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Phantom tooth pain (PTP) is one type of non-odontogenic neuropathic toothache, which rarely occurs after appropriate pulpectomy or tooth extraction. The cause of PTP is unknown. We investigated pain-related genetic factors that are associated with PTP. Four pain-associated genes, including G protein-coupled receptor 158 (GPR158) and phosphoribosyl transferase domain containing 1 (PRTFDC1), are adjacent to each other on the human genome. Some of these four genes or their genomic region may be related to PTP. We statistically analyzed associations between single-nucleotide polymorphisms (SNPs) in the genomic region and PTP in patients with PTP (PTP group), other orofacial pain (OFP group), and healthy control subjects. We then performed a database search of expression quantitative trait loci (eQTLs). For the seven SNPs that were significantly associated with PTP even after Bonferroni correction, we focused on the rs12411980 tag SNP (P = 9.42 × 10-4). Statistical analyses of the PTP group and healthy subject groups (group labels: NOC and TD) revealed that the rate of the GG genotype of the rs12411980 SNP was significantly higher in the PTP group than in the healthy subject groups (PTP group vs. NOC group: P = 2.92 × 10-4, PTP group vs. TD group: P = 5.46 × 10-4; percentage of GG: 30% in PTP group, 12% in NOC group, 11% in TD group). These results suggest that the GG genotype of the rs12411980 SNP is more susceptible to PTP. The rs2765697 SNP that is in strong linkage disequilibrium with the rs12411980 SNP is an eQTL that is associated with higher PRTFDC1 expression in the minor allele homozygotes in the healthy subject groups of the rs2765697 SNP. Thus, PRTFDC1 expression similarly increases in the minor allele homozygotes (GG genotype) in the healthy subject groups of the rs12411980 SNP, which would lead to greater susceptibility to PTP.
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BACKGROUND: Artificial intelligence (AI) is a promising new technology that has the potential of diagnosing allergic conjunctival diseases (ACDs). However, its development is slowed by the absence of a tailored image database and explainable AI models. Thus, the purpose of this study was to develop an explainable AI model that can not only diagnose ACDs but also present the basis for the diagnosis. METHODS: A dataset of 4942 slit-lamp images from 10 ophthalmological institutions across Japan were used as the image database. A sequential pipeline of segmentation AI was constructed to identify 12 clinical findings in 1038 images of seasonal and perennial allergic conjunctivitis (AC), atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), giant papillary conjunctivitis (GPC), and normal subjects. The performance of the pipeline was evaluated by determining its ability to obtain explainable results through the extraction of the findings. Its diagnostic accuracy was determined for 4 severity-based diagnosis classification of AC, AKC/VKC, GPC, and normal. RESULTS: Segmentation AI pipeline efficiently extracted crucial ACD indicators including conjunctival hyperemia, giant papillae, and shield ulcer, and offered interpretable insights. The AI pipeline diagnosis had a high diagnostic accuracy of 86.2%, and that of the board-certified ophthalmologists was 60.0%. The pipeline had a high classification performance, and the area under the curve (AUC) was 0.959 for AC, 0.905 for normal subjects, 0.847 for GPC, 0.829 for VKC, and 0.790 for AKC. CONCLUSIONS: An explainable AI model created by a comprehensive image database can be used for diagnosing ACDs with high degree of accuracy.
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Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. The present study focused on the CACNA1C gene, which encodes the α1C subunit of the Cav1.2 L-type Ca2+ channel (LTCC) that has been reported to be associated with neuropathic pain in previous studies. We investigated genetic polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 33 patients with PTP and 118 patients without PTP but with pain or dysesthesia in the orofacial region. From within and around the CACNA1C gene, 155 polymorphisms were selected and analyzed for associations with clinical data. We found that the rs216009 single-nucleotide polymorphism (SNP) of the CACNA1C gene in the recessive model was significantly associated with the vulnerability to PTP. Homozygote carriers of the minor C allele of rs216009 had a higher rate of PTP. Nociceptive transmission in neuropathic pain has been reported to involve Ca2+ influx from LTCCs, and the rs216009 polymorphism may be involved in CACNA1C expression, which regulates intracellular Ca2+ levels, leading to the vulnerability to PTP. Furthermore, psychological factors may lead to the development of PTP by modulating the descending pain inhibitory system. Altogether, homozygous C-allele carriers of the rs216009 SNP were more likely to be vulnerable to PTP, possibly through the regulation of intracellular Ca2+ levels and affective pain systems, such as those that mediate fear memory recall.
