Corneal Inflammatory Diseases Research Articles

Applications of photodynamic therapy in keratitis.

Keratitis is corneal inflammatory disease which may be caused by several reason such as an injury, allergy, as well as a microbial infection. Besides these, overexposure to ultraviolet light and unhygienic practice of contact lenses are also associated with keratitis. Based on the cause of keratitis, different lines of treatments are recommended. Photodynamic therapy is a promising approach that utilizes light activated compounds to instigate either killing or healing mechanism to treat various diseases including both communicable and non-communicable diseases. This review focuses on clinically-important patent applications and the recent literature for the use of photodynamic therapy against keratitis.

Reports of New and Recurrent Keratitis following mRNA-based COVID-19 Vaccination

ABSTRACT Purpose As ophthalmic side effects of messenger RNA (mRNA)-based COVID-19 vaccination are not well understood, it is crucial to document and report such instances should they occur. Methods In this observational case series, we report nine patients (55.6% male, mean age 58.9) who received either the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) COVID-19 vaccinations from January to June of 2021, and presented with symptoms of keratitis within 14 days. All patients underwent slit-lamp examination and histories were taken. Results Most subjects (66.7%) had a history of corneal inflammatory diseases and resolved under antiviral and/or steroidal treatment. Patients who reported symptoms after their second vaccine dose presented earlier than those who reported symptoms after the first dose (mean 4.4 days vs 10.5 days, respectively). Conclusions The immunological reaction following mRNA-based COVID-19 vaccinations may trigger new-onset or reactivation of keratitis, though causality cannot be proven. Despite its rarity, clinicians should be aware of this possible complication and be prepared to treat.

Clinical and Histopathological Study of the Effect of Adipose-Derived Mesenchymal Stem Cells on Corneal Neovascularization following Alkali Burn in a Rabbit Model.

The cornea, the transparent part of the eye, performs a significant function in eyesight by refracting the light to focus a visual image. Since the cornea is indispensable for vision, corneal inflammation may induce visual disturbance and blindness. Several investigations have reported that various corneal inflammatory diseases cause visual impairment and chronic inflammation of the cornea, which can lead to blindness. The present study aimed to assess the effect of adipose-derived mesenchymal stem cells (ADMSCs) on corneal healing after alkali injuries. Corneal alkali injuries were induced in the eyes of 20 rabbits. The MSC group (n=10) was treated with subconjunctival injections, while the control group (n=10) was left without any treatment. Rabbits underwent slit-lamp examination and photography and were evaluated for corneal neovascularization. Based on the histological evaluation, the eyes treated with MSCs showed better recovery. Furthermore, the MSC and control groups were significantly different in the degree of corneal neovascularization and re-epithelialization, as well as the elevation of the neovascular tissue at two and four weeks post-surgery.

HDL nanoparticles have wound healing and anti-inflammatory properties and can topically deliver miRNAs.

microRNAs regulate numerous biological processes, making them potential therapeutic agents. Problems with delivery and stability of these molecules have limited their usefulness as treatments. We demonstrate that synthetic high-density lipoprotein nanoparticles (HDL NPs) topically applied to the intact ocular surface are taken up by epithelial and stromal cells. microRNAs complexed to HDL NPs (miR-HDL NPs) are similarly taken up by cells and tissues and retain biological activity. Topical treatment of diabetic mice with either HDL NPs or miR-HDL NPs significantly improved corneal re-epithelialization following wounding compared with controls. Mouse corneas with alkali burn-induced inflammation, topically treated with HDL NPs, displayed clinical, morphological and immunological improvement. These results should yield a novel HDL NP-based eye drop for patients with compromised wound healing ability (diabetics) and/or corneal inflammatory diseases (e.g. dry eye).

Immunohistochemical proofs of the efficiency of hyaluronic acid in keratopathy treatment

An analysis of changes in the CD44 and MMP9 expression during the keratopathy after corneal inflammatory diseases treatment with injected hyaluronic acid is presented.

