Lung inflammation in cystic fibrosis: pathogenesis and novel therapies

Abstract

Despite remarkable progress following the identification of the causing gene, the final outcome of cystic fibrosis (CF) remains determined mainly by the progressive reduction of lung function. Inflammation of the airways is one of the key elements of the pathogenesis of the disease: it is responsible for the destruction of lung architecture, resulting in progressive loss of respiratory function. Bronchial infection induces an intense inflammatory reaction characterized by a massive invasion of neutrophils, the properties of which seems altered in CF. Moreover, the inflammatory process is also marked by a profuse release of soluble pro-inflammatory mediators, such as interleukin (IL)-6, IL-1β and IL-8 cytokines. In contrast, release of the anti-inflammatory mediator IL-10 is reduced, thus reflecting a pro-/anti-inflammatory imbalance. The inflammation/infection pair seems hard to dissociate, and the origin of the baneful consequences of the persisting excessive inflammatory responses remains to be cleared up: does inflammation follow or rather precede infection? Recent data suggest that uncontrolled inflammation is constitutive in CF. Countering it at early stages of the disease in order to prevent irretrievable damages in lungs remains a major priority in treating patients with CF. In this review, we discuss the usefulness and limitations of mouse models of CF to study the pathogenesis of human lung inflammatory disease, and the development of new potential strategies to reduce the inflammatory burden in the airways.

Keywords: CFTR; Cystic fibrosis; Cytokines; Inflammation; New therapies.