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Neuralgia , Polimorfismo de Nucleotídeo Único , Humanos , Polimorfismo de Nucleotídeo Único/genética , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Neuralgia/genéticaRESUMO
Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) in 362 healthy patients who underwent cosmetic surgery using the dominant, recessive, and genotypic models. Next, we validated the associations between relevant SNPs on the one hand and pain intensity and daily opioid dosages on the other in 89 patients with cancer-related pain. In this validation study, a Bonferroni correction for multiplicity was applied on all relevant SNPs of the ENPP2 gene and their respective models. In the exploratory study, three models of two SNPs (rs7832704 and rs2249015) were significantly associated with postoperative opioid doses, although the postoperative pain intensity was comparable. In the validation study, the three models of the two SNPs were also significantly associated with cancer pain intensity (p < 0.017). Patients with a minor allele homozygosity complained of more severe pain compared with patients with other genotypes when using comparable daily opioid doses. Our findings might suggest that autotaxin is associated with nociceptive pain processing and the regulation of opioid requirements.
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Dor do Câncer , Dor Nociceptiva , Humanos , Analgésicos Opioides/efeitos adversos , Medição da Dor , Polimorfismo de Nucleotídeo Único , Dor do Câncer/tratamento farmacológico , Dor do Câncer/genética , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/genéticaRESUMO
Myostatin (Myo) is known to suppress skeletal muscle growth, and was recently reported to control tendon homeostasis. The purpose of the present study was to investigate the regulatory involvement of Myo in the myotendinous junction (MTJ) in vivo and in vitro. After Achilles tendon injury in mice, we identified unexpected cell accumulation on the tendon side of the MTJ. At postoperative day 7 (POD7), the nuclei had an egg-like profile, whereas at POD28 they were spindle-shaped. The aspect ratio of nuclei on the tendon side of the MTJ differed significantly between POD7 and POD28 (p = 4.67 × 10-34). We then investigated Myo expression in the injured Achilles tendon. At the MTJ, Myo expression was significantly increased at POD28 relative to POD7 (p = 0.0309). To investigate the action of Myo in vitro, we then prepared laminated sheets of myoblasts (C2C12) and fibroblasts (NIH3T3) (a pseudo MTJ model). Myo did not affect the expression of Pax7 and desmin (markers of muscle development), scleraxis and temonodulin (markers of tendon development), or Sox9 (a common marker of muscle and tendon development) in the cell sheets. However, Myo changed the nuclear morphology of scleraxis-positive cells arrayed at the boundary between the myoblast sheet and the fibroblast sheet (aspect ratio of the cell nuclei, myostatin(+) vs. myostatin(-): p = 0.000134). Myo may strengthen the connection at the MTJ in the initial stages of growth and wound healing.
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Tendão do Calcâneo , Junção Miotendínea , Camundongos , Animais , Miostatina/genética , Células NIH 3T3 , Músculos/fisiologia , Músculo EsqueléticoRESUMO
Chronic pain is reportedly associated with the transient receptor potential canonical 3 (TRPC3) gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the TRPC3 gene and chronic pain. The genomic samples from 194 patients underwent linkage disequilibrium (LD) analyses of 29 SNPs within and around the vicinity of the TRPC3 gene. We examined the associations between the SNPs and the susceptibility to chronic pain by comparing the genotype distribution of 194 patients with 282 control subjects. All SNP genotype data were extracted from our previous whole-genome genotyping results. Twenty-nine SNPs were extracted, and a total of four LD blocks with 15 tag SNPs were observed within and around the TRPC3 gene. We further analyzed the associations between these tag SNPs and chronic pain. The rs11726196 SNP genotype distribution of patients was significantly different from the control subjects even after multiple-testing correction with the number of SNPs. The TT + TG genotype of rs11726196 is often carried by chronic pain patients, suggesting a causal role for the T allele. These results contribute to our understanding of the genetic risk factors for chronic pain.
