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University of Rochester

1. Hanson, Kelly M. Contribution of Toll-like Receptor 4 Signaling to the Pathogenesis of Pulmonary Fibrosis: Origins of Fibroblast Apoptosis Resistance.

Degree: PhD, 2020, University of Rochester

Chronic epithelial damage resulting from ionizing radiation exposure, certain genetic polymorphisms, or sustained inhalation of environmental toxicants is associated with increased risk for pulmonary fibrosis (PF), which is characterized by progressive fibroblast accumulation. Although PF is the most common and most severe interstitial lung disease, treatment strategies are currently lacking. Recent studies suggest that Toll-like receptor 4 (TLR4) is a key element in PF pathogenesis. Chronic epithelial damage often results in chronic lung inflammation, or pneumonitis, involving release of endogenous TLR4 agonists. TLR4 has been previously linked to pro-survival signaling, which may help cells evade apoptosis. Fibroblast apoptosis is critical for wound resolution, but in PF, fibroblasts become apoptosis resistant and proliferate excessively. We hypothesized that chronic epithelial damage leads to release of endogenous TLR4 agonists, causing fibroblast apoptosis resistance and interfering with wound resolution, thus contributing to PF development. An in vitro model of TLR4-mediated apoptosis resistance was developed and validated in primary mouse lung fibroblasts (MLFs) to study TLR4 pro-survival signaling. This signaling pathway appears to be mediated by NF-κB activation and altered transcription of apoptotic mediators such as XIAP and Thy1, thus promoting survival in lung fibroblasts. The present hypothesis was also supported by an in vivo model of radiation-induced PF. Female C57BL/6J (C57) and TLR4-/- mice were exposed to 13 Gy whole-lung ionizing radiation. Although both strains showed similar levels of immediate epithelial damage, C57 mice exhibited more extensive fibrosis at 22 wk post-irradiation (PI) than TLR4-/- mice. Isolated C57 MLFs cultured ex vivo showed decreased apoptosis susceptibility as early as 8 wk PI, which persisted for the remainder of the radiation response. TLR4-/- MLFs did not exhibit significant apoptosis resistance at any point. Systemic release of HMGB1, a TLR4 agonist, was observed during the pneumonitis phase of the radiation response and may act through TLR4 to contribute to fibroblast apoptosis resistance and thus interfere with wound resolution. These studies demonstrate that fibroblast apoptosis resistance occurs earlier in radiation-induced PF pathogenesis than previously assumed, and that TLR4 is a key mediator in this process.

Subjects/Keywords: TLR4; IPF; RIPF; Radiation; Pulmonary fibrosis; Apotosis resistance; DAMP; Pneumonitis; HMGB1.

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Hanson, K. M. (2020). Contribution of Toll-like Receptor 4 Signaling to the Pathogenesis of Pulmonary Fibrosis: Origins of Fibroblast Apoptosis Resistance. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/35551

Chicago Manual of Style (16th Edition):

Hanson, Kelly M. “Contribution of Toll-like Receptor 4 Signaling to the Pathogenesis of Pulmonary Fibrosis: Origins of Fibroblast Apoptosis Resistance.” 2020. Doctoral Dissertation, University of Rochester. Accessed April 09, 2020. http://hdl.handle.net/1802/35551.

MLA Handbook (7th Edition):

Hanson, Kelly M. “Contribution of Toll-like Receptor 4 Signaling to the Pathogenesis of Pulmonary Fibrosis: Origins of Fibroblast Apoptosis Resistance.” 2020. Web. 09 Apr 2020.

Vancouver:

Hanson KM. Contribution of Toll-like Receptor 4 Signaling to the Pathogenesis of Pulmonary Fibrosis: Origins of Fibroblast Apoptosis Resistance. [Internet] [Doctoral dissertation]. University of Rochester; 2020. [cited 2020 Apr 09]. Available from: http://hdl.handle.net/1802/35551.

Council of Science Editors:

Hanson KM. Contribution of Toll-like Receptor 4 Signaling to the Pathogenesis of Pulmonary Fibrosis: Origins of Fibroblast Apoptosis Resistance. [Doctoral Dissertation]. University of Rochester; 2020. Available from: http://hdl.handle.net/1802/35551

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