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Abstract
This study was to explore the mechanism by which reactive oxygen species (ROS)-induced oxidative stress involved in the pathogenesis of fungal keratitis using an in vivo experimental keratitis mouse model and an in vitro culture model of human corneal epithelial cells (HCECs). Compared to normal control mice and HCECs, ROS production was markedly increased in fungal corneas and HCECs exposed to Candida albicans, accompanied by p38 mitogen-activated protein kinases (MAPK) activation. Increased products of oxidative markers, malondialdehyde (MDA), 4–hydroxynonenal (HNE), mitochondria DNA 8-OHdG and aconitase-2 were observed in fungal infected corneas and HCECs. Fungal infection also increased the mRNA expression and protein production of heme oxygenase-1 (HMOX1) and cyclooxygenase-2 (COX2), with suppressed levels of antioxidant enzymes, superoxide dismutase-1 (SOD1), glutathione peroxidase-1 (GPx1) and peroxiredoxin-4 (PRDX4). Interestingly, the levels of ROS, oxidative markers and oxygenases were significantly reduced by co-cultured p38 inhibitor SB203580. Furthermore, SB203580 restored the levels of antioxidant enzymes suppressed by fungus. Our findings demonstrated for the first time that ROS-induced oxidative injury is involved in pathogenesis of fungal keratitis via p38 MAPK pathway, suggesting the novel therapeutic targets for the potential treatment of fungal keratitis.
Highlights
Fungal keratitis is one of the leading causes of corneal blindness in developing countries[1], and its incidence is increasing in highly populous countries in Asia and Africa[2, 3]
An experimental mouse model of fungal keratitis was created by inoculation with 1 × 106 colony-forming units (CFU) of C. albicans after the cornea in the right eye of C57BL/6 J mice were scarified with a 22-gauge needle
The oxidants heme oxygenase-1 (HMOX1) and COX2 were found to be respectively upregulated by 9.87 ± 2.50-fold and 8.82 ± 1.67-fold at the gene level and 6.79 ± 1.23-fold and 4.43 ± 1.23-fold at the protein level, whereas the antioxidative enzymes superoxide dismutase-1 (SOD1) and glutathione peroxidase-1 (GPX1) were respectively downregulated by 0.36 ± 0.12-fold and 0.43 ± 0.18-fold at the gene level and 0.46 ± 0.26-fold and 0.52 ± 0.17-fold at the protein level in human corneal epithelial cells (HCECs) challenged with C. albicans
Summary
Fungal keratitis is one of the leading causes of corneal blindness in developing countries[1], and its incidence is increasing in highly populous countries in Asia and Africa[2, 3]. The signaling pathway of one of the MAPK family members, p38 MAPK, has been found to be involved in ROS generation in different models of cell death[18, 19], and a possible relationship between MAPKs and ROS has been noted[20, 21] It is still not clear whether and how fungal pathogens induce oxidative injury in keratitis and in human corneal epithelial cells (HCECs). The present study explored corneal oxidative damage and the imbalance between oxidative and antioxidant enzymes in a mouse model of fungal keratitis as well as in a culture model of primary HCECs exposed to C. albicans, and our data reveal a potential mechanism by which ROS can induce oxidative stress via p38 MAPK activation
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