Antibiotic and anti-inflammatory therapies for cystic fibrosis

Abstract

Cystic fibrosis (CF) lung disease is characterized by chronic bacterial infection and an unremitting inflammatory response, which are responsible for most of CF morbidity and mortality. The median expected survival has increased from <6 mo in 1940 to >38 yr now. This dramatic improvement, although not great enough, is due to the development of therapies directed at secondary disease pathologies, especially antibiotics. The importance of developing treatments directed against the vigorous inflammatory response was realized in the 1990s. New therapies directed toward the basic defect are now visible on the horizon. However, the impact of these drugs on downstream pathological consequences is unknown. It is likely that antibiotics and anti-inflammatory drugs will remain an important part of the maintenance regimen for CF in the foreseeable future. Current and future antibiotic and anti-inflammatory therapies for CF are reviewed.

Figure 1.

Infection and inflammation in the CF lung. CF lung disease is essentially an endobronchial/peribronchial process. The alveoli do not become involved until late in the disease course. In CF, the gene defect leads to an abnormal airway surface environment and then to airway obstruction with mucus (represented as an amorphous gray area in the center of the airway), chronic bacterial infection, and persistent inflammation. Although there are several different types of bacteria that infect the CF airway, S. aureus predominates early in life but typically yields to P. aeruginosa. However, most patients have polymicrobic infections, thus making selection of appropriate antibiotics for treatment of a pulmonary exacerbation difficult. The bacterial infection is associated with a vigorous inflammatory response that is characterized by a large neutrophilic infiltration. Other inflammatory cells are also involved in the inflammatory response including epithelial cells, macrophages, dendritic cells, B lymphocytes, and T lymphocytes. These cells release many inflammatory cytokines and mediators that further promote the inflammatory response. The inflammatory response is ineffectual in eliminating bacteria from the airway, but the excess inflammatory mediators released into the endobronchial and peribronchial spaces damage the airway wall architecture and ultimately lead to bronchiectasis. This figure focuses on the proinflammatory aspects of CF airway inflammation. The abnormalities in the counter-regulatory mechanisms in CF are not depicted.