CF airway smooth muscle transcriptome reveals a role for PYK2

Cook, Daniel P.; Adam, Ryan J.; Zarei, Keyan; Deonovic, Benjamin; Stroik, Mallory R.; Gansemer, Nicholas D.; Meyerholz, David K.; Au, Kin Fai; Stoltz, David A.

doi:10.1172/jci.insight.95332

Cited by 8 publications

(5 citation statements)

References 60 publications

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“…Ad-TGF␤ treatment produced profound increases in two markers of noncanonical signaling (p-ERK1/2 and p-Akt) uniquely in CF mice compared with littermate controls. Previous reports have described increased MAPK and PI3K signaling in CF cells compared with non-CF controls both at baseline and after exposure to stimuli, including oxidative stress and LPS (5,6,11,44,58). Our results build upon these previous observations and suggest fundamental in vivo differences in cellular responses to stimuli of these pathways.…”

Section: P B S a D -T G F E M P Ty P B S A D -T G F E M P Tysupporting

confidence: 87%

Subacute TGFβ expression drives inflammation, goblet cell hyperplasia, and pulmonary function abnormalities in mice with effects dependent on CFTR function

Kramer

Hardie

Madala

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cystic fibrosis (CF) produces variable lung disease phenotypes that are, in part, independent of the CF transmembrane conductance regulator ( CFTR) genotype. Transforming growth factor-β (TGFβ) is the best described genetic modifier of the CF phenotype, but its mechanism of action is unknown. We hypothesized that TGFβ is sufficient to drive pathognomonic features of CF lung disease in vivo and that CFTR deficiency enhances susceptibility to pathological TGFβ effects. A CF mouse model and littermate controls were exposed intratracheally to an adenoviral vector containing the TGFβ1 cDNA (Ad-TGFβ), empty vector, or PBS only. Studies were performed 1 wk after treatment, including lung mechanics, collection of bronchoalveolar lavage fluid, and analysis of lung histology, RNA, and protein. CF and non-CF mice showed similar weight loss, inflammation, goblet cell hyperplasia, and Smad pathway activation after Ad-TGFβ treatment. Ad-TGFβ produced greater abnormalities in lung mechanics in CF versus control mice, which was uniquely associated with induction of phosphoinositide 3-kinase and mitogen-activated protein kinase signaling. CFTR transcripts were reduced, and epithelial sodium channel transcripts were increased in CF and non-CF mice, whereas the goblet cell transcription factors, forkhead ortholog A3 and SAM-pointed domain-containing ETS-like factor, were increased in non-CF but not CF mice following Ad-TGFβ treatment. Pulmonary TGFβ1 expression was sufficient to produce pulmonary remodeling and abnormalities in lung mechanics that were associated with both shared and unique cell signaling pathway activation in CF and non-CF mice. These results highlight the multifunctional impact of TGFβ on pulmonary pathology in vivo and identify cellular-response differences that may impact CF lung pathology.

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Section: P B S a D -T G F E M P Ty P B S A D -T G F E M P Tysupporting

confidence: 87%

Subacute TGFβ expression drives inflammation, goblet cell hyperplasia, and pulmonary function abnormalities in mice with effects dependent on CFTR function

Kramer

Hardie

Madala

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Possible pathophysiologic mechanisms for MI include a lack of CFTR function in the intestinal epithelial cells causing (a) abnormal pH or HCO 3 − concentration in the intestinal lumen, (b) decreased hydration of the meconium making it more solid than in the non-CF intestine, (c) abnormal mucin cross-linking, (d) CFTR-dependent smooth muscle dysfunction causing intestinal dysmotility, or (e) CFTR-dependent intestinal growth anomalies leading to atresia, malrotation, or other structural abnormalities. It is possible that a combination of these factors contribute to physical obstruction of the distal small intestine ( 1 , 3 , 17 , 22 – 27 ). Our data suggest that the lack of pancreatic enzyme activity could contribute to MI.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic enzymes digest obstructive meconium from cystic fibrosis pig intestines

Gangadharan Nambiar,

Gonzalez Szachowicz,

Zirbes

et al. 2024

Front. Pediatr.

