Abstract
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.
Highlights
We address the role of corneal fibroblasts in the metabolism of collagen in the corneal stroma, how bacterial invasion disrupts this homeostatic role, and potential new directions for the development of novel therapies for corneal ulceration [34,35,36]
Bacteria themselves secrete collagen-degrading enzymes that mediate direct collagen degradation by the bacterial cells. It is corneal fibroblasts, whose activation is triggered by factors released from the bacteria, that are largely responsible through the production of collagen-degrading matrix metalloproteinase (MMP) for the destruction of extracellular collagen associated with corneal ulcer
Two principal pathways of collagen destruction are operative during bacterial keratitis: (1) collagen degradation mediated directly by proteases released by bacteria, and (2) that mediated by corneal fibroblasts (Figure 1)
Summary
Tear fluid serves as a lubricant and wetting solution for the ocular surface, and as a source of biological protective factors including components of the innate immune system It contains more than 60 proteins [2], some of which are bactericidal, with important constituents including inflammatory cytokines, lactoferrin, lysozyme, immunoglobulin A, and members of the cationic antimicrobial peptide family [3,4,5,6,7,8,9,10]. To help identify the relevant literature for this review, we searched PubMed and Google Scholar with the use of broad terms relating to the etiology, epidemiology, pathobiology, management, and therapy of bacterial keratitis or corneal ulcer
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