Experimental Eye Infections Caused by Pseudomonas aeruginosa

Hazlett, Linda D.; Rosen, Dalia; Berk, Richard S.

doi:10.1159/000264837

Cited by 47 publications

(41 citation statements)

References 3 publications

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“…Many clinical features of the disease are reproducible in rodent models, including the rat (4) and mouse (5,6). The mouse scarification model of Pseudomonas keratitis has been well characterized, and the genetic susceptibility of C57BL/6 (B6) 3 (7) and related inbred strains (8) to eye infection resulting in perforation of the cornea and blindness correlated with a CD4 ϩ T cell (Th1)-regulated inflammatory response.…”

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confidence: 99%

B7/CD28 Costimulation Is Critical in Susceptibility toPseudomonas aeruginosaCorneal Infection: A Comparative Study Using Monoclonal Antibody Blockade and CD28-Deficient Mice

Hazlett

McClellan

Barrett

et al. 2001

The Journal of Immunology

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Evidence suggests that Pseudomonas aeruginosa stromal keratitis and corneal perforation (susceptibility) is a CD4+ T cell-regulated inflammatory response following experimental P. aeruginosa infection. This study examined the role of Langerhans cells (LC) and the B7/CD28 costimulatory pathway in P. aeruginosa-infected cornea and the contribution of costimulatory signaling by this pathway to disease pathology. After bacterial challenge, the number of LC infiltrating the central cornea was compared in susceptible C57BL/6 (B6) vs resistant (cornea heals) BALB/c mice. LC were more numerous at 1 and 6 days postinfection (p.i.), but were similar at 4 days p.i., in susceptible vs resistant mice. Mature, B7 positive-stained LC in the cornea and pseudomonas Ag-associated LC in draining cervical lymph nodes also were increased significantly p.i. in susceptible mice. To test the relevance of these data, B6 mice were treated systemically and subconjunctivally with neutralizing B7 (B7-1/B7-2) mAbs. Treatment decreased corneal disease severity and reduced significantly the number of B7-positive cells as well as the recruitment and activation of CD4+ T cells in the cornea. IFN-γ mRNA levels also were decreased significantly in the cornea and in draining cervical lymph nodes of mAb-treated mice. When CD28−/− animals were tested, they exhibited a less severe disease response (no corneal perforation) than wild-type B6 mice and had a significantly lower delayed-type hypersensitivity response to heat-killed pseudomonas Ag. These results support a critical role for B7/CD28 costimulation in susceptibility to P. aeruginosa ocular infection.

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confidence: 99%

B7/CD28 Costimulation Is Critical in Susceptibility toPseudomonas aeruginosaCorneal Infection: A Comparative Study Using Monoclonal Antibody Blockade and CD28-Deficient Mice

Hazlett

McClellan

Barrett

et al. 2001

The Journal of Immunology

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“…Many clini cal features of the disease can be experimen tally produced and have been studied in mice [2,3], rats [4] and rabbits [5], Previous studies have shown that inbred mouse strains, such as DBA/2J and DBA/1J [6][7][8][9], as well as outbred Swiss-Webster [3] mice topically infected onto the sacrificed cornea with pseudomonas were able to resolve the bacterial infection, to re store corneal clarity and hence were classed as resistant. Other mouse strains.…”

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confidence: 99%

“…Other mouse strains. C57BL/6J, C3H/HeJ and A/J failed to restore corneal clarity following similar bacterial challenge and were classed as susceptible [6][7][8][9], In sev eral animal species, including the mouse, the response to pseudomonas ocular challenge has been shown histologically to consist almost entirely of a local infiltration of PMN and few mononuclear cells [3][4][5][10][11][12]], Yet, no study has systematically examined and character ized the distribution and kinetics of the in flammatory cell response to pseudomonas ocular challenge beyond the initial few days.…”

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Distribution and Kinetics of the Inflammatory Cell Response to Ocular Challenge with Pseudomonas aeruginosa in Susceptible versus Resistant Mice

Hazlett¹,

Zucker²,

Berk

1992

Ophthalmic Res

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This study examined and characterized the distribution and kinetics of the inflammatory cell response to pseudomonas ocular challenge in susceptible C57BL/6J and resistant DBA/2J mice. Initially, in the cornea, the number of neutrophilic leukocytes (PMNs), macrophages/monocytes or lymphocytes was 2–2.5 times greater in resistant versus susceptible mice. The peak cellular response in the cornea was also greater in resistant than in susceptible animals. Further, resistant mice, when compared with susceptible mice, had a shorter duration of inflammatory cells as well as bacteria in the cornea. These data were similar for the cell infiltrate in the anterior chamber, with the exception that PMNs were initially greater in number in C57BL/6J than in DBA/2J mice. Collectively these data suggest that susceptible mice are, in general, cellularly hyporesponsive to pseudomonas ocular challenge when compared with resistant animals. This, together with persistence of inflammatory cells and bacteria in the cornea of susceptible animals, may contribute to their failure to restore corneal clarity following pseudomonas ocular challenge.

