Access Type

Open Access Dissertation

Date of Award

January 2012

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Anatomy and Cell Biology

First Advisor

Linda D. Hazlett

Abstract

This body of work examined the mechanism by which SP regulates host immunity, specifically, its control of growth factors and TLR expression in the P. aeruginosa-infected cornea. The role of mTOR and VIP in corneal infection and inflammation also was tested.

SP has a dual role in bacterial infection, unexpectedly upregulating growth factor production. This was accompanied by macrophage-specific upregulation of pro-inflammatory cytokines, downregulation of anti-inflammatory cytokines, and upregulation of anti-apoptotic genes, as well as a decrease in arginase-producing macrophages (M2 cells), important in stromal healing in these mice. All of these lead to worsened disease, despite the stimulatory effects on growth factor production and contraindicate clinical use of SP in cornea to promote wound healing, if an infection is present or suspected.

Next, we provided evidence that IL-10 is regulated in the infected cornea via the mTOR pathway. This conclusion is based upon data showing that inhibition of mTOR by rapamycin decreased anti-inflammatory cytokines, particularly IL-10, and upregulated several pro-inflammatory cytokines (IL-12p40, IFN-γ) and their regulators/effectors. Furthermore, rapamycin downregulated caspase-3 and upregulated Bcl-2, the latter prolonging inflammatory cell viability, possibly further contributing to stromal destruction and unresolved disease.

Finally, we demonstrated that endogenous VIP is not required for normal corneal expression of GF or their receptors. However, if VIP is absent or reduced, GFs and their receptors are dysregulated and the infected cornea perforates rapidly.

In summary, the impact of the neuropeptides SP and VIP on growth factors and Toll-like receptors in the cornea provides insight and direction in the development of better therapeutics to regulate corneal infection and other inflammatory pathologies.

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