Background. In patients with Cystic Fibrosis (CF), the progressive decline of pulmonary function is due to a vicious cycle of airways infection and inflammation. Inflammation can be more damaging than the insult itself if uncontrolled, excessive, or prolonged. Although there is debate over whether inflammation in the CF lung is primary (i.e., caused by CFTR mutations) or secondary to chronic infection, inflammation remains the single most significant contributor to disease progression, and its control is crucial for improving patient outcomes. Building upon the results from our past projects–indicating how the application of a systems biology approach and new findings from the laboratory may translate into the development of new therapeutics and rationales for their use–we have proposed a preclinical evaluation study of anakinra, a recombinant, non-glycosylated version of human IL-1 receptor I antagonist (IL-1Ra) in CF. Since 2001, anakinra has proved to be efficacious in a broad spectrum of auto-inflammatory diseases with a remarkable record of safety.
Hypothesis and Objectives. 1. The relative contribution of different inflammasomes to fungal and bacterial infections and inflammation in CF mice. 2.The evaluation of the efficacy of anakinra in experimental and preclinical models of CF. 3. The definition of the molecular mechanisms underlying anakinra activity. 4. The screening of CF patients for IL-1Ra deficiency and the definition of anakinra-responsive signatures through microarray gene expression profiling.