Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets

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221

Inflammation plays a critical role in cystic fibrosis (CF) lung pathology and disease progression making it an active area of research and important therapeutic target. In this review, we explore the most recent research on the major contributors to the exuberant inflammatory response seen in CF as well as potential therapeutics to combat this response. Absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) alters anion transport across CF airway epithelial cells and ultimately results in dehydration of the airway surface liquid. The dehydrated airway surface liquid in combination with abnormal mucin secretion contributes to airway obstruction and subsequent infection that may serve as a trigger point for inflammation. There is also evidence to suggest that airway inflammation may be excessive and sustained relative to the infectious stimuli. Studies have shown dysregulation of both pro-inflammatory mediators such as IL-17 and pro-resolution mediators including metabolites of the eicosanoid pathway. Recently, CFTR potentiators and correctors have garnered much attention in the CF community. Although these modulators address the underlying defect in CF, their impact on downstream consequences such as inflammation are not known. Here, we review pre-clinical and clinical data on the impact of CFTR modulators on inflammation. In addition, we examine other cell types including neutrophils, macrophages, and T-lymphocytes that express CFTR and contribute to the CF inflammatory response. Finally, we address challenges in developing anti-inflammatory therapies and highlight some of the most promising anti-inflammatory drugs under development for CF.

Section: Associations Between Abnormal Cftr and Airway Inflammationmentioning

confidence: 99%

Section: Associations Between Abnormal Cftr and Airway Inflammationmentioning

confidence: 99%

Section: Associations Between Abnormal Cftr and Airway Inflammationmentioning

confidence: 99%

Section: Associations Between Abnormal Cftr and Airway Inflammationmentioning

confidence: 99%

Section: Associations Between Abnormal Cftr and Airway Inflammationmentioning

confidence: 99%

See 3 more Smart Citations

Inflammation in cystic fibrosis: An update

Roesch

Nichols

Chmiel

2018

202

221

Highlights from the 2018 North American cystic fibrosis conference

Martiniano

Daines

Dellon

et al. 2019

The 32nd annual North American Cystic Fibrosis Conference was held in Denver, CO on Oct. 18 to 20, 2018. This review highlights presentations in several topic areas, including the pathophysiology and basic science of cystic fibrosis lung disease, clinical trials, clinical care, and quality improvement. Citations from the conference are by first author and abstract or symposium number, as designated in the previously published supplement.

Mucus obstruction and inflammation in early cystic fibrosis lung disease: Emerging role of the IL‐1 signaling pathway

Balázs

Mall

2019

Mucus plugging constitutes a nutrient‐rich nidus for a bacterial infection that has long been recognized as a potent stimulus for neutrophilic airway inflammation driving progressive lung damage in people with cystic fibrosis (CF). However, mucus plugging and neutrophilic inflammation are already present in many infants and young children with CF even in the absence of detectable bacterial infection. A series of observational studies in young children with CF, as well as investigations in animal models with CF‐like lung disease support the concept that mucus plugging per se can trigger inflammation before the onset of airways infection. Here we review emerging evidence suggesting that activation of the interleukin‐1 (IL‐1) signaling pathway by hypoxic epithelial cell necrosis, leading to the release of IL‐1α in mucus‐obstructed airways, may be an important mechanistic link between mucus plugging and sterile airway inflammation in early CF lung disease. Furthermore, we discuss recent data from preclinical studies demonstrating that treatment with the IL‐1 receptor (IL‐1R) antagonist anakinra has anti‐inflammatory as well as mucus modulating effects in mice with CF‐like lung disease and primary cultures of human CF airway epithelia. Collectively, these studies support an important role of the IL‐1 signaling pathway in sterile neutrophilic inflammation and mucus hypersecretion and suggest inhibition of this pathway as a promising anti‐inflammatory strategy in patients with CF and potentially other muco‐obstructive lung diseases.