Suppression of lipopolysaccharide-induced corneal opacity by hepatocyte growth factor

Keratitis induced by bacterial toxins, including lipopolysaccharide (LPS), is a major cause of corneal opacity and vision loss. Our previous study demonstrates hepatocyte growth factor (HGF) promotes epithelial wound healing following mechanical corneal injury. Here, we investigated whether HGF has the capacity to suppress infectious inflammatory corneal opacity using a new model of LPS-induced keratitis. Keratitis, induced by two intrastromal injections of LPS on day 1 and 4 in C57BL/6 mice, resulted in significant corneal opacity for up to day 10. Following keratitis induction, corneas were topically treated with 0.1% HGF or PBS thrice daily for 5 days. HGF-treated mice showed a significantly smaller area of corneal opacity compared to PBS-treated mice, thus improving corneal transparency. Moreover, HGF treatment resulted in suppression of α-SMA expression, compared to PBS treatment. HGF-treated corneas showed normalized corneal structure and reduced expression of pro-inflammatory cytokine, demonstrating that HGF restores corneal architecture and immune quiescence in corneas with LPS-induced keratitis. These findings offer novel insight into the potential application of HGF-based therapies for the prevention and treatment of infection-induced corneal opacity.

Evaluation of a novel combination of TRAM-34 and ascorbic acid for the treatment of corneal fibrosis in vivo

Corneal injury and aberrant wound healing commonly result in corneal fibrosis and subsequent vision loss. Intermediate-conductance calmodulin/calcium-activated K+ channels (KCa3.1) have been shown to promote fibrosis in non-ocular and ocular tissues via upregulation of transforming growth factor beta (TGFβ). TRAM-34 is a selective inhibitor of KCa3.1 and reduces fibrosis by downregulation of TGFβ-induced transdifferentiation of stromal fibroblasts to myofibroblasts. Ascorbic acid has been demonstrated to be effective in promoting corneal re-epithelialization and reduction of neovascularization via anti-VEGF and anti-MMP mechanisms. This study evaluates tolerability and efficacy of a novel combination of TRAM-34 (25μM) and ascorbic acid (10%) topical treatment for corneal fibrosis using an established in vivo rabbit model and conducting clinical eye examinations. Markers of corneal fibrosis were evaluated in all corneas at study endpoint via histopathology, immunofluorescence, and quantitative real-time PCR. The eyedrop treated eyes showed significantly improved clinical outcomes based on modified McDonald Shadduck scores, reduction of clinical haze on Fantes scores, and reduction of central corneal thickness (CCT). At cellular and molecular levels, eyedrop treatment also significantly reduced expression of alpha smooth muscle actin (α-SMA) mRNA and protein, collagen III mRNA, and fibronectin mRNA compared to non-treated eyes. Our study suggests that a tested new bimodal eyedrop is well tolerated and effectively reduces corneal fibrosis/haze in rabbits in vivo.

Potential Therapeutic Role of Pituitary Adenylate Cyclase-Activating Polypeptide for Dry Eye Disease

Dry eye disease (DED) is caused by a reduction in the volume or quality of tears. The prevalence of DED is estimated to be 100 million in the developed world. As aging is a risk factor for DED, the prevalence of DED is expected to grow at a rapid pace in aging populations, thus creating an increased need for new therapies. This review summarizes DED medications currently in clinical use. Most current medications for DED focus on stimulating tear secretion, mucin secretion, or suppressing inflammation, rather than simply replenishing the ocular surface with moisture to improve symptoms. We recently reported that the neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) induces tear secretion and suppresses corneal injury caused by a reduction in tears. Moreover, it has been reported that a PACAP in water and a 0.9% saline solution at +4 °C showed high stability and achieved 80–90% effectiveness after 2 weeks of treatment. These results reveal PACAP as a candidate DED medication. Further research on the clinical applications of PACAP in DED is necessary.