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Dor Crônica , Polimorfismo de Nucleotídeo Único , Canais de Cátion TRPC , Humanos , Dor Crônica/genética , Ligação Genética , Predisposição Genética para Doença , Genótipo , Desequilíbrio de Ligação , Canais de Cátion TRPC/genéticaRESUMO
Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation and chronic pain; therefore, we focused on the autoimmune-related protease-activated receptor 2 (PAR2/F2RL1) and interleukin 17A (IL-17A/IL17A) genes. PAR2 and IL-17A are associated with autoimmune diseases that lead to chronic pain, and PAR2 regulates T-helper (Th) cell activation and differentiation. We hypothesized that the PAR2 and IL-17A genes are associated with chronic pain. The present study used a case-control design to statistically examine associations between genetic polymorphisms and the vulnerability to chronic pain. The rs2243057 polymorphism of the PAR2 gene and rs3819025 polymorphism of the IL-17A gene were previously reported to be associated with pain- or autoimmune-related phenotypes. Thus, these polymorphisms were investigated in the present study. We found that both rs2243057 and rs3819025 were significantly associated with a susceptibility to chronic pain. The present findings revealed autoimmune-related genetic factors that are involved in individual differences in chronic pain, further aiding understanding of the pathomechanism that underlies chronic pain and possibly contributing to future personalized medicine.
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Doenças Autoimunes , Dor Crônica , Interleucina-17 , Receptor PAR-2 , Humanos , Estudos de Casos e Controles , Dor Crônica/genética , Predisposição Genética para Doença , Interleucina-17/genética , Polimorfismo de Nucleotídeo Único , Receptor PAR-2/genéticaRESUMO
Biologics applying antibodies against IgE, IL-5, IL-5 receptor α, IL-4 receptor α, and IL-13 have dramatically improved recent treatment outcomes in allergic diseases including asthma, rhinitis, and atopic dermatitis. However, these drugs have not been approved for ocular allergic diseases such as allergic conjunctivitis, vernal keratoconjunctivitis, and atopic keratoconjunctivitis. Although the putative mechanisms suggest that these drugs should have beneficial effects in patients with ocular allergies and some studies have reported such beneficial effects, various adverse ocular symptoms have also been observed in clinical trials and off-label use studies. Since ocular allergic diseases have distinct pathogeneses, each biologic drug must be examined regarding specific effects on each ocular allergy. For example, IgE-mediated type 1 hypersensitivity plays a critical role in allergic conjunctivitis. By contrast, T cells and eosinophilic and non-IgE-mediated type 2 inflammation play important roles in vernal keratoconjunctivitis. Allergists must fully understand the effects of each drug on the eye. This review outlines both potential therapeutic and adverse effects of various biologics on allergic diseases of the eye.
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Produtos Biológicos , Conjuntivite Alérgica , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Ceratoconjuntivite , Humanos , Conjuntivite Alérgica/diagnóstico , Produtos Biológicos/efeitos adversos , Olho , Ceratoconjuntivite/diagnóstico , Ceratoconjuntivite/terapia , InflamaçãoRESUMO
Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. We focused on solute carrier family 17 member 9 (SLC17A9)/vesicular nucleotide transporter (VNUT) and purinergic receptor P2Y12 (P2RY12), both of which have been associated with neuropathic pain and pain transduction signaling in the trigeminal ganglion in rodents. We sought to corroborate these associations in humans. We investigated gene polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 150 patients with orofacial pain, including PTP, and 500 healthy subjects. We found that the rs735055 polymorphism of the SLC17A9 gene and rs3732759 polymorphism of the P2RY12 gene were associated with the development of PTP. Carriers of the minor allele of rs735055 and individuals who were homozygous for the major allele of rs3732759 had a higher rate of PTP. Carriers of the minor allele of rs735055 reportedly had high SLC17A9 mRNA expression in the spinal cord, which may increase the storage and release of adenosine triphosphate. Individuals who were homozygous for the major allele of rs3732759 may have higher P2RY12 expression that is more active in microglia. Therefore, these carriers may be more susceptible to PTP. These results suggest that specific genetic polymorphisms of the SLC17A9 and P2RY12 genes are involved in PTP. This is the first report on genes that are associated with PTP in humans.