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IntroductionMeconium ileus (MI) is a life-threatening obstruction of the intestines affecting ∼15% of newborns with cystic fibrosis (CF). Current medical treatments for MI often fail, requiring surgical intervention. MI typically occurs in newborns with pancreatic insufficiency from CF. Meconium contains mucin glycoprotein, a potential substrate for pancreatic enzymes or mucolytics. Our study aim was to determine whether pancreatic enzymes in combination with mucolytic treatments dissolve obstructive meconium using the CF pig model.MethodsWe collected meconium from CF pigs at birth and submerged it in solutions with and without pancreatic enzymes, including normal saline, 7% hypertonic saline, and the reducing agents N-acetylcysteine (NAC) and dithiothreitol (DTT). We digested meconium at 37 °C with agitation, and measured meconium pigment release by spectrophotometry and residual meconium solids by filtration.Results and discussionIn CF pigs, meconium appeared as a solid pigmented mass obstructing the ileum. Meconium microscopically contained mucus glycoprotein, cellular debris, and bile pigments. Meconium fragments released pigments with maximal absorption at 405 nm after submersion in saline over approximately 8 h. Pancreatic enzymes significantly increased pigment release and decreased residual meconium solids. DTT did not improve meconium digestion and the acidic reducing agent NAC worsened digestion. Pancreatic enzymes digested CF meconium best at neutral pH in isotonic saline. We conclude that pancreatic enzymes digest obstructive meconium from CF pigs, while hydrating or reducing agents alone were less effective. This work suggests a potential role for pancreatic enzymes in relieving obstruction due to MI in newborns with CF.

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“…This has been especially true in the case of kidney transplantation. The increasing prevalence of end-stage kidney disease Lung (inflammation/infection, 9,13,89,127 mucus, 73,90,148 mucociliary transport, 49,90 antimicrobial proteins, 96 airway development, 2,3,28,77,78 smooth muscle, 20,21 epithelial lineages, 134 airway surface liquid pH, 64,65,115 gene therapy 22,23 ), sinonasal cavity, 17,129 exocrine pancreas, 1,79,104,135 endocrine, 63,102,136 central/ peripheral nervous systems (CNS/PNS), 101 hepatobiliary, 79,135,151,152 gastrointestinal, 79,104,129 cardiovascular, 39 skeletal, 14 and reproductive 98 Ataxia telangiectasia (ATM) CNS/cognitive, 11 growth abnormalities, 11 ataxia, 11 thymus, …”

Section: Swine In Xenotransplantationmentioning

confidence: 99%

Swine models in translational research and medicine

Meyerholz,

Burrough,

Kirchhof

et al. 2024

Vet Pathol

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Swine are increasingly studied as animal models of human disease. The anatomy, size, longevity, physiology, immune system, and metabolism of swine are more like humans than traditional rodent models. In addition, the size of swine is preferred for surgical placement and testing of medical devices destined for humans. These features make swine useful for biomedical, pharmacological, and toxicological research. With recent advances in gene-editing technologies, genetic modifications can readily and efficiently be made in swine to study genetic disorders. In addition, gene-edited swine tissues are necessary for studies testing and validating xenotransplantation into humans to meet the critical shortfall of viable organs versus need. Underlying all of these biomedical applications, the knowledge of husbandry, background diseases and lesions, and biosecurity needs are important for productive, efficient, and reproducible research when using swine as a human disease model for basic research, preclinical testing, and translational studies.

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CF airway smooth muscle transcriptome reveals a role for PYK2

Cited by 8 publications

References 60 publications

Subacute TGFβ expression drives inflammation, goblet cell hyperplasia, and pulmonary function abnormalities in mice with effects dependent on CFTR function

Subacute TGFβ expression drives inflammation, goblet cell hyperplasia, and pulmonary function abnormalities in mice with effects dependent on CFTR function

Pancreatic enzymes digest obstructive meconium from cystic fibrosis pig intestines

Swine models in translational research and medicine

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