Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022568 (keratitis)
 5,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Herpes simplex viruses (HSV) are highly pervasive pathogens in the human host with a seroconversion rate upwards of 60% worldwide. HSV type 1 (HSV-1) is associated with the disease herpetic stromal keratitis, the leading cause of infectious corneal blindness in the industrialized world. Individuals suffering from genital herpes associated with HSV type 2 (HSV-2) are found to be two- to threefold more susceptible in acquiring human immunodeficiency virus (HIV). The morbidity associated with these infections is principally due to the inflammatory response, the development of lesions, and scarring. Chemokines have become an important aspect in understanding the host immune response to microbial pathogens due in part to the timing of expression. In this paper, we will explore the current understanding of chemokine production as it relates to the orchestration of the immune response to HSV infection.
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PMID:Herpes simplex virus and the chemokines that mediate the inflammation. 1657 Aug 56

Pseudomonas is one of the leading causes of contact lens-related microbial keratitis. Despite the use of antibiotics, the host inflammatory response continues to cause damage to the cornea, which may lead to blindness. CXCR2-binding chemokines have been implicated in the pathogenesis of Pseudomonas keratitis, and the exact role of this receptor remains to be elucidated. Corneas of CXCR2 knockout and wild-type mice (Cmkar 2-/- and Cmkar 2+/+) were scratched, and 2x10(6) CFU/mL Pseudomonas 6294 or 6206 was added to corneas. Twenty-four hours postinfection, mice were killed, and eyes were harvested for enumeration of bacteria, myeloperoxidase (MPO) levels, and inflammatory mediators. Cmkar 2-/- had 20- to 100-fold more bacteria than Cmkar 2+/+ mice. There were no differences in MPO levels between gene knockout and Cmkar 2+/+ mice. Histology revealed PMN were restricted to the limbal area. Levels of CXCR2 chemokines (keratinocyte-derived chemokine and MIP-2) were elevated significantly in gene knockout mice. A lack of CXCR2 leads to an inability to control bacterial numbers as a result of the inability of PMN to reach the site of infection in the avascular cornea. These results imply that CXCR2 is critical to the extravasation of neutrophils into the avascular cornea.
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PMID:The role of CXC chemokine receptor 2 in Pseudomonas aeruginosa corneal infection. 1702 1

The severity of corneal inflammation depends on the activity of infiltrating neutrophils responding to chemotactic factors such as CXC chemokines. This study examines the relative contribution of CXCL1/keratinocyte-derived chemokine (KC), CXCL2/monocyte-inhibitory protein-2 (MIP-2), and CXCL5/LPS-induced chemokine (LIX) in neutrophil recruitment to the corneal stroma during LPS keratitis, where neutrophils infiltrate the corneal stroma at 6 h after LPS injection and peak at 24 h. Consistent with this timeframe, KC was detected after 3 h, reached peak levels at 24 h, and decreased thereafter. In contrast, LIX production was not detected until 8 h after injection and peaked at 24 h. MIP-2 was detected at 3 h but did not reach the levels of KC and LIX. Cell types associated with corneal inflammation produced markedly different chemokines in vitro: Murine corneal fibroblasts (MK/T-1) produced LIX and KC in response to LPS but did not produce MIP-2, whereas peritoneal macrophages and neutrophils produced MIP-2 and KC but did not produce LIX. To determine the role of these chemokines in neutrophil recruitment to the cornea, anti-LIX, anti-KC, or anti-MIP-2 was injected into the corneal stroma of enhanced GFP chimeric mice prior to LPS, and total cell and neutrophil infiltration was examined. Antibody to LIX and KC, injected individually or in combination, significantly inhibited neutrophil recruitment to the cornea, whereas anti-MIP-2 had no inhibitory effect. Together, these findings demonstrate cell-specific production of CXC chemokines and show that LIX and KC mediate neutrophil recruitment into the cornea during LPS keratitis.
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PMID:CXCL1/KC and CXCL5/LIX are selectively produced by corneal fibroblasts and mediate neutrophil infiltration to the corneal stroma in LPS keratitis. 1711 Apr 18