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Neuralgia , Proteínas de Transporte de Nucleotídeos , Humanos , Trifosfato de Adenosina/metabolismo , Proteínas de Transporte de Nucleotídeos/genética , Proteínas de Transporte de Nucleotídeos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Receptores Purinérgicos P2Y12/genética , Receptores Purinérgicos P2Y12/metabolismoRESUMO
Mast cells and conjunctival fibroblasts contribute to conjunctival wound healing and allergic ocular inflammation. The number of mast cells in the conjunctiva is increased in individuals with cicatricial fibrosis-causing ocular surface diseases and after glaucoma filtering surgery, suggesting that these cells may contribute to the scarring observed after such surgery. We studied the potential mechanism of fibroblast-mast cell interaction in the healing of conjunctival wounds using a three-dimensional collagen gel culture system. We found that mast cells derived from the bone marrow of mice embedded in a collagen gel did not induce gel contraction. However, an increase in mast cells was associated with increased collagen gel contraction mediated by mouse conjunctival fibroblasts. The extent of collagen degradation was not affected by the co-culture of mast cells and conjunctival fibroblasts. Gelatin zymography disclosed that mast cells increased the amounts of both the pro form of matrix metalloproteinase (MMP)-9 and the active form of MMP-2 in supernatants of conjunctival fibroblast cultures. Furthermore, the potentiating effect of mast cells on contraction of the collagen gel through conjunctival fibroblasts was attenuated by the addition of a synthetic MMP inhibitor. Thus, current results suggest that mast cells accelerate the conjunctival fibroblast-dependent contraction of collagen gel by increasing the release as well as activation of MMPs. Therefore, the interaction between mast cells and conjunctival fibroblasts may contribute to conjunctival scar formation after glaucoma filtering surgery.
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Glaucoma , Mastócitos , Animais , Células Cultivadas , Colágeno/metabolismo , Túnica Conjuntiva/metabolismo , Fibroblastos/metabolismo , Glaucoma/metabolismo , Mastócitos/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos , Regulação para CimaRESUMO
BACKGROUND: Coats disease is a retinal vascular disorder characterized by aneurysms and telangiectasias. Macular fibrosis is a complication of Coats disease that results in vision loss. Macular fibrosis rarely develops in the natural course and often occurs after treatment with intravitreal bevacizumab, photocoagulation, or cryotherapy. Here, we have described an unusual case of spontaneous peeling of preretinal macular fibrosis in a patient with untreated Coats disease. CASE PRESENTATION: A 10-year-old Japanese boy presented with vision loss in his left eye. The patient's left visual acuity was 20/28. Fundus examination of his left eye revealed thick preretinal macular fibrosis around the optic disc and macula. In addition, retinal telangiectasis, microaneurysms, hard exudates, and retinal hemorrhages were observed in the left peripheral temporal retina. We diagnosed his condition as Coats disease with preretinal macular fibrosis. Two months later, optical coherence tomography revealed preretinal macular fibrosis detachment at the foveal lesion without any treatment. During follow-up, preretinal macular fibrosis at the macular lesion was completely detached. Further, posterior vitreous detachment was observed and the shape of the macula and the patient's left visual acuity had improved. CONCLUSIONS: In our case, both formation and spontaneous peeling of preretinal macular fibrosis occurred without any treatment for Coats disease, which is an unusual finding. Vitreous changes might have occurred during the natural clinical course, causing subsequent posterior vitreous detachment and resulting in spontaneous peeling of fibrosis.
