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Corneal lymphangiogenesis ameliorates corneal inflammation and edema in late stage of bacterial keratitis.

ABSTRACT: Lymphatic vessels play a crucial role in systemic immune response and regulation of tissue fluid homeostasis. Corneal lymphangiogenesis in bacterial keratitis has not been studied. In this study, we investigated the mechanism and the role of corneal lymphangiogenesis in a murine bacterial keratitis model using Pseudomonas aeruginosa. We first demonstrated that corneal lymphangiogenesis was enhanced mainly in the late stage of bacterial keratitis, contrary to corneal angiogenesis that started earlier. Corresponding to the delayed lymphangiogenesis, expression of the pro-lymphangiogenic factors VEGF-C and VEGFR-3 increased in the late stage of bacterial keratitis. We further found that F4/80 and CD11b positive macrophages played an essential role in corneal lymphangiogenesis. Notably, macrophages were specifically involved in corneal lymphangiogenesis in the late stage of bacterial keratitis. Finally, we demonstrated the beneficial role of corneal lymphangiogenesis in ameliorating the clinical course of bacterial keratitis. Our study showed that bacterial activity was not directly involved in the late stage of keratitis, while corneal lymphangiogenesis reduced corneal edema and clinical manifestation in the late stage of bacterial keratitis. These findings suggest that the process of lymphangiogenesis in bacterial keratitis ameliorates corneal inflammation and edema in the late stage of bacterial keratitis.

SUBMITTER: Narimatsu A

PROVIDER: S-EPMC6393676 | biostudies-other | 2019 Feb

REPOSITORIES: biostudies-other

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Corneal lymphangiogenesis ameliorates corneal inflammation and edema in late stage of bacterial keratitis.

Narimatsu Akitomo A Hattori Takaaki T Koike Naohito N Tajima Kazuki K Nakagawa Hayate H Yamakawa Naoyuki N Usui Yoshihiko Y Kumakura Shigeto S Matsumoto Tetsuya T Goto Hiroshi H

Scientific reports 20190227 1

Lymphatic vessels play a crucial role in systemic immune response and regulation of tissue fluid homeostasis. Corneal lymphangiogenesis in bacterial keratitis has not been studied. In this study, we investigated the mechanism and the role of corneal lymphangiogenesis in a murine bacterial keratitis model using Pseudomonas aeruginosa. We first demonstrated that corneal lymphangiogenesis was enhanced mainly in the late stage of bacterial keratitis, contrary to corneal angiogenesis that started ear ...[more]

PMID: 30814667

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Project description:To evaluate the effect of application of 3% air in helium cold atmospheric plasma jet, using an inexpensive device termed iCAP, in corneal scratch wound closure in vitro and the treatment of Pseudomonas aeruginosa (P. aeruginosa) keratitis in vivo. Thermal imaging to measure temperature of surfaces to which iCAP was applied and UV energy density delivered by iCAP were measured. Scratch wounds inflicted on in vitro cultures of a human corneal epithelial cell line were treated with iCAP and wound widths at various times post-application were measured. Rabbit eyes infected with P. aeruginosa were treated with iCAP and slit lamp biomicroscope examination conducted to determine corneal health outcomes 25h post infection. Corneal homogenates were plated on agar and viable bacterial colonies enumerated to determine the effect of iCAP on bacterial load in vivo in P. aeruginosa keratitis. iCAP was shown to operate in the non-thermal regime and also shown to deliver much lower UV energy density than that necessary to cause harmful effects on ocular tissue. iCAP treatment significantly improved the rate of scratch wound gap closure in vitro in a human corneal epithelial cell line compared to controls. In vivo, iCAP treatment of P. aeruginosa keratitis infection in the rabbit eyes (N = 20) significantly reduced the incidence of corneal ulcer (P = 0.003) and corneal edema (P = 0.011) and significantly improved total cornea health (P = 0.034) compared to untreated (N = 10). Finally, in vivo iCAP treatment of P. aeruginosa keratitis infection in the rabbit eyes (N = 19) significantly reduced bacterial loads (P = 0.012) compared to untreated (N = 9). Our results strongly suggest that iCAP treatment was effective in improving corneal epithelial defect closure in vitro, reducing ulcer formation and decreasing inflammation in P. aeruginosa infected corneas in vivo and decreasing bacterial loads in P. aeruginosa infected corneas in vivo which led to improved overall cornea health outcomes in vivo. Further studies to investigate iCAP's safety and efficacy against other infectious microbes responsible for causing ulcerative keratitis, with and without co-treatment with antimicrobial therapies are warranted.

Project description:Microbial keratitis (MK) is a major cause of blindness worldwide. Despite adequate antimicrobial treatment, tissue damage can ensue. We compared the human corneal transcriptional profile in late stage MK to normal corneal tissue to identify pathways involved in pathogenesis. Total RNA from MK tissue and normal cadaver corneas was used to determine transcriptome profiles with Illumina HumanHT-12 v4 beadchips. We performed differential expression and network analysis of genes in bacterial keratitis (BK) and fungal keratitis (FK) compared with control (C) samples. Results were validated by RTqPCR for 45 genes in an independent series of 183 MK patients. For the microarray transcriptome analysis, 27 samples were used: 12 controls, 7 BK culture positive for Streptococcus pneumoniae (n = 6), Pseudomonas aeruginosa (n = 1), and 8 FK, culture positive for Fusarium sp. (n = 5), Aspergillus sp. (n = 2), or Lasiodiplodia sp. (n = 1). There were 185 unique differentially expressed genes in BK, 50 in FK, and 339 common to both [i.e., genes with fold-change (FC) < -4 or ≥4 and false discovery rate (FDR) adjusted P < 0.05]. MMP9 had the highest FC in BK (91 FC, adj p = 3.64 E-12) and FK (FC 64, adj. p = 6.10 E-11), along with other MMPs (MMP1, MMP7, MMP10, MMP12), pro-inflammatory cytokines (IL1B, TNF), and PRRs (TLR2, TLR4). HIF1A and its induced genes were upregulated uniquely in BK. Immune/defense response and extracellular matrix terms were the most enriched Gene Ontology terms in both BK and FK. In the network analysis, chemokines were prominent for FK, and actin filament reorganization for BK. Microarray and RTqPCR results were highly correlated for the same samples tested with both assays, and with the larger RTqPCR series. In conclusion, we found a great deal of overlap in the gene expression profile of late stage BK and FK, however genes unique to fungal infection highlighted a corneal epithelial wound healing response and for bacterial infection the prominence of HIF1A-induced genes. These sets of genes may provide new targets for future research into therapeutic agents.

Dataset Information

Corneal lymphangiogenesis ameliorates corneal inflammation and edema in late stage of bacterial keratitis.

Publications

Corneal lymphangiogenesis ameliorates corneal inflammation and edema in late stage of bacterial keratitis.

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