Interleukin-4 (IL-4) has previously been implicated in a protective response to Staphylococcus aureus corneal infection. Consequently, the specific role of IL-4 during S. aureus corneal infection was investigated using IL-4 gene knockout mice. The eyes of IL-4-/- mice and wild-type mice were challenged topically with S. aureus and examined at 24 h post-infection. Keratitis was examined clinically and histologically. Bacterial and polymorphonuclear leucocytes (PMN) numbers were enumerated and cytokine and chemokine levels determined by enzyme-linked immunosorbent assay. Exogenous IL-4 was administered to both IL-4-/- and wild-type mice and clinical parameters were determined. A lack of IL-4 resulted in a significant increase in clinical scores, pathology, bacterial load and neutrophil numbers. The absence of IL-4 also resulted in an upregulation of interferon (IFN)-gamma and a downregulation of IL-6, IL-10 and the chemokines KC and macrophage inflammatory protein-2. Administration of exogenous IL-4 to IL-4-/- mice was protective but time-dependent. This study highlights the protective role of IL-4 during S. aureus infection and emphasizes the balance between IL-4 and IFN-gamma in achieving bacterial control and maintaining the integrity of the cornea. This information may lead to the development of novel therapeutic strategies potentially improving the prognosis for infection of this unique avascular site.
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PMID:The corneal response to infection with Staphylococcus aureus in the absence of interleukin-4. 1738 70

Keratocan and lumican are keratan-sulfate proteoglycans (KSPG), which have a critical role in maintaining corneal clarity. To determine whether these KSPGs have a role in corneal inflammation, we examined Kera(-/-) and Lum(-/-) mice in a model of lipopolysaccharide (LPS)-induced keratitis in which wild-type mice develop increased corneal thickness and haze due to neutrophil infiltration to the corneal stroma. Corneal thickness increases caused by LPS mice were significantly lower in Kera(-/-) and Lum(-/-) than wild-type mice. Further, LPS-injected Lum(-/-) mice had elevated corneal haze levels compared with that of Kera(-/-) and wild-type. At 24 h post-injection, total enhanced green fluorescent protein-positive bone marrow-derived inflammatory cells in chimeric mice was significantly lower in Kera(-/-) mice and Lum(-/-) mice compared with wild-type mice. Neutrophil infiltration was inhibited in Kera(-/-) and Lum(-/-) mice at 6 and 24 h post-stimulation, with Lum(-/-) corneas having the most profound defect in neutrophil migration. Reconstitution of keratocan and lumican expression in corneas of Kera(-/-) and Lum(-/-) mice using adeno-keratocan and adeno-lumican viral vectors, respectively, resulted in normal neutrophil infiltration in response to LPS. Immunoprecipitation/Western blot analysis showed that lumican and keratocan core proteins bind the CXC chemokine KC during a corneal inflammatory response, indicating that corneal KSPGs mediate neutrophil recruitment to the cornea by regulating chemokine gradient formation. Together, these data support a significant role for lumican and keratocan in a corneal inflammatory response with respect to edema, corneal clarity, and cellular infiltration.
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PMID:Keratocan and lumican regulate neutrophil infiltration and corneal clarity in lipopolysaccharide-induced keratitis by direct interaction with CXCL1. 1791 Nov 2

Herpes simplex virus encephalitis (HSE) is the most common fatal sporadic encephalitis in humans. HSE is primarily caused by herpes simplex virus (HSV)-1 infection of the brain. HSE results in increased levels of oxidative stress, including the production of reactive oxygen species, free radicals, and neuroinflammation. The most biologically active form of vitamin E (VE) is alpha-tocopherol (alpha-TOC). In cellular membranes, alpha-TOC prevents lipid peroxidation by scavenging free radicals and functioning as an antioxidant. Supplementation with VE has been shown to decrease immunosenescence, improve immune function, and may be neuroprotective. To determine how VE deficiency and VE supplementation would alter the pathogenesis of HSE, we placed weanling male BALB/cByJ mice on VE-deficient (VE-D), VE-adequate (VE-A), or 10x VE-supplemented diets for 4 wk, and then infected the mice intranasally with HSV-1. VE-D mice had more severe symptoms of encephalitis than VE-A mice, including weight loss, keratitis, hunched posture, and morbidity. VE-D mice had increased cytokine and chemokine expression in the brain and increased viral titers. In contrast, VE supplementation failed to decrease cytokine production and had no effect on viral titer. We demonstrated that adequate levels of VE are important in limiting HSE pathology and that 10x supplementation does not enhance protection.
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PMID:The immune response to herpes simplex virus encephalitis in mice is modulated by dietary vitamin E. 1815 15

