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(Investigative Ophthalmology and Visual Science. 2008;49:1502-1511.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1369
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Substance P Promotes Susceptibility to Pseudomonas aeruginosa Keratitis in Resistant Mice: Anti-inflammatory Mediators Downregulated

Sharon A. McClellan, Yunfan Zhang, Ronald P. Barrett, and Linda D. Hazlett

From the Department of Anatomy & Cell Biology, Wayne State University, School of Medicine, Detroit, Michigan.

PURPOSE. Studies have shown that blocking substance P (SP) binding to neurokinin 1 receptor with spantide I prevents Pseudomonas aeruginosa–induced corneal perforation in susceptible C57BL/6 mice. This study tested the effect of SP injection on the resistance response (cornea heals) of BALB/c mice.

METHODS. The day before infection, mice were injected intraperitoneally with SP or PBS. Disease was graded by clinical score, slit lamp, plate count, real-time RT-PCR, and ELISA assays, and polymorphonuclear neutrophils (PMNs) were quantitated using a myeloperoxidase assay. In additional experiments, BALB/c mice were injected intraperitoneally with vasoactive intestinal peptide (VIP) antagonist and similarly analyzed.

RESULTS. Mice injected with SP exhibited worsened disease on days 1 to 7 after infection compared with controls. SP injection resulted in elevated PMN levels and viable bacterial counts in the cornea 3 and 5 days after infection. mRNA expression for NF{kappa}B and type 1 cytokines (e.g., IFN-{gamma}), as well as for TNF-{alpha}, MIP-2, IL-18, IL-6, and IL-1β, were significantly elevated, whereas VIP and cytokines TGF-β and IL-10 were significantly reduced. Differences in mRNA expression were selectively confirmed at the protein level by ELISA for NF{kappa}B, IL-1β, and IL-10. VIP antagonist treatment also resulted in exacerbated disease scores, elevated proinflammatory mediators, and reduced anti-inflammatory mediators.

CONCLUSIONS. These data provide evidence that the neuropeptide SP, among its broad systemic effects, is a potent neuroimmunoregulator that promotes susceptibility in the resistant BALB/c mouse by overcoming the anti-inflammatory effects of VIP and IL-10 and that a balance between SP and VIP levels may be critical in disease resolution.






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