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Spantide I Decreases Type I Cytokines, Enhances IL-10, and Reduces Corneal Perforation in Susceptible Mice after Pseudomonas aeruginosa Infection

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

PURPOSE. To determine the effects of blocking substance P (SP) interactions with its major receptor (NK1-R) using the antagonist spantide I in susceptible mice infected with Pseudomonas aeruginosa.

METHODS. Immunohistochemistry and enzyme immunosorbent assay (EIA) tested levels of SP in the cornea of B6 and BALB/c mice. B6 mice were treated with spantide, and after infection, slit lamp examination; clinical score; bacterial counts; and myeloperoxidase (MPO), RT-PCR, ELISA, and polymorphonuclear (PMN) cell chemotaxis assays were performed.

RESULTS. SP corneal levels were significantly elevated constitutively and after infection in the B6 more than in BALB/c mice. Spantide treatment of B6 mice significantly decreased the number of perforated corneas, bacterial counts, and PMNs. mRNA levels for type I cytokines (e.g., IFN-) as well as MIP-2, IL-6, TNF-, and IL-1ß (mRNA and protein) also were significantly reduced after spantide treatment. The type II cytokine IL-10 (mRNA and protein) was elevated, whereas TGF-ß mRNA levels were unchanged after spantide treatment. PMN chemotaxis was induced by SP and other neuropeptides in vitro, but was not affected by spantide I. mRNA for neurokinin-1-receptor-1 (NK-1R) was detected in the normal and infected corneas and on macrophages (Ms), but not on PMNs (unstimulated or stimulated with endotoxin [LPS]). Spantide treatment of Ms reduced IL-1ß after LPS+SP treatment but not after either alone.

CONCLUSIONS. The SP antagonist Spantide provides a novel approach to reduce type 1 and enhance the type 2 cytokine IL-10 in the infected cornea of B6 mice, leading to a significant reduction in corneal perforation and improved disease outcome.

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				Z. Zhou, R. P. Barrett, S. A. McClellan, Y. Zhang, E. A. Szliter, N. van Rooijen, and L. D. Hazlett Substance P Delays Apoptosis, Enhancing Keratitis after Pseudomonas aeruginosa Infection Invest. Ophthalmol. Vis. Sci., October 1, 2008; 49(10): 4458 - 4467. [Abstract] [Full Text] [PDF]

				S. A. McClellan, Y. Zhang, R. P. Barrett, and L. D. Hazlett Substance P Promotes Susceptibility to Pseudomonas aeruginosa Keratitis in Resistant Mice: Anti-inflammatory Mediators Downregulated Invest. Ophthalmol. Vis. Sci., April 1, 2008; 49(4): 1502 - 1511. [Abstract] [Full Text] [PDF]