Innate Immune Defect and Neutrophilic Inflammation in Cystic Fibrosis

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ABSTRACT Cystic fibrosis (CF) is one of the most common and deadly genetic disorders, affecting ~1/3,000 live births in the United States. The responsible genetic mutations are linked to the gene that encodes CF Transmembrane-conductance Regulator (CFTR), a cAMP-activated chloride channel. Although this disease affects almost all organs and systems, its lung complications claim the most morbidity and mortality. The prominent lung pathology is marked by chronic bacterial infection, persistent neutrophilic inflammation, and purulent small airway obstruction, of which persistent lung inflammation is responsible for lung structure damage and function loss. Even though the CF molecular defect was discovered three decades ago, the link between the CFTR chloride channel defect and the destructive lung inflammation has not been defined. Such a knowledge gap impedes any informed development of effective therapies for CF. The current proposal is to address this outstanding problem in the field. Our overarching hypothesis is that CFTR loss-of-function in marrow-derived innate immune cells compromises their ability to molecularly modify and functionally deactivate inflammatory agonists, leading to excessive stimulation and neutrophilic inflammation in CF lungs. To test this hypothesis, we propose three specific aims: Aim 1: Determine that lineage-specific CFTR loss-of-function in neutrophils and monocytes/macrophages leads to persistent neutrophilic inflammation in the lung differentially; Aim 2: Determine that CF lung neutrophilic inflammation is due to neutrophil excessive recruitment, reduced apoptosis, and/or inefficient efferocytosis; Aim 3: Define that CF neutrophils and macrophages are compromised in chemical modification and functional deactivation of neutrophil chemotactic factors. Completion of this research will provide novel insights into CF lung disease pathogenesis. The new knowledge obtained will guide the rational design of interventions for effective treatment of this devastating disease.