Stat3: A Novel Regulator of Airway Inflammation and Remodeling in Asthma

Given that asthma prevalence and morbidity are steadily increasing and that some individuals on maximal medication still have poorly controlled asthma, there is a need for improved understanding of asthma pathogenesis as well as the development of novel therapeutics. Currently, the cellular and molecular pathways that regulate asthma pathogenesis are incompletely defined. Signal Transducer and Activator of Transcription factor 3 (STAT3) is a pleiotrophic transcription factor involved in the regulation of the immune and inflammatory responses. While other STATs, such as STAT1 and STAT6, have been implicated in asthma, the role of STAT3 in asthma is currently incompletely defined due, in part, to the fact that global deletion of STAT3 in mice results in embryonic lethality. In the first part of this dissertation, I describe a role for airway epithelial STAT3 in the regulation of the allergic cascade. The airway epithelium serves as the protective barrier between the external and internal environment and it is the first line of contact for inhaled particles; as such it is a central regulator of the immune response. Given that the asthmatic epithelium is thought to function abnormally, a better understanding of the pathways that regulate epithelial function in asthma will aid in our understanding of disease pathogenesis. Thus, in chapter 2 of this thesis, I use genetic and pharmacological approaches to determine the role of epithelial STAT3 in a house dust mite (HDM) model of asthma. I show that the epithelial STAT3 deletion results in decreased HDM-induced airway inflammation. Additionally, I determine that epithelial STAT3 regulates immune cell recruitment to the airways via chemokine production. Together these findings implicate both STAT3 and the airway epithelium as critical regulators of the allergic cascade. In chapter 3 of this dissertation, I describe experiments that expand upon results previously published by our laboratory implicating the STAT kinases, Jak and Src, in the regulation of STAT activation and human airway smooth muscle (HASMC) proliferation. Given that cellular proliferation is one mechanism by which airway smooth muscle (ASM) accumulates in asthma, I investigate the specific requirement for STAT3 in mitogen-induced HASMC proliferation. I also further investigate the mechanisms by which STAT3 is activated in response to PDGF. I show that STAT3 is required for maximal PDGF-induced HASMC proliferation and cell cycle regulation. Furthermore, I show that Rac1 is required for PDGF-induced STAT3 activation and HASMC proliferation thus implicating STAT3 and Rac1 in the regulation of ASM accumulation, a feature of airway remodeling often associated with asthma severity. In the final section of my dissertation, I describe a novel therapeutic approach for inhibiting STAT signaling in vivo. I use a STAT decoy oligonucleotide (ODN) molecule to inhibit STAT DNA binding and transcriptional activity. I show that intranasal administration of the STAT decoy ODN inhibits both STAT1 and STAT3 and results in decreased HDM-induced inflammation and chemokine production. I also determine that the STAT dODN is more effective than the inhaled corticosteroid fluticasone, the current mainstay of asthma therapeutics. Thus, these data suggest that pharmacological inhibition of STAT1 and STAT3 may be a novel therapeutic approach in asthma. In summary, the data I describe in this dissertation suggest that targeting STAT3 therapeutically may inhibit airway inflammation and remodeling in asthma.