SPLUNC1 and Neutrophilic Inflammation in Cystic Fibrosis

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): Cystic fibrosis (CF), is the most common fatal genetic disease in the United States. The main cause of mortality in CF patients is CF lung disease, which is characterized by persistent inflammation and neutrophilic infiltration. The mechanisms that lead to increased airway neutrophilia in CF are not well understood, and antiinflammatory therapies are limited. Short Palate, Lung and Nasal epithelium Clone 1 (SPLUNC1) is an abundant airway protein with host protective functions that may be important in the development of CF lung disease. SPLUNC1 is low in the airways of patients with allergic inflammation, and based on our preliminary work, it appears to play a role in regulating neutrophilic airway inflammation. SPLUNC1 is rapidly decreased by LPS and common respiratory pathogens in wild-type mice, a potentially protective mechanism that limits neutrophilic injury during acute airway inflammation. Interestingly, SPLUNC1 is increased in the inflamed, infected lungs of CF patients undergoing lung transplantation suggesting that the downregulation of SPLUNC1, and thus its protective effect against neutrophilic inflammation, may be impaired. Similarly to CF patients, SPLUNC1 is increased in the bronchoalveolar lavage fluid of CF-specific animal models. SPLUNC1- deficient (splunc1-/-) mice and CF-specific animal models seem to have divergent responses to LPS: SPLUNC1-deficient mice have limited neutrophilic inflammation, whereas CF-specific mouse models have increased neutrophilic inflammation. The researchers hypothesize that high levels of SPLUNC1 may contribute to the exaggerated neutrophilic responses observed in CF airways. The objective of this proposal is to discern the molecular details of the regulatin of SPLUNC1 and its molecular interactions in neutrophil chemotaxis, transmigration and survival in airway inflammation, in order to propose an initial approach to modulate SPLUNC1 with therapeutic purposes in CF. The specific aims of this project are: 1) Define how SPLUNC1 controls neutrophilic inflammation in the lungs by performing neutrophil function assays with splunc1-/- neutrophils and airway epithelial cells~ 2) Define mechanisms of SPLUNC1 regulation by establishing the kinetics of SPLUNC1 expression, and dissecting signaling pathways of cytokines that regulate SPLUNC1 expression, and 3) Define the effects of increased SPLUNC1 in CF by establishing mechanisms of increased SPLUNC1 in CF, and measuring airway inflammation after SPLUNC1 is decreased by siRNA or blocking SPLUNC1-increasing mechanisms in CF-specific animal models. This work will provide insights into the role of this abundant airway protein in modulating airway inflammation, its regulatory mechanisms, and its role in CF lung disease pathogenesis. If successful, this project will identify the mechanisms by which SPLUNC1 controls neutrophilia in CF, laying a foundation for new therapeutic targets in the prevention and treatment of CF lung disease. (End of Abstract)