Mechanisms of Basal Cell Dysfunction in Chemical-induced Bronchiolitis Obliterans

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PROJECT SUMMARY This Mentored Clinical Scientist Research Career Development application will support Dr. Matthew McGraw in his transition to independence as a clinician scientist studying the mechanisms of airway basal cell dysfunction in chemical-induced bronchiolitis obliterans (BO). BO is a devastating fibrotic airways disease, most commonly seen after organ transplant. However, BO is becoming more frequently associated with inhalation exposures to certain viruses or chemicals. One of the most well-known chemicals associated with inhalation-induced BO is diacetyl (DA; 2,3-butanedione), a highly reactive diketone found in foods, coffee and e-cigarettes. Despite DA’s common use as a flavoring additive, the mechanisms of DA-induced BO remain poorly understood. Central to BO development is injury to the airway epithelium. When injured, the airway relies on epithelial progenitor cells for proper repair. The objective of this application is to better understand the functional role of airway basal cells, the primary progenitor cell of the human airway, in chemical-induced BO. Two preclinical models of chemical- induced BO were developed for this application. First, rats exposed consecutively to DA vapors developed persistent hypoxemia, reduced weight gain, and histologic evidence of BO. Poly-ubiquitinated proteins accumulated in rat airways after DA exposures not seen in air controls. Second, in human airway epithelial cells exposed to DA vapors, poly-ubiquitinated proteins accumulated and co-localized primarily with airway basal cells. With repetitive DA exposures, the accumulation of polyubiquitinated proteins resulted in proteotoxicity of airway basal cells. Our central hypothesis is repetitive DA vapor exposures results in abundant protein damage, leading to proteotoxicity of airway basal cells, impairing airway epithelial repair and promoting BO development. Aim I of this proposal will determine how abundant protein damage in airway basal cells impairs epithelial repair and promotes BO development using both models of repetitive DA vapor exposure. Aim II will determine the role of the ubiquitin proteasome system in airway basal cell toxicity and BO development. Aim III will compare the efficacy of multiple ubiquitin proteasome pathway drug targets in preventing basal cell toxicity and BO development. Dr. McGraw has assembled a mentoring team of experts in the fields of airway epithelial biology (T Mariani, PhD; primary), inhalation toxicology (JN Finkelstein, PhD; I Rahman, PhD), and proteomics (WJ Qian, PhD) for critically examining the role of airway basal cells in chemical-induced BO. Mentoring in airway stem cell biology and proteomics, as described in this proposal, will facilitate Dr. McGraw’s transition to independence. At K08 completion, the data generated from this application will significantly advance our understanding of airway basal cell function following inhalation exposures and have a broader impact on neighboring research fields of inhalation toxicology and BO development.