Inflammation in CF: Key Characteristics and Therapeutic Discovery

Inflammation is a cardinal feature of CF lung pathophysiology with a wide range of contributing factors. In addition to chronic airway infection leading to pulmonary inflammation, mechanisms of imbalanced oxidative stress response and pro-inflammatory lipid homeostasis as well as exuberant cytokine responses all contribute to a dysregulated inflammatory milieu in the CF host. Previous studies of anti-inflammatory steroidal and nonsteroidal interventions in CF have proven clinical benefit, but intolerance, side effects, and challenges in proper dosing have hampered their widespread use. Widely adopted in CF clinical care, azithromycin confers anti-inflammatory benefits through a variety of putative mechanisms. Current preclinical and clinical research in this area seeks to leverage endogenous anti-inflammatory mechanisms, promoting resolution of inflammation in the CF host. CFTR modulator drugs and efforts to develop gene-based therapies agnostic to CFTR mutations are key advances in the current era of CF science and medicine. It is exciting to consider how these interventions may influence the inflammatory state within the CF airway, but a need for direct anti-inflammatory interventions appears likely to persist. This chapter reviews several key pathophysiologic mechanisms contributing to CF pulmonary inflammation, along with previous and existing therapeutic strategies to mitigate this host response without impairing host defense to infection or environmental insult.