Date of Award

5-9-2016

Degree Type

Closed Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Jian-Dong Li

Second Advisor

Timothy Denning

Third Advisor

Roberta Attanasio

Fourth Advisor

Didier Merlin

Abstract

Airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) affect more than one-half billion people globally resulting in billions of dollars in healthcare costs and there are no cures. These diseases are characterized by excessive inflammation and are exacerbated by respiratory pathogens such as nontypeable Haemophilus influenzae (NTHi). While inflammation is necessary to eliminate a pathogen, excessive inflammation causes epithelial injury and airflow limitation. Therefore, the inflammatory response must be tightly regulated. The limited success of currently available pharmaceuticals used to manage these diseases presents an urgent need for the development of novel, non-antibiotic therapeutics. An alternative therapeutic strategy is to upregulate the negative regulators of inflammation. Understanding the regulation of these negative regulators is crucial to this alternative strategy. One such negative regulator that has not been widely studied is the alternative spliced short variant of myeloid differentiation factor 88 (MyD88) called MyD88 short (MyD88s). Studies show that phosphodiesterase (PDE) inhibitors have promising therapeutic potential. Resveratrol is a PDE inhibitor and is being widely studied for its anti-inflammatory effects. However, the molecular mechanisms underlying the clinical efficacy remain largely unknown. In this dissertation we first show that NTHi induces expression of MyD88s and MyD88s is a negative regulator of inflammation in bronchial epithelial cells and in the lung of mice. We further demonstrate that MyD88s is positively regulated by IKKβ and CREB and negatively regulated by ERK1/2 signaling pathways. Next we show for the first time that resveratrol decreases expression of pro-inflammatory cytokines in vitro and in the lung of mice by enhancing NTHi-induced MyD88 short via inhibition of ERK1/2 activation. Furthermore, resveratrol inhibits NTHi-induced ERK1/2 phosphorylation by increasing MKP-1 expression via a cAMP-PKA-dependent signaling pathway. Lastly, we show that resveratrol has anti-inflammatory effects post NTHi infection, and therefore, its therapeutic potential is clinically significant. Together these data reveal a novel mechanism by which resveratrol alleviates NTHi-induced inflammation in airway disease by upregulating the negative regulator of inflammation MyD88s.

Share

COinS