Icmje

Cystic fibrosis transmembrane conductance regulator (CFTR) functions as a channel that regulates the transport of ions and the movement of water across the epithelial barrier. Mutations in CFTR, which form the basis for the clinical manifestations of cystic fibrosis, affect the epithelial innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pulmonary pathogens. Compounding the effects of excessive neutrophil recruitment, the mutant CFTR channel does not transport antioxidants to counteract neutrophil-associated oxidative stress. Whereas mutant CFTR expression in leukocytes outside of the lung does not markedly impair their function, the expected regulation of inflammation in the airways is clearly deficient in cystic fibrosis. The resulting bacterial infections, which are caused by organisms that have substantial genetic and metabolic flexibility, can resist multiple classes of antibiotics and evade phagocytic clearance. The development of animal models that approximate the human pulmonary phenotypes-airway inflammation and spontaneous infection-may provide the much-needed tools to establish how CFTR regulates mucosal immunity and to test directly the effect of pharmacologic potentiation and correction of mutant CFTR function on bacterial clearance.

/pdf/cystic-fibrosis-a-mucosal-immunodeficiency-syndrome-4i581s95tf.pdf

Cystic fibrosis: a mucosal immunodeficiency syndrome.

https://www.cysticfibrosisjournal.com/article/S1569-1993(15)00058-2/pdf

Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy

Rationale: Characterization of bacterial populations in infectious respiratory diseases will provide improved understanding of the relationship between the lung microbiota, disease pathogenesis, and treatment outcomes.Objectives: To comprehensively define lung microbiota composition during stable disease and exacerbation in patients with bronchiectasis.Methods: Sputum was collected from patients when clinically stable and before and after completion of antibiotic treatment of exacerbations. Bacterial abundance and community composition were analyzed using anaerobic culture and 16S rDNA pyrosequencing.Measurements and Main Results: In clinically stable patients, aerobic and anaerobic bacteria were detected in 40 of 40 (100%) and 33 of 40 (83%) sputum samples, respectively. The dominant organisms cultured were Pseudomonas aeruginosa (n = 10 patients), Haemophilus influenzae (n = 12), Prevotella (n = 18), and Veillonella (n = 13). Pyrosequencing generated more than 150,000 sequences, representing 113 distinc...

/pdf/lung-microbiota-and-bacterial-abundance-in-patients-with-3vl3hu6bou.pdf

Lung Microbiota and Bacterial Abundance in Patients with Bronchiectasis when Clinically Stable and during Exacerbation

http://www.stritch.luc.edu/lumen/MedEd/hostdef/CysticFibrosis.pdf

Innate immunity in cystic fibrosis lung disease

Background Women with cystic fibrosis are at increased risk for mucoid conversion of Pseudomonas aeruginosa, which contributes to a sexual dichotomy in disease severity. Methods We evaluated the effects of estradiol and its metabolite estriol on P. aeruginosa in vitro and in vivo and determined the effect of estradiol on disease exacerbations in women with cystic fibrosis. Results Estradiol and estriol induced alginate production in P. aeruginosa strain 01 and in clinical isolates obtained from patients with and those without cystic fibrosis. After prolonged exposure to estradiol, P. aeruginosa adopted early mucoid morphology, whereas short-term exposure inhibited bacterial catalase activity and increased levels of hydrogen peroxide, which is potentially damaging to DNA. Consequently, a frameshift mutation was identified in mucA, a key regulator of alginate biosynthesis in P. aeruginosa. In vivo levels of estradiol correlated with infective exacerbations in women with cystic fibrosis, with the majority oc...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1106126

Effect of Estrogen on Pseudomonas Mucoidy and Exacerbations in Cystic Fibrosis

Pulmonary Proteases in the Cystic Fibrosis Lung Induce Interleukin 8 Expression from Bronchial Epithelial Cells via a Heme/Meprin/Epidermal Growth Factor Receptor/Toll-like Receptor Pathway

Alpha-1 antitrypsin (AAT) is the most abundant proteinase inhibitor within the circulation and AAT deficiency is a genetic disorder characterised by serum levels of less than 11μmol/L. The Z mutation is the most common AAT allele associated with the disease and causes the most severe plasma deficiency, as the mutant protein polymerizes and accumulates within the endoplasmic reticulum of hepatocytes. The retained polymers are associated with cirrhosis and reduced serum levels of AAT contribute to the development of chronic pulmonary disease in AAT deficient individuals. This article will review the importance of AAT as a serine anti-protease, the clinical manifestations of AAT deficiency and specific treatment of the disease. Current therapies including AAT replacement and treatment with synthetic or alternative protease inhibitors are reviewed, along with possible future therapies including those focusing on targeting AAT polymer formation or based on gene therapy.

Sonya Cosgrove

Papers

Effect of Estrogen on Pseudomonas Mucoidy and Exacerbations in Cystic Fibrosis

Pulmonary Proteases in the Cystic Fibrosis Lung Induce Interleukin 8 Expression from Bronchial Epithelial Cells via a Heme/Meprin/Epidermal Growth Factor Receptor/Toll-like Receptor Pathway

New Strategies in Drug Development Focusing on the Anti-Protease- Protease Balance in Alpha-1 Antitrypsin Deficiency

The Effects of Differential Protease Secretion by Pseudomonas aeruginosa under Aerobic and Anaerobic Conditions In Vitro.

Pulmonary Proteases In The Cystic Fibrosis Lung Induce IL-8 Expression From Bronchial Epithelial Cells Via A HEME/MEPRIN/EGFR/TLR Pathway