Hypoxia and sterile inflammation in cystic fibrosis airways: mechanisms and potential therapies

Abstract

Cystic fibrosis is one of the most common autosomal recessive genetic diseases in Caucasian populations. Diagnosis via newborn screening and targeted nutritional and antibiotic therapy have improved outcomes, however respiratory failure remains the key cause of morbidity and mortality. Progressive respiratory disease in cystic fibrosis is characterised by chronic neutrophilic airway inflammation associated with structural airway damage leading to bronchiectasis and decreased lung function. Mucus obstruction is a characteristic early abnormality in the cystic fibrosis airway, associated with neutrophilic inflammation often in the absence of detectable infection. Recent studies have suggested a link between hypoxic cell death and sterile neutrophilic inflammation in cystic fibrosis and other diseases via the IL-1 signalling pathway. In this review, we consider recent evidence regarding the cellular responses to respiratory hypoxia as a potential driver of sterile neutrophilic inflammation in the lung, current knowledge on hypoxia as a pathogenic mechanism in cystic fibrosis and the potential for current and future therapies to alleviate hypoxia-driven sterile inflammation.

Effect of inhaled steroids on clinical and inflammatoryparameters in children with cystic fibrosis

“…Airway infection is a predominant and persistent cause of neutrophilic inflammation. However, inflammation can also be seen in asymptomatic children with CF without lower airway colonization, and the pathogenesis of noninfectious inflammation in these cases is poorly understood (30). Airway inflammation in asthma consists of mucosal, submucosal, and adventitial edema; cellular infiltration, particularly by eosinophils, activated helper T cells, mast cells, and sometimes neutrophils; increased airway secretions, including secreted mucus, desquamated lining cells, and intraluminal eosinophils; capillary engorgement; hyperplasia of smooth muscle; and deposition of excess collagen, particularly immediately beneath the basement membrane of the epithelium (31).…”

Mapping targetable inflammation and outcomes with cystic fibrosis biomarkers

“…Localized hypoxia in the CF lung could explain the early inflammation seen in the absence of obvious infection. 3 The gene mutated in CF, the cystic fibrosis transmembrane conductance regulator (CFTR), encodes a cAMP dependent anion channel that conducts chloride and bicarbonate and regulates the balance of chloride secretion and sodium absorption in the airway. 4 Loss of CFTR channel activity produces a dehydrated airway surface environment where the total mass of salt and volume of water are inadequate to maintain mucus hydration, leading to defects in mucociliary clearance.…”

“…The resulting thickened mucus and mucus plugging in the small airway create localized areas of hypoxia, which can trigger inflammatory responses including release of cytokines such as IL‐1 and activation of the inflammatory cascade via binding to the IL‐1 receptor . The resultant increase in inflammation may then worsen hypoxia and contribute to a niche for anaerobic bacteria, thus further propagating the inflammatory cycle …”

CrossTalk opposing view: mucosal acidification does not drive early progressive lung disease in cystic fibrosis

“…These observations, therefore, provide an important direct link between known pathogenic mechanisms in cystic fibrosis and sterile inflammation (Montgomery et al . ).…”