On dysregulated inflammation and airway host defense

Sammanfattning: Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) are characterized by dysregulated inflammation of the airways. The increased influx of immune cells and the accumulation of cytokines lead to cell death, tissue destruction and impaired pulmonary function. Intracellular proteins like histones and granule proteins of neutrophils, DNA fibers act as Danger-Associated Molecular Patterns (DAMPs), further promoting tissue damage. As a result, the lungs of such patients are at an increased risk of infection due to impaired host defense functions. During inflammation, there is an increased expression of osteopontin (OPN), a highly anionic phosphoglycoprotein, in the airways and it is involved in cell recruitment, tissue remodeling, and repair. In this thesis we show that OPN can interact with many cationic proteins and peptides present in the extracellular milieu of the inflamed airways. In the first paper included in this thesis we show that OPN bound to extracellular histones have protective function against DAMPs-induced inflammation. In the second paper, we show that OPN binds to several common innate antibiotics and abrogate their antimicrobial activities. Taken together, these data suggest that OPN can modulate the host immune functions, thereby increasing the susceptibility of the patients with airway inflammatory diseases to acquire infections.Use of anti-inflammatory drugs like roflumilast is a common treatment strategy in COPD to ameliorate severe exacerbations. In the third paper we highlight the adverse effects of roflumilast, in a murine acute airway infection model. The findings suggest that use of this drug can impair host defense functions of immune cells, thereby increasing the susceptibility of COPD patients to bacterial pathogens. DNase I is used to clear the airways of CF patients from highly viscous, high molecular weight eDNA rich sputum. In the fourth paper of this thesis, we elucidated the molecular aspects of the fragmented DNA that are important to exhibit antimicrobial properties against the common CF lung pathogen, i.e. P. aeruginosa. The findings highlight a novel aspect of host defense that could be employed treating bacteria resistant against conventional antibiotics.