Date on Master's Thesis/Doctoral Dissertation
Environmental and Occupational Health Sciences
Chlorine; Nerve growth factor; Repair; Beta-catenin; Acute lung injury
Epithelium; Regeneration (Biology); Wound healing; Chlorine--Health aspects
Chlorine is a widely used toxic chemical that is considered a chemical threat agent. Chlorine inhalation injures airway epithelium, and efficient epithelial repair is necessary to restore normal lung structure and function. Regeneration of injured tissues typically proceeds through the proliferation and differentiation of stem or progenitor cells. Knowledge of underlying mechanisms that regulate these processes during airway epithelial repair is lacking. This dissertation characterizes respiratory epithelial repair after chlorine injury to investigate potential signaling pathways that could be manipulated to regulate stem/progenitor cells in airway repair. Repair of the pseudostratified tracheal epithelium after chlorine-induced injury was characterized in C57BL/6 mice by morphometric analysis of tracheal sections following standard histological staining and specific staining for proliferating cells and epithelial cell types. Surviving basal epithelial cells served as progenitor cells for tracheal epithelial regeneration after chlorine injury. In areas where repair was inefficient owing to few remaining basal cells, airway fibrosis was observed. To investigate potential signaling pathways that could be manipulated to facilitate epithelial repair after chlorine-induced injury, the low affinity nerve growth factor receptor (NGFR) and the Wnt/ß-catenin pathway were examined. Pharmacological treatment of isolated tracheal epithelial cells with NGFR ligands did not influence the growth of tracheal basal cells in vitro. Overexpression of nerve growth factor (NGF) in airway epithelium or mutation of NGFR increased the pool of stem cells that formed a differentiated pseudostratified epithelium in vitro. Treatment of chlorine-exposed mice with NGF did not impact epithelial repair in vivo. Minimal effect of NGF overexpression on epithelial repair in transgenic mice was observed. NGFR mutation resulted in increased sensitivity of mice to chlorine-induced airway injury, but unexpectedly protected mice from the development of fibrosis. Stimulation of Wnt/ß-catenin signaling with lithium chloride prevented the formation of pseudostratified epithelium in vitro. Chlorine inhalation in mice activated ß-catenin signaling in the tracheal epithelium. Treatment of mice with lithium chloride or the Wnt/ß-catenin signaling modulator ICG-001 reduced collagen content in the lung after chlorine exposure. This work highlights the potential contribution of NGFR and Wnt/ß-catenin signaling to airway epithelial repair and identifies potential therapeutic targets for inhibiting chlorine-induced airway fibrosis.
Musah, Sadiatu, "Repair of the airway epithelium after chlorine-induced injury." (2013). Electronic Theses and Dissertations. Paper 1031.