Unilateral zebrafish corneal injury induces bilateral cell plasticity supporting wound closure

The cornea, transparent and outermost structure of camera-type eyes, is prone to environmental challenges, but has remarkable wound healing capabilities which enables to preserve vision. The manner in which cell plasticity impacts wound healing remains to be determined. In this study, we report rapid wound closure after zebrafish corneal epithelium abrasion. Furthermore, by investigating the cellular and molecular events taking place during corneal epithelial closure, we show the induction of a bilateral response to a unilateral wound. Our transcriptomic results, together with our TGF-beta receptor inhibition experiments, demonstrate conclusively the crucial role of TGF-beta signaling in corneal wound healing. Finally, our results on Pax6 expression and bilateral wound healing, demonstrate the decisive impact of epithelial cell plasticity on the pace of healing. Altogether, our study describes terminally differentiated cell competencies in the healing of an injured cornea. These findings will enhance the translation of research on cell plasticity to organ regeneration.

Corneal Trauma

Trauma is often the main cause of unilateral loss of vision in developing countries. Although corneal trauma can range from tiny corneal abrasions to sight-threatening and penetrating ocular injuries, even minor corneal trauma that breaches the epithelium has the potential to result in microbial keratitis and its associated complications, up until complete loss of vision. Even though ocular trauma is a global problem, blindness from eye injuries occurs mostly in developing countries, especially those where wars and civil conflicts bring around eye traumas from various weapons such as land mines, chemical substances, etc. Chemical injuries from both acids and alkalies are common causes of corneal injury due to their easy availability and soft regulations regarding their use. This chapter includes photos of trauma cases of the anterior segment, corneal and conjunctival foreign bodies, sequelae of blunt and penetrating trauma, chemical injuries, as well as a case of posttraumatic iris cyst.

Establishment of a prediction tool for ocular trauma patients with machine learning algorithm

AIM: To predict final visual acuity and analyze significant factors influencing open globe injury prognosis. METHODS: Prediction models were built using a supervised classification algorithm from Microsoft Azure Machine Learning Studio. The best algorithm was selected to analyze the predicted final visual acuity. We retrospectively reviewed the data of 171 patients with open globe injury who visited the Pusan National University Hospital between January 2010 and July 2020. We then applied cross-validation, the permutation feature importance method, and the synthetic minority over-sampling technique to enhance tool performance. RESULTS: The two-class boosted decision tree model showed the best predictive performance. The accuracy, precision, recall, F1 score, and area under the receiver operating characteristic curve were 0.925, 0.962, 0.833, 0.893, and 0.971, respectively. To increase the efficiency and efficacy of the prognostic tool, the top 14 features were finally selected using the permutation feature importance method: (listed in the order of importance) retinal detachment, location of laceration, initial visual acuity, iris damage, surgeon, past history, size of the scleral laceration, vitreous hemorrhage, trauma characteristics, age, corneal injury, primary diagnosis, wound location, and lid laceration. CONCLUSION: Here we devise a highly accurate model to predict the final visual acuity of patients with open globe injury. This tool is useful and easily accessible to doctors and patients, reducing the socioeconomic burden. With further multicenter verification using larger datasets and external validation, we expect this model to become useful worldwide.

Approach to Facial Weakness

Facial palsy is a common neurologic concern and is the most common cranial neuropathy. The facial nerve contains motor, parasympathetic, and special sensory functions. The most common form of facial palsy is idiopathic (Bell's palsy). A classic presentation requires no further diagnostic measures, and generally improves with a course of corticosteroid and antiviral therapy. If the presentation is atypical, or concerning features are present, additional studies such as brain imaging and cerebrospinal fluid analysis may be indicated. Many conditions may present with facial weakness, either in isolation or with other neurologic signs (e.g., multiple cranial neuropathies). The most important ones to recognize include infections (Ramsay-Hunt syndrome associated with herpes zoster oticus, Lyme neuroborreliosis, and complications of otitis media and mastoiditis), inflammatory (demyelination, sarcoidosis, Miller–Fisher variant of Guillain–Barré syndrome), and neoplastic. No matter the cause, individuals may be at risk for corneal injury, and, if so, should have appropriate eye protection. Synkinesis may be a bothersome residual phenomenon in some individuals, but it has a variety of treatment options including neuromuscular re-education and rehabilitation, botulinum toxin chemodenervation, and surgical intervention.