Platelet-Activating Factor (PAF) Receptor Antagonism Modulates Inflammatory Signaling in Experimental Uveitis

ABSTRACT

Background: The phospholipid mediator platelet-activating factor (PAF) activates an inflammatory response that includes arachidonic acid release and prostaglandin production in the eye, increasing vascular permeability and inflammation.

The purpose of this study is to investigate the action of LAU-0901, a novel PAF receptor antagonist, on experimental uveitis.

Methods: Uveitis was induced in Lewis rats by lipopolysaccharide treatment. LAU-0901 was then delivered systemically in different concentrations at plus 4 and 16 hours, or vehicle injected as controls. Additional animals were used for histological analyses of untreated, uveitis, and uveitis-plus-LAU-0901 retinas. Conventional histological and immunohistochemical methods were employed. A slit lamp and Spectral Domain-Ocular Coherence Tomography (SD-OCT) retinal imager was used for anterior segment photography and posterior pole OCT. Rats were euthanized 4 hours after the second LAU-0901 injection in this 24-hour model. Aqueous humor was collected and quantified, and also analyzed for tumor necrosis factor alpha (TNF-α).

Results: Uveitic eyes demonstrated hypopyon formation, leukocyte infiltration, and an increase in aqueous protein and TNF-α levels. LAU-0901 treatment resulted in a dose-dependent reduction in inflammation, reflected by reduced total protein levels (up to a 64% reduction). Moreover, hypopyon was prevented, leukocytes were absent in vitreous and aqueous humor, and TNF-α levels were reduced by 91%.

Conclusions: The PAF receptor antagonist LAU-0901 decreases ocular inflammation in a rat model of anterior uveitis in a dose-dependent manner, suggesting that use of this molecule may provide a means to attenuate inflammation onset and offer a future alternative or adjunctive treatment for ocular inflammation.

KEYWORDS:

• Inflammation
• LAU-0901
• lipopolysaccharide
• neuroprotection
• platelet-activating factor
• uveitis

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Additional information

Funding

This work was supported by the Louisiana State University Health Sciences Center Translational Research Initiative (JRE) and National Institutes of Health grants EY005121 and GM103340 (NGB). It was also supported in part by the Louisiana Lions Eye Foundation, New Orleans, LA and by an unrestricted departmental grant from Research to Prevent Blindness, Inc., New York, NY; National Eye Institute [EY005121]; National Institute of General Medical Sciences [GM103340].