Proteome analysis of lung, lung-derived leukocytes and PBMCs in a pig model for cystic fibrosis.
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF
ORGANISM(S): Sus Scrofa Domesticus (domestic Pig)
TISSUE(S): Lung
SUBMITTER: 
Thomas Fröhlich
LAB HEAD: Thomas Fröhlich
PROVIDER: PXD055249 | Pride | 2025-02-21
REPOSITORIES: pride
Dataset's files
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Items per page: 5 1 - 5 of 52 |
Publications
Perinatal dysfunction of innate immunity in cystic fibrosis.
Jaudas Florian F Bartenschlager Florian F Shashikadze Bachuki B Santamaria Gianluca G Reichart Daniel D Schnell Alexander A Stöckl Jan Bernd JB Degroote Roxane L RL Cambra Josep M JM Graeber Simon Y SY Bähr Andrea A Kartmann Heike H Stefanska Monika M Liu Huan H Naumann-Bartsch Nora N Bruns Heiko H Berges Johannes J Hanselmann Lea L Stirm Michael M Krebs Stefan S Deeg Cornelia A CA Blum Helmut H Schulz Christian C Zawada Dorota D Janda Melanie M Caballero-Posadas Ignacio I Kunzelmann Karl K Moretti Alessandra A Laugwitz Karl-Ludwig KL Kupatt Christian C Saalmüller Armin A Fröhlich Thomas T Wolf Eckhard E Mall Marcus A MA Mundhenk Lars L Gerner Wilhelm W Klymiuk Nikolai N
Science translational medicine 20250122 782
In patients with cystic fibrosis (CF), repeated cycles of infection and inflammation eventually lead to fatal lung damage. Although diminished mucus clearance can be restored by highly effective CFTR modulator therapy, inflammation and infection often persist. To elucidate the role of the innate immune system in CF etiology, we investigated a CF pig model and compared these results with those for preschool children with CF. In newborn CF pigs, we observed changes in lung immune cell composition ...[more]
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Project description:Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how loss of CFTR first disrupts airway host defense has remained uncertain. We asked what abnormality impairs elimination when a bacterium lands on the pristine surface of a newborn CF airway? To investigate this defect, we interrogated the viability of individual bacteria immobilized on solid grids and placed on the airway surface. As a model we studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly killed bacteria in vivo, when removed from the lung, and in primary epithelial cultures. Lack of CFTR reduced bacterial killing. We found that ASL pH was more acidic in CF, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defense defect to loss of CFTR, an anion channel that facilitates HCO3- transport. Without CFTR, airway epithelial HCO3- secretion is defective, ASL pH falls and inhibits antimicrobial function, and thereby impairs killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF and that assaying ASL pH or bacterial killing could report on the benefit of therapeutic interventions.
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