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Membrana Epirretiniana , Macula Lutea , Telangiectasia Retiniana , Descolamento do Vítreo , Criança , Membrana Epirretiniana/patologia , Fibrose , Seguimentos , Humanos , Macula Lutea/patologia , Masculino , Telangiectasia Retiniana/diagnóstico , Transtornos da Visão/patologia , Descolamento do Vítreo/patologiaRESUMO
Dry eye disease (DED) and allergic conjunctivitis affect a large number of patients, and many patients usually have both symptoms. We investigated the interactions between DED and allergic conjunctivitis in mice. Four experimental groups were compared: control, DED, allergy, and allergy with DED. DED was induced by removing the extraorbital lacrimal glands of the mice. Allergic conjunctivitis was induced by intraperitoneal administration of ovalbumin and antigen eye drops. The early phase reaction of the allergy was evaluated using the clinical score, scratching behavior, and vascular permeability in the conjunctiva. Epithelial barrier function was assessed by an LC-biotin assay. Tear fluid volume and corneal fluorescein staining decreased in the DED and allergy with DED groups. LC-biotin penetrated the entire epithelium of both the cornea and conjunctiva in DED mice. The clinical score of the early phase reaction was higher in allergy-induced mice than in non-allergy mice. Edema of the eyelid and conjunctiva were aggravated in mice with DED. The number of scratching episodes and leakage of Evans blue into the conjunctiva were higher in allergy-induced DED mice than in control mice. The presence of aqueous-deficient dry eye caused ocular surface epithelial damage and exacerbated allergic signs and symptoms.
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Conjuntivite Alérgica , Síndromes do Olho Seco , Animais , Biotina , Conjuntivite Alérgica/diagnóstico , Síndromes do Olho Seco/complicações , Síndromes do Olho Seco/diagnóstico , Aparelho Lacrimal , Camundongos , LágrimasRESUMO
Allergic conjunctival disease (ACD) is an inflammatory disease of the conjunctiva that is mainly caused by type I hypersensitivity response to allergens and accompanied by subjective symptoms and other findings induced by antigens. ACD is classified as allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. This article summarizes the third edition of the Japanese guidelines for allergic conjunctival diseases published in 2021 and outlines the diagnosis, pathogenesis, and treatment of ACD. Since the introduction of immunosuppressive eye drops, the treatment strategies for severe ACDs have significantly changed. To clarify the recommended standard treatment protocols for ACD, the advantages and disadvantages of these treatments were assessed using clinical questions, with a focus on the use of steroids and immunosuppressive drugs. This knowledge will assist healthcare providers and patients in taking an active role in medical decision making.
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Doenças da Túnica Conjuntiva , Conjuntivite Alérgica , Alérgenos/uso terapêutico , Túnica Conjuntiva , Doenças da Túnica Conjuntiva/diagnóstico , Conjuntivite Alérgica/tratamento farmacológico , Conjuntivite Alérgica/terapia , Humanos , Japão/epidemiologia , Soluções Oftálmicas/uso terapêuticoRESUMO
PURPOSE: To evaluate the outcomes of flanged intraocular lens fixation combined with microhook trabeculotomy. PATIENTS AND METHODS: This study was a retrospective case series and included nine eyes of nine exfoliation glaucoma patients with subluxated lens or intraocular lens who underwent flanged intraocular lens fixation combined with microhook trabeculotomy between May 2019 and February 2020 at the Kochi University Hospital. The mean best-corrected visual acuity, intraocular pressure, and number of antiglaucoma medications were compared before and after surgery. RESULTS: The mean follow-up period was 5.67 ± 2.50 months. The mean best-corrected visual acuity improved significantly from 0.83 ± 0.72 preoperatively to 0.22 ± 0.34 at the last visit (p = 0.015). The mean intraocular pressure had significantly reduced from 27.1 ± 8.12 mmHg preoperatively to 13.2 ± 3.73 at the last visit (p = 0.008). The mean number of antiglaucoma medications decreased significantly from 4.56 ± 1.88 to 2.0 ± 1.0 at the last visit (p = 0.008). Postoperative intraocular pressure control to 21 mmHg or lower was achieved or maintained in all patients. Postoperative vitreous hemorrhage was observed in six eyes (66.7%), two of which needed reoperation. CONCLUSIONS: This study showed that flanged intraocular lens fixation combined with microhook trabeculotomy might be effective for exfoliation glaucoma with subluxated lens or intraocular lens.