Although many factors that trigger the herpes simplex virus (HSV) reactivation from latency have been reported, how HSV resides in a latent state in the normal human cornea still needs to be defined. We therefore conducted a series of studies regarding various aspects of HSV infections. To understand how patients subjectively perceived changes in their daily life that could have induced HSV reactivation, we first performed a comprehensive survey on the subjective factors in patients who had experienced recurrent herpetic keratitis. The result of our survey revealed that stress, lack of sleep, shoulder stiffness, and physical fatigue were the key factors. There were various causes for stress, and stress associated with reactivation often occurred between spring and summer. Regarding HSV latency in the normal cornea, we used real-time polymerase chain reaction (PCR) to determine the presence of HSV in the donor and host corneas. The findings showed that on average, those host corneas with a history of HSV keratitis had 1.6 x 10(4) copies/mg of HSV DNA, while the host corneas without a history and the donor corneas had 8.7 and 4.9 x 10(2) copies/mg of HSV DNA, respectively. Based on these observations, it is reasonable to infer that latent viruses could have resided in a normal cornea without a history and were transmitted to a host cornea through corneal transplantation. We also quantified the virus load in tears before and after ocular surgery (one week after corneal transplantation or the next day after vitreous surgery). Our results indicated that both the detection rate and the average copy number of HSV DNA had a tendency to increase postperatively. Moreover, we tried to differentiate the HSV strains that were involved in the recurrent lesions. In only one of the studied cases, could we find a single different nucleotide between two HSV strains. It seemed possible that two different strains of HSV had set off the same episode of reactivation. In recent years, chemokines have become known for their action in mediating inflammatory diseases. We suspected that chemokines might also play a role in the antiviral mechanism and examined the chemokine-derived antiviral activity. We used eight chemokines, including RANTES/CCL5, MIP-lalpha/ CCL3, and MIP-1beta/CCL4, in a murine HSK model with Vero cells. These chemokines directly bound to HSV and the chemokine-bound HSV was later resisted by the neutralizing antibody of envelope protein gB. Furthermore, by electron microscope analysis, it became clear that these chemokines had cut an opening in the HSV envelope. Consequently, these chemokines had significantly inhibited the HSV infection on Vero cells. In addition, the virus load in tears was decreased and the corneal opacity was less severe. We concluded in that study that during early infection, chemokines accumulated in the corneal stroma have the ability to protect cells and tissues from HSV infection. As for antiviral therapy, acyclovir (ACV) eye ointment has been effective for patients with herpetic keratitis. However, patients often find it difficult to successfully follow the treatment due to the required frequent application and the blurred vision after application. On the other hand, valaciclovir (VCV), which is the oral prodrug of ACV, has become commercially available in recent years for treating nonocular herpetic diseases. We therefore examined and compared the efficacies of oral VCV, oral ACV, ACV eye ointment, and ACV eye drops in a murine keratitis model; the group treated with oral VCV did show a significantly good antiviral effect. We have proved that oral VCV can be a beneficial alternative antiviral therapy for patients with difficulty in complying with the ACV eye ointment treatment.
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PMID:[Herpes simplex virus latency, reactivation, and a new antiviral therapy for herpetic keratitis]. 1841 13

