Pseudomonas aeruginosa (P. aeruginosa) is a common organism associated with bacterial keratitis, especially in more tropical climates and in extended wear contact lens users. The incidence of microbial keratitis is 25,000-30,000 cases annually with cost of treatment estimated at $15-30 million, making the disease of considerable medical and economic impact. In the studies proposed, we will test the overall hypothesis that after corneal infection with P. aeruginosa, the neuropeptides VIP/PACAP inhibit/downregulate sustained pro-inflammatory cytokine and nitric oxide (NO) production and upregulate anti-inflammatory cytokine production, leading to the resistance response of BALB/c mice. A corollary to this hypothesis is that inflammatory neuropeptides such as SP/CGRP will have a converse effect, leading to the susceptible response of B6 mice.
The aims of this proposal are: 1) to test the hypothesis that the distribution of neuropeptides VlP/PACAP, SP and CGRP in the cornea will differ both spatially and temporally in BALB/c (resistant) vs. B6 (susceptible) mice after infection with P. aeruginosa; 2) to test the hypothesis that the neuropeptides VIP/PACAP, SP, CGRP and secretoneurin (SN) differentially affect the migration into and arrest of Langerhans cells (LC) in the infected cornea of B6 vs. BALB/c mice; 3) to test the hypothesis that SP/CGRP promote pro-inflammatory cytokine and chemokine production and the influx and persistence of PMN in the infected cornea of susceptible vs. resistant mice; 4) to test the hypothesis that in infected resistant vs. susceptible mice, VIP/PACAP inhibit sustained macrophage (Mphi) inflammatory cytokine/chemokine and NO production and enhance anti-inflammatory cytokines such as IL-10; 5) to test the hypothesis that SP/CGRP induce sustained upregulation of adhesion molecules after infection in susceptible vs. resistant mice. In the proposed studies, a combination of in vivo and in vitro systems will be used to analyze the immunomodulatory activities of these neuropeptides. It is expected that the findings will be particularly significant with respect to management of P. aeruginosa keratitis and should lead to better characterization of molecules which are potential targets for more effective treatment of corneal inflammation.
| McClellan, Sharon A; Ekanayaka, Sandamali A; Li, Cui et al. (2015) Thrombomodulin Protects Against Bacterial Keratitis, Is Anti-Inflammatory, but Not Angiogenic. Invest Ophthalmol Vis Sci 56:8091-100 |
| McClellan, Sharon; Jiang, Xiaoyu; Barrett, Ronald et al. (2015) High-mobility group box 1: a novel target for treatment of Pseudomonas aeruginosa keratitis. J Immunol 194:1776-87 |
| Jiang, Xiaoyu; McClellan, Sharon A; Barrett, Ronald et al. (2014) HGF signaling impacts severity of Pseudomonas aeruginosa keratitis. Invest Ophthalmol Vis Sci 55:2180-90 |
| Li, Cui; McClellan, Sharon A; Barrett, Ronald et al. (2014) Interleukin 17 regulates Mer tyrosine kinase-positive cells in Pseudomonas aeruginosa keratitis. Invest Ophthalmol Vis Sci 55:6886-900 |
| Hazlett, Linda D; Jiang, Xiaoyu; McClellan, Sharon A (2014) IL-10 function, regulation, and in bacterial keratitis. J Ocul Pharmacol Ther 30:373-80 |
| Foldenauer, Megan E B; McClellan, Sharon A; Berger, Elizabeth A et al. (2013) Mammalian target of rapamycin regulates IL-10 and resistance to Pseudomonas aeruginosa corneal infection. J Immunol 190:5649-58 |
| Berger, Elizabeth A; McClellan, Sharon A; Vistisen, Kerry S et al. (2013) HIF-1? is essential for effective PMN bacterial killing, antimicrobial peptide production and apoptosis in Pseudomonas aeruginosa keratitis. PLoS Pathog 9:e1003457 |
| Berger, Elizabeth A; Vistisen, Kerry S; Barrett, Ronald P et al. (2012) Effects of VIP on corneal reconstitution and homeostasis following Pseudomonas aeruginosa induced keratitis. Invest Ophthalmol Vis Sci 53:7432-9 |
| Jiang, Xiaoyu; McClellan, Sharon A; Barrett, Ronald P et al. (2012) The role of VIP in cornea. Invest Ophthalmol Vis Sci 53:7560-6 |
| Foldenauer, Megan E B; McClellan, Sharon A; Barrett, Ronald P et al. (2012) Substance P affects growth factors in Pseudomonas aeruginosa-infected mouse cornea. Cornea 31:1176-88 |
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