scholarly journals Airway acidification initiates host defense abnormalities in cystic fibrosis mice

Science ◽  
2016 ◽  
Vol 351 (6272) ◽  
pp. 503-507 ◽  
Author(s):  
V. S. Shah ◽  
D. K. Meyerholz ◽  
X. X. Tang ◽  
L. Reznikov ◽  
M. Abou Alaiwa ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Host Defense ◽  
Airway Acidification

scholarly journals Attenuation of host defense function of lung phagocytes in young cystic fibrosis patients

2006 ◽  
Vol 5 (1) ◽  
pp. 17-25 ◽  
Author(s):  
Neil E. Alexis ◽  
Marianne S. Muhlebach ◽  
David B. Peden ◽  
Terry L. Noah
Keyword(s):  
Cystic Fibrosis ◽  
Host Defense ◽  
Defense Function ◽  
Host Defense Function

scholarly journals UPR Induced Modulation of Host Defense by P. Aeruginosa in Cystic Fibrosis

2020 ◽  
Author(s):  
B. Bedi ◽  
K.-C. Lin ◽  
N.M. Maurice ◽  
J.B. Goldberg ◽  
A.A. Stecenko ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Host Defense

scholarly journals UPR modulation of host immunity by Pseudomonas aeruginosa in cystic fibrosis

2020 ◽  
Vol 134 (14) ◽  
pp. 1911-1934
Author(s):  
Brahmchetna Bedi ◽  
Kuo-Chuan. Lin ◽  
Nicholas M. Maurice ◽  
Zhihong Yuan ◽  
Kaiser Bijli ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Er Stress ◽  
Host Defense ◽  
Molecular Mechanisms ◽  
Nuclear Hormone Receptor ◽  
Respiratory Pathogen ◽  
Airway Epithelial ◽  
Pparγ Agonist ◽  
Pparγ Expression

Abstract Cystic fibrosis (CF) is a progressive multiorgan autosomal recessive disease with devastating impact on the lungs caused by derangements of the CF transmembrane conductance regulator (CFTR) gene. Morbidity and mortality are caused by the triad of impaired mucociliary clearance, microbial infections and chronic inflammation. Pseudomonas aeruginosa is the main respiratory pathogen in individuals with CF infecting most patients in later stages. Despite its recognized clinical impact, molecular mechanisms that underlie P. aeruginosa pathogenesis and the host response to P. aeruginosa infection remain incompletely understood. The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) γ (PPARγ), has shown to be reduced in CF airways. In the present study, we sought to investigate the upstream mechanisms repressing PPARγ expression and its impact on airway epithelial host defense. Endoplasmic reticulum-stress (ER-stress) triggered unfolded protein response (UPR) activated by misfolded CFTR and P. aeruginosa infection contributed to attenuated expression of PPARγ. Specifically, the protein kinase RNA (PKR)-like ER kinase (PERK) signaling pathway led to the enhanced expression of the CCAAT-enhancer-binding-protein homologous protein (CHOP). CHOP induction led to the repression of PPARγ expression. Mechanistically, we showed that CHOP induction mediated PPARγ attenuation, impacted the innate immune function of normal and ∆F508 primary airway epithelial cells by reducing expression of antimicrobial peptide (AMP) and paraoxanse-2 (PON-2), as well as enhancing IL-8 expression. Furthermore, mitochondrial reactive oxygen species production (mt-ROS) and ER-stress positive feedforward loop also dysregulated mitochondrial bioenergetics. Additionally, our findings implicate that PPARγ agonist pioglitazone (PIO) has beneficial effect on the host at the multicellular level ranging from host defense to mitochondrial re-energization.

scholarly journals Pathological mucus and impaired mucus clearance in cystic fibrosis patients result from increased concentration, not altered pH

2018 ◽  
Vol 52 (6) ◽  
pp. 1801297 ◽  
Author(s):  
David B. Hill ◽  
Robert F. Long ◽  
William J. Kissner ◽  
Eyad Atieh ◽  
Ian C. Garbarine ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Disulfide Bonds ◽  
Chemical Reduction ◽  
Length Scales ◽  
Mucus Clearance ◽  
Alternative Hypotheses ◽  
Series Of Experiments ◽  
Airway Mucus ◽  
Water Secretion ◽  
Airway Acidification

Cystic fibrosis (CF) is a recessive genetic disease that is characterised by airway mucus plugging and reduced mucus clearance. There are currently alternative hypotheses that attempt to describe the abnormally viscous and elastic mucus that is a hallmark of CF airways disease, including: 1) loss of CF transmembrane regulator (CFTR)-dependent airway surface volume (water) secretion, producing mucus hyperconcentration-dependent increased viscosity, and 2) impaired bicarbonate secretion by CFTR, producing acidification of airway surfaces and increased mucus viscosity.A series of experiments was conducted to determine the contributions of mucus concentration versus pH to the rheological properties of airway mucus across length scales from the nanoscopic to macroscopic.For length scales greater than the nanoscopic, i.e. those relevant to mucociliary clearance, the effect of mucus concentration dominated over the effect of airway acidification.Mucus hydration and chemical reduction of disulfide bonds that connect mucin monomers are more promising therapeutic approaches than alkalisation.

scholarly journals Electrolyte transport properties in distal small airways from cystic fibrosis pigs with implications for host defense

2016 ◽  
Vol 310 (7) ◽  
pp. L670-L679 ◽  
Author(s):  
Xiaopeng Li ◽  
Xiao Xiao Tang ◽  
Luis G. Vargas Buonfiglio ◽  
Alejandro P. Comellas ◽  
Ian M. Thornell ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Transport Properties ◽  
Host Defense ◽  
Bacterial Colonization ◽  
Short Circuit ◽  
Airway Epithelial Cells ◽  
Small Airway ◽  
Small Airways ◽  
Bacterial Killing ◽  
Airway Epithelia

While pathological and clinical data suggest that small airways are involved in early cystic fibrosis (CF) lung disease development, little is known about how the lack of cystic fibrosis transmembrane conductance regulator (CFTR) function contributes to disease pathogenesis in these small airways. Large and small airway epithelia are exposed to different airflow velocities, temperatures, humidity, and CO2 concentrations. The cellular composition of these two regions is different, and small airways lack submucosal glands. To better understand the ion transport properties and impacts of lack of CFTR function on host defense function in small airways, we adapted a novel protocol to isolate small airway epithelial cells from CF and non-CF pigs and established an organotypic culture model. Compared with non-CF large airways, non-CF small airway epithelia cultures had higher Cl− and bicarbonate (HCO3−) short-circuit currents and higher airway surface liquid (ASL) pH under 5% CO2 conditions. CF small airway epithelia were characterized by minimal Cl− and HCO3− transport and decreased ASL pH, and had impaired bacterial killing compared with non-CF small airways. In addition, CF small airway epithelia had a higher ASL viscosity than non-CF small airways. Thus, the activity of CFTR is higher in the small airways, where it plays a role in alkalinization of ASL, enhancement of antimicrobial activity, and lowering of mucus viscosity. These data provide insight to explain why the small airways are a susceptible site for the bacterial colonization.

scholarly journals 398: Host and pathogens contribute to decreased host defense protein SPLUNC1 in cystic fibrosis

2021 ◽  
Vol 20 ◽  
pp. S188
Author(s):  
J. Zielonka ◽  
S. Khanal ◽  
M. Webster ◽  
N. Shiner ◽  
A. Carpio ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Host Defense ◽  
Defense Protein
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