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“…The rise in its occurrence has been attributed to the increased use of extended-wear contact lenses (7,12). Following adherence of the organism to a damaged corneal epithelium (14,29), the release of exogenous enzymes, including proteases (16), elastases (16,24), and exotoxins (1,13,15), is necessary for stromal penetration of the organism to occur. Evidence suggests that these enzymes contribute to corneal destruction (3,16,18,24) and that their inhibition may lead to a reduction in the amount of corneal destruction which occurs (17,22,23).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Pseudomonas aeruginosa elastase and Pseudomonas keratitis using a thiol-based peptide

Burns

Paterson

Gray

et al. 1990

Antimicrob Agents Chemother

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Pseudomonas aeruginosa elastase is a zinc metalloproteinase which is released during P. aeruginosa infections. Pseudomonas keratitis, which occurs following contact lens-induced corneal trauma, can lead to rapid, liquefactive necrosis of the cornea. This destruction has been attributed to the release of both hostderived enzymes and the bacterial products P. aeruginosa elastase, alkaline protease, exotoxin A, and lipopolysaccharide endotoxin. A synthetic metalloproteinase inhibitor, HSCH2 (DL)CH[CH2CH(CH3)2]COPhe-Ala-NH2, which we previously showed to be a potent inhibitor of corneal coliagenase and alkali-induced corneal ulceration, was tested as a potential inhibitor of P. aeruginosa elastase. Inhibition constants (K,s) for the resolved diastereomers were determined with the chromogenic substrate furylacryloyl-glycyl-L-leucyl-Lalanine. One isomer had a K1 of 0.3 ,M, while the other had a Ki of 0.4 ,uM. The more potent diastereomer was evaluated in vivo in experimentally induced Pseudomonas keratitis in rabbits. Following inoculation of one cornea of each rabbit, topical treatment with a 1 mM solution of the inhibitor significantly delayed the onset of corneal melting and perforation, as compared with the results for the control and gentamicin-treated groups. This protective effect suggests that the inhibitor may have a therapeutic application by delaying the progression of corneal destruction in Pseudomonas keratitis.Pseudomonas aeruginosa is one of the most commonly encountered organisms found in infectious keratitis (26,28). Pseudomonas keratitis causes rapid, liquefactive destruction of the human cornea and is being seen with increasing frequency following corneal trauma from extended-wear contact lenses (7,12). Destruction of the cornea in Pseudomonas keratitis results from the release of degradative enzymes from both the organism (3,16,18,24) and hostderived sources (17). The metalloproteinase P. aeruginosa elastase is one of the main enzymes released by P. aeruginosa and is thought to be a major contributor to the pathogenesis of the organism (16,24).It has been demonstrated that immunization of rabbits and mice with elastase provides protection from Pseudomonas keratitis (25). Recent studies have suggested that inhibition of P. aeruginosa elastase may lead to more effective therapeutic approaches to this disease (19,21,22). Compounds which inhibit metalloproteinases such as P. aeruginosa elastase have been shown to alter the clinical course of Pseudomonas keratitis. The compound 2-mercaptoacetyl-LPhe-L-Leu, an inhibitor of P. aeruginosa elastase (17), reduced the amount of corneal melting in experimental Pseudomonas keratitis in rabbits when combined with gentamicin (31). Recently, tetracycline was shown to reduce the incidence of alkali-induced corneal ulceration (30) and Pseudomonas keratitis-induced corneal perforation in rabbits (27). This effect was thought to be secondary to the anticollagenase effect of tetracycline.The metalloproteinase inhibitor HSCH2 (DL)CH[CH2CH (CH3)2]CO-Phe-Ala-NH2 is a pote...

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Experimental Eye Infections Caused by Pseudomonas aeruginosa

Cited by 47 publications

References 3 publications

B7/CD28 Costimulation Is Critical in Susceptibility toPseudomonas aeruginosaCorneal Infection: A Comparative Study Using Monoclonal Antibody Blockade and CD28-Deficient Mice

B7/CD28 Costimulation Is Critical in Susceptibility toPseudomonas aeruginosaCorneal Infection: A Comparative Study Using Monoclonal Antibody Blockade and CD28-Deficient Mice

Distribution and Kinetics of the Inflammatory Cell Response to Ocular Challenge with Pseudomonas aeruginosa in Susceptible versus Resistant Mice

Inhibition of Pseudomonas aeruginosa elastase and Pseudomonas keratitis using a thiol-based peptide

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