The Role of Il-6 In Adenosine-Mediated Pulmonary Fibrosis

<p> <p>Adenosine is a purinergic signaling molecule that regulates various aspects of inflammation and has been implicated in the pathogenesis of chronic lung diseases. Previous studies have demonstrated that adenosine up-regulates IL-6 production through the engagement of the A_2B adenosine receptor in various cell types, including alveolar macrophages. IL-6 is elevated in mouse models and humans with chronic lung disease, suggesting a potential role in disease progression. Furthermore, chronic elevation of adenosine in the lungs of adenosine deaminase deficient (<em>Ada^-/-</em>) mice leads to the development of pulmonary inflammation, alveolar destruction, and fibrosis, in conjunction with IL-6 elevation. Thus, it was hypothesized that IL-6 contributes to pulmonary inflammation and fibrosis in this model. To test this hypothesis, <em>Ada/IL-6</em> double knockout mice (<em>Ada/IL-6^-/-</em>) were generated to assess the consequences of genetically removing IL-6 on adenosine-dependent pulmonary injury. <em>Ada/IL-6^-/-</em>mice exhibited a significant reduction in inflammation, alveolar destruction, and pulmonary fibrosis. Next, <em>Ada^-/-</em> mice were treated systematically with IL-6 neutralizing antibodies to test the efficacy of blocking IL-6 on chronic lung disease. These treatments were associated with decreased pulmonary inflammation, alveolar destruction, and fibrosis. To determine the role of IL-6 in a second model of pulmonary fibrosis, wild type mice and <em>IL-6^-/-</em> mice were subjected to intraperitoneal injections of bleomycin twice a week for four weeks. Results demonstrated that <em>IL-6^-/-</em> mice developed reduced pulmonary fibrosis. To examine a therapeutic approach in this model, wild type mice exposed to bleomycin were treated with IL-6 neutralizing antibodies. Similar results were observed as with <em>Ada^-/-</em> mice, namely diminished pulmonary inflammation and fibrosis. In both models, elevations in IL-6 were associated with increased phosphorylated STAT-3 in the nuclei of numerous cell types in the airways, including type II alveolar epithelial cells (AEC). Genetic removal and neutralization of IL-6 in both models was associated with decreased STAT-3 activation in type II AEC. The mechanism of activation in these cells that lack the membrane bound IL-6Ra suggests IL-6 trans-signaling may play a role in regulating fibrosis. Characterization of this mechanism demonstrated that the soluble IL-6Ra (sIL-6Ra) is upregulated in both models during chronic conditions. <em>In vitro</em> studies in MLE-12 alveolar epithelial cells confirmed that IL-6, in combination with the sIL-6Ra, activates STAT-3 and TWIST in association with enhancement of epithelial-to-mesenchymal transition, which can contribute to fibrosis. Similarly, patients with idiopathic pulmonary fibrosis demonstrated a similar pattern of increased IL-6 expression, STAT-3 activation, and sIL-6Ra increases. These findings demonstrate that adenosine-dependent elevations in IL-6 contribute to the development and progression of pulmonary inflammation and fibrosis. The implications from these studies are that adenosine and/or IL-6 neutralizing agents represent novel therapeutic targets for the treatment of pulmonary disorders where fibrosis is a detrimental component.</p> </p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2011

Author dc:creator

• Pedroza, Mesias

Contributors dc:contributor

• Michael R. Blackburn, PhD
• Rodney E. Kellems, PhD
• Sandeep K. Agarwal, MD/PhD

• Adenosine
• A2BR
• IL-6
• Chronic lung disease
• Pulmonary Fibrosis
• EMT
• Biochemistry

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/142

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1166