Bevacizumab and corneal pathology

The purpose of this paper is to present a review of the current literature on anti-vascular endothelial growth factor (anti-VEGF) bevacizumab therapy for corneal neovascular disorders. Cornea is unique avascular, immunoprivileged connective tissue that acts as transparent mechanical barrier and the anterior eye refractive surface. Corneal neovascularizations (NV) are caused by chronic corneal ischemia with pathological ingrowth of perylimbal blood vessels into the cornea. Abnormal blood vessels cause scarring of the cornea and compromise visual acuity. Pathological conditions that cause corneal neoangiogenesis are: chemical burns, ischemia, infections, degeneration, trauma and immune processes. Corneal neovascularization occurs because of corneal pro-angiogenic and anti-angiogenic factors disequilibrium. The former treatment of corneal NV does not target the molecular mediators of angiogenesis. VEGF-A is the main regulator of angiogenesis. Bevacizumab recognizes all VEGF isoforms. Studies have demonstrated partial reduction of neovascularization through topical, subconjunctival and intrastromal bevacizumab application. Bevacizumab can be used in corneal inflammatory diseases, infections and traumatic/iatrogenic causes. Anti-VEGF agents have created enormous hope for the treatment of corneal neovascularization. Treatment of corneal NV with anti-VEGF antibody has limits and depends on the size of the scar, durability and range of neovascularization. Anti-VEGF agents are especially effective when administered early (less then 2 weeks in neoangiogenesis). Controlled prospective studies are needed to establish long-term safety, efficacy and minimum effective and maximum security concentration of the drug to treat neovascularisation of anterior eye segment.

Neuropilin-2 contributes to LPS-induced corneal inflammatory lymphangiogenesis

Neuropilin-2 (NP2), a high-affinity kinase-deficient co-receptor for vascular endothelial growth factor (VEGF)-C, is involved in embryonic vessel development, tumor growth, tumor lymphangiogenesis and metastasis. However, the pathological role of NP2 in other disorders, particularly under inflammatory lymphangiogenic conditions, remains largely unknown. In this study, we investigated the role of NP2 in inflammation-induced lymphangiogenesis in vivo using a lipopolysaccharide (LPS)-induced corneal neovascularization mouse model and in vitro using a macrophage-mouse lymphatic endothelial cell (mLEC) co-culture system. In the mouse model of LPS-induced inflammatory corneal neovascularization, NP2 and VEGFR-3 expression were rapidly up-regulated after LPS stimulation, and microRNA-mediated knockdown of NP2 significantly inhibited the up-regulation of VEGFR-3. Moreover, NP2 knockdown specifically inhibited the increase in the number of corneal lymphatic vessels but did not influence the increase in the number of blood vessels or macrophage recruitment induced by LPS. In a macrophage-LEC co-culture system, LPS up-regulated VEGFR-3 expression and induced mLEC migration and proliferation, and NP2 knockdown inhibited the up-regulation of VEGFR-3 expression and mLEC migration but not proliferation. Taken together, these results suggested that NP2 might be involved in the regulation of lymphangiogenesis via the regulation of VEGFR-3 expression during corneal inflammation. Therefore, NP2-targeted therapy might be a promising strategy for selective inhibition of inflammatory lymphangiogenesis in corneal inflammatory diseases, transplant immunology and oncology.

Activity of matrix metalloproteinases 2 and 9 in cultured rabbit corneal epithelium cells stimulated by tumor necrosis factor alpha.

We studied the activity of matrix metalloproteinases (MMP) 2 and 9 generated by cultured rabbit corneal epithelium cells that had been stimulated with tumor necrosis factor alpha (TNF-α), to investigate the possible regulative mechanisms of MMP-2/9 and their potential effect on corneal inflammatory diseases. The rabbit corneal epithelium cells were cultured in vitro and incubated with different concentrations of TNF-α (0, 1, 10, and 100 ng/mL) for 24 h. The activity of MMP-2/9 was examined using gelatin zymography. The results were analyzed by computer image analysis and statistical tests. TNF-α stimulated the secretion of MMP-2/9 in a dose-dependent manner, and MMP-2 was activated by TNF-α. Inflammatory factors such as TNF-α can stimulate MMP-2/9 activity in corneal epithelium cells. This may be a potential manipulating mechanism of MMP expression in the pathogenesis of corneal diseases, and could play an important role in the prevention and treatment of corneal inflammatory diseases.

Significance of arachidonic acid in ocular infections and inflammation.

Innate immune responses in the cornea mainly play an important role to mobilize multiple interrelated pathways of corneal lipid, which involve in inflammatory corneal diseases. Signaling lipid mediators derived from arachidonic acid (AA) control cell proliferation, apoptosis, metabolism, and migration, are known as eicosanoids, phosphoinositides, sphingolipids, and fatty acids. Emerging evidences have highlighted the implication of lipid mediators in both injury and repair mechanisms in the cornea. Recently, the role of AA and its metabolites to induce proinflammatory mediators and inflammatory cell infiltration in the pathogen-infected cornea and to cause severe keratitis have been revealed. In this review, we focus on the novel roles of AA downstream signaling in the corneal inflammatory diseases and also the biological relevance of AA signaling in the therapeutic strategies for targeting sight-threatening diseases.

