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Establishing a Porcine Ex Vivo Cornea Model for Studying Drug Treatments against Bacterial Keratitis
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Role of the Fas pathway in Pseudomonas aeruginosa keratitis

Zimei Zhou1, Minhao Wu, Ronald P Barrett

  • 1Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA.

Investigative Ophthalmology & Visual Science
|December 19, 2009
PubMed
Abstract

Insights

The Fas-FasL pathway in the cornea promotes early apoptosis, controlling inflammation and improving outcomes in Pseudomonas aeruginosa infections. Disruption leads to increased bacterial growth and severe disease.

Area of Science:

  • Ophthalmology
  • Immunology
  • Microbiology

Background:

  • The Pseudomonas aeruginosa bacterial keratitis model is crucial for studying host-pathogen interactions.
  • The Fas pathway's role in ocular infections remains incompletely understood.

Purpose of the Study:

  • To investigate the role of the Fas ligand (FasL) pathway in the murine cornea during Pseudomonas aeruginosa infection.
  • To compare the immune response and disease outcomes in FasL knockout (FasL(-/-)) and wild-type (WT) mice.

Main Methods:

  • Corneal infection model using Pseudomonas aeruginosa in FasL(-/-) and WT mice.
  • Assessment of bacterial load, leukocyte infiltration, and disease severity.
  • Analysis of apoptosis using TUNEL staining.
  • Gene and protein expression analysis via real-time RT-PCR, immunostaining, and ELISA.

Main Results:

  • FasL(-/-) mice exhibited higher bacterial counts, increased polymorphonuclear leukocytes, and worse disease outcomes compared to WT mice.
  • Earlier apoptosis and increased pro-apoptotic markers (caspases 3, 8, 9, BAX) were observed in WT mice, correlating with lower bacterial burden.
  • Elevated levels of pro-inflammatory mediators (TNF-alpha, MIP-2, iNOS, nitrite) were found in infected FasL(-/-) corneas and LPS-stimulated macrophages.
  • In vitro studies showed FasL(-/-) macrophages produced less IL-10 and more pro-inflammatory cytokines.

Conclusions:

  • The Fas-FasL interaction in the cornea is vital for balancing the innate immune response, promoting timely apoptosis, and regulating inflammation.
  • Dysregulation of the Fas-FasL pathway exacerbates Pseudomonas aeruginosa keratitis by increasing bystander tissue damage and bacterial proliferation.
  • Targeting the Fas pathway may offer therapeutic strategies for bacterial keratitis.

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