguided attempt to prevent infection by SARS-CoV-2. One patient had repeated emesis and survived, while the other was unable to vomit, despite attempts, and suffered fatal cardiac dysrhythmias. CONCLUSION: These cases illustrate the spectrum of toxicity, varied presentations, and importance of early recognition and management of chloroquine poisoning. In addition, we can see the importance of sound medical guidance in an era of social confusion compounded by the extremes of public and social media.

Detecting abnormalities in choroidal vasculature in a mouse model of age-related macular degeneration by time-course indocyanine green angiography.

Indocyanine Green Angiography (or ICGA) is a technique performed by ophthalmologists to diagnose abnormalities of the choroidal and retinal vasculature of various eye diseases such as age-related macular degeneration (AMD). ICGA is especially useful to image the posterior choroidal vasculature of the eye due to its capability of penetrating through the pigmented layer with its infrared spectrum. ICGA time course can be divided into early, middle, and late phases. The three phases provide valuable information on the pathology of eye problems. Although time-course ICGA by intravenous (IV) injection is widely used in the clinic for the diagnosis and management of choroid problems, ICGA by intraperitoneal injection (IP) is commonly used in animal research. Here we demonstrated the technique to obtain high-resolution ICGA time-course images in mice by tail-vein injection and confocal scanning laser ophthalmoscopy. We used this technique to image the choroidal lesions in a mouse model of age-related macular degeneration. Although it is much easier to introduce ICG to the mouse vasculature by IP, our data indicate that it is difficult to obtain reproducible ICGA time course images by IP-ICGA. In contrast, ICGA via tail vein injection provides high quality ICGA time-course images comparable to human studies. In addition, we showed that ICGA performed on albino mice gives clearer pictures of choroidal vessels than that performed on pigmented mice. We suggest that time-course IV-ICGA should become a standard practice in AMD research based on animal models.

Angiographic features of transgenic mice with increased expression of human serine protease HTRA1 in retinal pigment epithelium.

PURPOSE: Polypoidal choroidal vasculopathy (PCV) is characterized by a branching vascular network (BVN) of choroid that terminates in polypoidal dilations. We have previously reported the generation of the first PCV model by transgenically expressing human HTRA1 (hHTRA1(+)), a multifunctional serine protease, in mouse RPE. The purpose of this study was to perform a comprehensive examination of the PCV phenotypes (e.g., lesion type and distribution) of hHTRA1(+) mice by a variety of in vivo imaging techniques. METHODS: We generated improved hHTRA1(+) mice with a more consistent phenotype. Transgenic mice were examined by indocyanine green angiography (ICGA), fluorescein angiography, funduscopy, and spectral-domain optical coherence tomography. In particular, we performed ICGA by tail vein injection of ICG to obtain high-quality ICGA comparable to human studies in terms of the three phases (early, middle, and late) of angiography. RESULTS: The polyps can be detected in the early "fill-in" phase of ICGA, and most lesions become visible in the middle phase and are more distinct in the late phase with the fading of surrounding vessels. In addition to the two key features of PCV (polypoidal dilations and BVNs), hHTRA1(+) mice exhibit other features of PCV (i.e., late geographic hyperfluorescence, pigment epithelial detachment, and hyperfluorescent plaque). Polypoidal lesions appear as reddish orange nodules on funduscopy. CONCLUSIONS: Transgenic hHTRA1(+) mice exhibit a rich spectrum of "clinical" features that closely mimic human PCV. This animal model will serve as an invaluable tool for future mechanistic and translational studies of PCV and other forms of choroidal vasculopathies.