Targeting inflammation resolution, a new therapeutic paradigm using the body’s own ability to modulate inflammatory responses, thus resolving inflammation without inducing immunosuppression.


Cystic Fibrosis: a genetic disease with a compromised immuno-inflammatory response

The lung is a huge interface with the outside world, and through its very complex and redundant system of inflammatory responses occurring in the normal airway is able to combat infectious pathogens and other toxic agents. Multiple studies involving infants have demonstrated that the inflammatory response in CF lung is up-regulated even before evidence of infection, including increased levels of multiple cytokines and infiltration of neutrophils. Once infection occurs, these signals markedly increase leading to destructive by-products such as neutrophil elastase leading to destruction of lung tissue and scarring. Paradoxically, the opportunistic pathogens survive and multiply within the CF lung, despite the presence of abundant neutrophilic infiltrate.

The imbalance between pro-inflammatory and anti-inflammatory cytokines in the airways of CF patients was suggested as one of the leading causes of the destruction of the lung and why CF patients are highly susceptible to infections with Pseudomonas aeruginosa. However, the relationship between the aberrant immuno-inflammatory response and the ion transport abnormality remains unclear. Constant inflammation stimulates mucus secretion and the inability to clear mucus from the lungs results in frequent bacterial infections which trigger a greater inflammatory response. Ultimately, these events result in an inflammation-infection vicious cycle that leads to chronic inflammation and a loss in lung function over time.

Despite the advancements made in addressing the basic defect, CFTR-modulators are not expected to completely reverse the existing organ dysfunction, and patients still have exaggerated but ineffective airway inflammation failing to eradicate pulmonary opportunistic pathogens. Due to its complexity, abnormal regulation and chronic manifestations, the regulation of inflammatory response remains one of the most important and not fully understood pathogenic mechanisms in CF. Current anti-inflammatory treatments have limited effectiveness in improving the symptoms of inflammation and the side effects associated with these drugs are severe thus they are rarely prescribed. Drugs that interfere upstream with the cycle of infection and inflammation, and that can be administrated early in life, are the best hope for preventing the decline in lung function, representing one of the highest unmet needs for this disease.