Virological Analysis in Patients with Human Herpes Virus 6–Associated Ocular Inflammatory Disorders

To determine whether human herpes virus 6 (HHV-6) genomic DNA and mRNA can be detected in ocular samples from patients with inflammatory disorders, and whether viral replication is involved in the development of inflammation in the eye. After informed consent was obtained, ocular fluid samples (aqueous humor and vitreous fluids) were collected from 350 patients with uveitis or endophthalmitis. Corneal samples were also collected from 65 patients with corneal infections. Multiplex PCR was performed to screen ocular samples from the patients for HHV-1 to HHV-8. Samples were also assayed for HHV-6 DNA using quantitative real-time PCR. Primers for nested RT-PCR were designed to detect amplification of mRNA (HHV-6 A IE1 U90). PCR results indicated a total of seven patients with uveitis or endophthalmitis (7/350, 2% +) and a single patient with corneal inflammatory disease were positive for HHV-6 DNA (1/65, 1.5% +). These eight patients had high copy numbers of HHV-6 DNA, with values ranging from 4.0 × 10(3) to 5.1 × 10(6) copies/mL. Real-time PCR analysis indicated that two of these cases were HHV-6 variant A and six cases were variant B. In addition, HHV-6 mRNA was clearly detected in vitreous cells collected from one of the patients, suggesting that viral replication may occur in the eye. Our results indicate that HHV-6 infection/reactivation is implicated in ocular inflammatory diseases.

Regressed lymphatic vessels develop during corneal repair

The fate of newly synthesized lymphatic vessels induced by inflammation is poorly understood. To address this question, we designed experiments to determine the morphologic, phenotypic, and functional differences in regressing lymphatic vessels in the context of corneal recovery after an inflammatory response. A suture removal modification was used to induce corneal recovery after suture induced inflammation. We identified an increase in markers of corneal inflammation in sutured cornea that resolved in 14 days after suture removal. Sprouting newly synthesized lymphatic vessels trafficking MHC-II-positive leukocytes were visualized in sutured cornea. Following suture removal and recovery, the visualized lymphatic vessels were thin and fragmented, had bulbous termini, discontinuous expression of CD31 and VE-cadherin, and excluded MHC-II-positive leukocytes. VEGF-A, VEGF-C, and TGF-β mRNA levels were increased during corneal recovery, suggesting a complex interaction between lymphangiogenic factors and the mechanisms that regulate corneal recovery. The balance of lymphatic vessel growth and regression is likely to have a central role in the pathogenesis of corneal inflammatory diseases.

The Corneal Expression of Antimicrobial Peptides during Experimental Fungal Keratitis

Purpose/Aim of Study: To investigate the expression of endogenous antimicrobial peptides within the murine cornea during the onset and progression of posttraumatic keratomycosis caused by Candida albicans.Materials and Methods: Scarified corneas of BALB/c mice were topically inoculated with C. albicans and monitored for one week. A murine gene microarray compared the relative expression of 36 antimicrobial peptide genes in infected corneas to controls. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) determined gene expression levels for murine cathelicidin and β-defensins in normal corneas, scarified corneas, and C. albicans-infected corneas. Immunofluorescent staining localized the expression of cathelicidin in corneal sections.Results: Traumatized eyes exposed to C. albicans developed progressive corneal inflammation, with a fungal inoculum of 106 colony-forming units (CFU) bringing about significantly (P < 0.05) more severe corneal inflammatory disease than a 105 CFU inoculum. Camp, encoding a murine cathelicidin-related antimicrobial peptide, was significantly upregulated 45-fold by microarray (P = 0.0007) and 36-fold by real-time RT-PCR (P = 0.0009). Camp increased significantly (P = 0.002) more in corneas receiving the higher than the lower fungal inoculum. Cathelicidin was preferentially expressed within the stroma on the first day after fungal inoculation, and Camp expression progressively declined over one week as the amount of recoverable fungi decreased. The genetic expression of β-defensin 1 and β-defensin 2 was initially downregulated (P ≤ 0.01) at the onset of fungal keratitis then returned toward normal levels.Conclusions: The antimicrobial peptide cathelicidin rapidly increases within the inflamed murine corneal stroma after the initiation of fungal keratitis and may play a role in the host responses that follow corneal trauma and infection.