Herpetic stromal keratitis (HSK) is an inflammatory disorder induced by HSV-1 infection and characterized by T cell-dependent destruction of corneal tissues. It is not known what triggers CD4(+) T cell migration into the stroma of HSV-1-infected corneas. The keratocyte is a fibroblast-like cell that can function as an antigen-presenting cell in the mouse cornea by expressing MHC class II and costimulatory molecules after HSV-1 infection. We hypothesized that chemokines produced by stromal keratocytes are involved in CD4(+) T cell infiltration into the cornea. We found that keratocytes produce several cytokines and chemokines, including MCP-1, RANTES, and T cell activation (TCA)-3. HSV-1 infection increased the production of MCP-1 and RANTES by keratocytes, and these acted as chemoattractants for HSV-1-primed CD4(+) T cells expressing CCR2 and CCR5. Expression of MCP-1 in the corneal stroma was confirmed in vivo. Finally, when HSV-1-primed CD4(+) T cells were adoptively transferred into wild type and MCP-1-deficient mice that had been sublethally irradiated to minimize chemokine production from immune cells, infiltration of CD4(+) T cells was markedly reduced in the MCP-1-deficient mice, suggesting that it is the MCP-1 from HSV-1-infected keratocytes that attracts CD4(+) T cells into the cornea.
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PMID:MCP-1 derived from stromal keratocyte induces corneal infiltration of CD4+ T cells in herpetic stromal keratitis. 1859 81

Epidemic keratoconjunctivitis (EKC), caused by human adenovirus (HAdV), is one of the most common ocular infections and results in corneal inflammation and subepithelial infiltrates. Adenoviral keratitis causes significant morbidity to the patients, and is characterized by infiltration of leukocytes in the corneal stroma, and expression of chemokines. The exact role of these chemokines in adenoviral infection has not been studied due to lack of animal models. Here, we have characterized the role of chemokine CXCL1/KC and receptor CXCR2 in adenoviral keratitis using a novel mouse model. Analysis of chemokine expression, leukocyte infiltration, and development of keratitis was performed by ELISA, flow cytometry, and histopathology, respectively. Deficiency of CXCL1 and CXCR2 resulted in delayed infiltration of neutrophils, but not inflammatory monocytes in HAdV-37 corneal infection. CXCL1(-/-) mice showed decreased expression of CXCL2/MIP-2, but not CCL2/MCP-1. CXCR2(-/-) mice showed increased expression of CXCL1 and CXCL2, but not CCL2. Both CXCL1(-/-) and CXCR2(-/-) mice demonstrated keratitis similar to wild-type mice. In conclusion, both CXCL1 and CXCR2 play an important role in chemokine expression and neutrophil infiltration following adenoviral corneal infection, but have a redundant role in the development of keratitis.
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PMID:Chemokine CXCL1/KC and its receptor CXCR2 are responsible for neutrophil chemotaxis in adenoviral keratitis. 1964 7

Purpose. To investigate the expression and function of toll-like receptors (TLRs) during experimental keratomycosis. Methods. Scarified corneas of BALB/c mice were topically inoculated with Candida albicans and compared with control corneas by a murine gene microarray and immunostaining. Real-time reverse transcription polymerase chain reaction (RT-PCR) determined relative TLR gene expression in murine and human donor corneas. The scarified corneas of TLR2(-/-) mice, TLR4(-/-) mice, and C57BL/6J control mice were also inoculated with C. albicans, to determine relative severity, fungal load, and cytokine transcript levels. Results. TLR1, -2, -4, -6, and -13 were significantly upregulated (5- to 10-fold; P < 0.01) by microarray, and TLR1, -2, -4, and -13 were significantly increased (4- to 11-fold; P < 0.05) by real-time RT-PCR in BALB/c murine corneas. Similarly, TLR2, -6, and -13 were significantly upregulated (5- to 16-fold; P < or = 0.001) by real-time RT-PCR in C57BL/6J murine corneas the day after inoculation, and TLR2 and -13 remained significantly (P < 0.05) increased after 1 week. TLR2 transcript was also upregulated twofold (P = 0.04) in C. albicans-inoculated explanted human corneas. Although murine keratitis severity scores were similar, significantly more fungi were recovered from TLR2(-/-) mouse corneas (P = 0.04) than from TLR4(-/-) mouse corneas (P = 0.9). Tumor necrosis factor-alpha, interleukin 23, chemokine C-C ligands 3 and 4, and dectin-1 were significantly (P < 0.05) downregulated in C. albicans-infected corneas of TLR2(-/-) mice. Conclusions. TLR2 signals proinflammatory cytokines that control fungal growth during C. albicans keratitis. TLR13 may have an additional role in the innate immune response of murine corneal candidiasis.
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PMID:Toll-like receptors involved in the pathogenesis of experimental Candida albicans keratitis. 1993 94


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