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Lentes Intraoculares , Trabeculectomia , Humanos , Pressão Intraocular , Complicações Pós-Operatórias , Estudos Retrospectivos , Acuidade VisualRESUMO
Pain sensitivity differs individually, but the mechanisms and genetic factors that underlie these differences are not fully understood. To investigate genetic factors that are involved in sensing cold pain, we applied a cold-induced pain test and evaluated protease-activated receptor 2 (PAR2/F2RL1) and transient receptor potential melastatin 8 (TRPM8), which are related to pain. We statistically investigated the associations between genetic polymorphisms and cold pain sensitivity in 461 healthy patients who were scheduled to undergo cosmetic orthognathic surgery for mandibular prognathism. We found an association between cold pain sensitivity and the rs2243057 polymorphism of the PAR2 gene. We also found a significant association between cold pain sensitivity and the rs12992084 polymorphism of the TRPM8 gene. Carriers of the minor A allele of the rs2243057 polymorphism of PAR2 and minor C allele of the rs12992084 polymorphism of TRPM8 exhibited a longer latency to pain perception in the cold-induced pain test, reflecting a decrease in cold pain sensitivity. These results suggest that genetic polymorphisms of both PAR2 and TRPM8 are involved in individual differences in cold pain sensitivity.
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Temperatura Baixa , Dor/genética , Receptor PAR-2/metabolismo , Canais de Cátion TRPM/metabolismo , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/metabolismo , Dor/fisiopatologia , Percepção da Dor/fisiologia , Limiar da Dor/fisiologia , Receptor PAR-2/genética , Canais de Cátion TRPM/genética , Sensação Térmica/fisiologia , Adulto JovemRESUMO
The cornea is a relatively unique tissue in the body in that it possesses specific features such as a lack of blood vessels that contribute to its transparency. The cornea is supplied with soluble blood components such as albumin, globulin, and fibrinogen as well as with nutrients, oxygen, and bioactive substances by diffusion from aqueous humor and limbal vessels as well as a result of its exposure to tear fluid. The healthy cornea is largely devoid of cellular components of blood such as polymorphonuclear leukocytes, monocytes-macrophages, and platelets. The location of the cornea at the ocular surface renders it susceptible to external insults, and its avascular nature necessitates the operation of healing and defense mechanisms in a manner independent of a direct blood supply. The fibrinolytic system, which was first recognized for its role in the degradation of fibrin clots in the vasculature, has also been found to contribute to various biological processes outside of blood vessels. Fibrinolytic factors thus play an important role in biological defense of the cornea. In this review, we address the function of the fibrinolytic system in corneal defense including wound healing and the inflammatory response.
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Córnea/metabolismo , Lesões da Córnea/metabolismo , Fibrinolisina/fisiologia , Cicatrização/fisiologia , Animais , Antifibrinolíticos/uso terapêutico , Fibrinólise/fisiologia , HumanosRESUMO
The shape and transparency of the cornea are essential for clear vision. However, its location at the ocular surface renders the cornea vulnerable to pathogenic microorganisms in the external environment. Pseudomonas aeruginosa and Staphylococcus aureus are two such microorganisms and are responsible for most cases of bacterial keratitis. The development of antimicrobial agents has allowed the successful treatment of bacterial keratitis if the infection is diagnosed promptly. However, no effective medical treatment is available after progression to corneal ulcer, which is characterized by excessive degradation of collagen in the corneal stroma and can lead to corneal perforation and corneal blindness. This collagen degradation is mediated by both infecting bacteria and corneal fibroblasts themselves, with a urokinase-type plasminogen activator (uPA)-plasmin-matrix metalloproteinase (MMP) cascade playing a central role in collagen destruction by the host cells. Bacterial factors stimulate the production by corneal fibroblasts of both uPA and pro-MMPs, released uPA mediates the conversion of plasminogen in the extracellular environment to plasmin, and plasmin mediates the conversion of secreted pro-MMPs to the active form of these enzymes, which then degrade stromal collagen. Bacterial factors also stimulate expression by corneal fibroblasts of the chemokine interleukin-8 and the adhesion molecule ICAM-1, both of which contribute to recruitment and activation of polymorphonuclear neutrophils, and these cells then further stimulate corneal fibroblasts via the secretion of interleukin-1. At this stage of the disease, bacteria are no longer necessary for collagen degradation. In this review, we discuss the pivotal role of corneal fibroblasts in corneal ulcer associated with infection by P. aeruginosa or S. aureus as well as the development of potential new modes of treatment for this condition.