Corneal Inflammatory Diseases - Infectious Keratitis in Dogs

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HLA and Mooren's ulceration

BACKGROUNDMooren's ulcer is a progressive intractable destructive peripheral ulceration of the cornea, probably of autoimmune aetiology. The disease is rare in the northern hemisphere but is more common in southern...

Detection of Cellular Adhesion Molecules in Inflamed Human Corneas

The expression of cellular adhesion molecules in 31 penetrating keratoplasty specimens from a broad range of corneal inflammatory diseases was studied using monoclonal antibodies and an immunoperoxidase technique. Corneas were divided into noninflamed, mild to moderately inflamed, and severely inflamed groups based on histologic findings. The panel of adhesion molecules studied included HLA-ABC, HLA-DR, CD3, LFA-1, MAC-1, ICAM-1, PECAM-1, VCAM-1, and E-selectin-1. The adhesion molecules ICAM-1, HLA-DR, PECAM-1, CD3, VCAM-1, LFA-1, and MAC-1 were selectively expressed in areas of corneal inflammation. In general, HLA-DR and intercellular adhesion molecule ICAM-1 were co-expressed in similar regions. PECAM-1 was restricted to zones of marked inflammation and vascularization. E-selectin-1 was detected only in the stroma of a graft melt in a patient with active ocular cicatricial pemphigoid, and may reflect a primary regulatory dysfunction in this disorder. The ICAM-1 ligand was, in general, more diffusely distributed than its receptor LFA-1, a beta-2 integrin found on leukocyte cell membranes. The localization of the integrin MAC-1, present on macrophages, neutrophils, and some lymphocytes, did not always parallel the staining pattern of ICAM-1, suggesting promiscuity in its binding to other ligands besides ICAM-1. Adhesion molecules are detected readily at sites of corneal inflammation and may play a critical role in facilitating the recruitment of immune regulatory cells to these areas. Future efforts to block or modulate the expression of intercellular adhesion molecules may provide new therapeutic options in the treatment of corneal inflammatory diseases.

Immunology of Herpes Simplex Virus Infection

The accompanying inflammation seen in ocular HSV infection-the result of interactions between viruses and the immune response-can be both beneficial and potentially harmful to the host. An understanding of the interaction of virus-immune cells is just evolving from current advances in basic research. Based on our studies on HSV keratitis [11], the control of ocular HSV infection appears to involve an early inflammatory phase with macrophage reactivity and elaboration of MIF. Transient virus-specific lymphocytes with effector reactivity, as well as neutrophils with chemotactic activity, occur during the stromal keratitis. Finally, antibody-dependent complement-mediated lysis provides another phase of restriction of infection. Thus, a rationale for effective management and therapy of occular HSV disease must be based on an understanding of (1) the immunological and immunopathological mechanisms of corneal inflammatory disease initiated by the virus; (2) the immunological mechanisms in recovery from the disease; and (3) the host's humoral and cellular immune status during virus persistence (latency) and during recurrent episodes of infection. We hope that new information obtained from assessment of roles of the humoral and cellular immune responses in recovery from disease and in recurrent disease will provide new approaches to the management of ocular HSV infections.

Pathogenetic Approach to Therapy of Peripheral Corneal Inflammatory Disease

Pathogenetic Approach to Therapy of Peripheral Corneal Inflammatory Disease

Corticosteroid Therapy in Central Stromal Keratitis

Use of adrenal corticosteroids in central corneal inflammatory disease has been heat­ edly discussed during the past 15 years. Kaufman and Thomas have recom­ mended topical corticosteroid therapy (com­ bined with IUDR) for disciform lesions in herpetic keratitis, while Thygeson has cau­ tioned that they may encourage virus prolif­ eration and lead to catastrophic events. Theo­ dore believes that some cases of deep stromal herpes cannot be controlled without corti­ costeroids. DeVoe has emphasized that corticosteroid therapy in herpes simplex kera­ titis should not be condemned on the basis of rabbit experiments. Corticosteroids may be used guard­ edly' in herpes zoster keratitis; they probably should be avoided in central bacterial ulcers. However, corticosteroids are the treatment of choice' in allergic cor­ neal disease. The general consensus indicates that the use of corticosteroids depends upon the etiologic agent involved rather than the degree of structural alteration. Specific therapy is always preferable but, when it is not successful, nonspecific (corticosteroid) therapy may be used. Following extensive experimental evalua­ tion of the mechanisms of inflammatory reac­ tivity in the rabbit and guinea pig cornea,