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Úlcera da Córnea/metabolismo , Fibroblastos/metabolismo , Ceratite/microbiologia , Animais , Colágeno/metabolismo , Córnea/metabolismo , Córnea/fisiologia , Substância Própria/metabolismo , Úlcera da Córnea/etiologia , Úlcera da Córnea/microbiologia , Infecções Oculares Bacterianas/microbiologia , Infecções Oculares Bacterianas/fisiopatologia , Fibrinolisina/metabolismo , Humanos , Metaloproteinases da Matriz/metabolismo , Plasminogênio/metabolismo , Ativadores de Plasminogênio/metabolismo , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidade , Staphylococcus aureus/metabolismo , Staphylococcus aureus/patogenicidade , Ativador de Plasminogênio Tipo Uroquinase/metabolismoRESUMO
Corneal stromal keratocytes contribute to the maintenance of corneal transparency and shape by synthesizing and degrading extracellular matrix. They are quiescent in the healthy cornea, but they become activated in response to insults from the external environment that breach the corneal epithelium, with such activation being associated with phenotypic transformation into fibroblasts. Corneal fibroblasts (activated keratocytes) act as sentinel cells to sense various external stimuli-including damage-associated molecular patterns derived from injured cells, pathogen-associated molecular patterns of infectious microorganisms, and inflammatory mediators such as cytokines-under pathological conditions such as trauma, infection, and allergy. The expression of various chemokines and adhesion molecules by corneal fibroblasts determines the selective recruitment and activation of inflammatory cells in a manner dependent on the type of insult. In infectious keratitis, the interaction of corneal fibroblasts with various components of microbes and with cytokines derived from infiltrated inflammatory cells results in excessive degradation of stromal collagen and consequent corneal ulceration. Corneal fibroblasts distinguish between type 1 and type 2 inflammation through recognition of corresponding cytokines, with their activation by type 2 cytokines contributing to the pathogenesis of corneal lesions in severe ocular allergic diseases. Pharmacological targeting of corneal fibroblast function is thus a potential novel therapeutic approach to prevention of excessive corneal stromal inflammation, damage, and scarring.
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Quimiocinas/metabolismo , Córnea/patologia , Doenças da Córnea/metabolismo , Biomarcadores/metabolismo , Células Cultivadas , Córnea/metabolismo , Doenças da Córnea/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , HumanosRESUMO
Endophthalmitis due to infection with Enterococcus spp. progresses rapidly and often results in substantial and irreversible vision loss. Given that the frequency of this condition caused by vancomycin-resistant Enterococcus faecalis has been increasing, the development of novel therapeutics is urgently required. We have demonstrated the therapeutic potential of bacteriophage ΦEF24C-P2 in a mouse model of endophthalmitis caused by vancomycin-sensitive (EF24) or vancomycin-resistant (VRE2) strains of E. faecalis Phage ΦEF24C-P2 induced rapid and pronounced bacterial lysis in turbidity reduction assays with EF24, VRE2, and clinical isolates derived from patients with E. faecalis-related postoperative endophthalmitis. Endophthalmitis was induced in mice by injection of EF24 or VRE2 (1 × 104 cells) into the vitreous. The number of viable bacteria in the eye increased to >1 × 107 CFU, and neutrophil infiltration into the eye was detected as an increase in myeloperoxidase activity at 24 h after infection. A clinical score based on loss of visibility of the fundus as well as the number of viable bacteria and the level of myeloperoxidase activity in the eye were all significantly decreased by intravitreous injection of ΦEF24C-P2 6 h after injection of EF24 or VRE2. Whereas histopathologic analysis revealed massive infiltration of inflammatory cells and retinal detachment in vehicle-treated eyes, the number of these cells was greatly reduced and retinal structural integrity was preserved in phage-treated eyes. Our results thus suggest that intravitreous phage therapy is a potential treatment for endophthalmitis caused by vancomycin-sensitive or -resistant strains of E. faecalis.