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  • 1
    Online Resource
    Online Resource
    Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 315, No. 5 ( 2018-11-01), p. G868-G878
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 315, No. 5 ( 2018-11-01), p. G868-G878
    Abstract: Gastrointestinal dysfunction in cystic fibrosis (CF) is a prominent source of pain among patients with CF. Linaclotide, a guanylate cyclase C (GCC) receptor agonist, is a US Food and Drug Administration-approved drug prescribed for chronic constipation but has not been widely used in CF, as the cystic fibrosis transmembrane conductance regulator (CFTR) is the main mechanism of action. However, anecdotal clinical evidence suggests that linaclotide may be effective for treating some gastrointestinal symptoms in CF. The goal of this study was to determine the effectiveness and mechanism of linaclotide in treating CF gastrointestinal disorders using CF mouse models. Intestinal transit, chloride secretion, and intestinal lumen fluidity were assessed in wild-type and CF mouse models in response to linaclotide. CFTR and sodium/hydrogen exchanger 3 (NHE3) response to linaclotide was also evaluated. Linaclotide treatment improved intestinal transit in mice carrying either F508del or null Cftr mutations but did not induce detectable Cl − secretion. Linaclotide increased fluid retention and fluidity of CF intestinal contents, suggesting inhibition of fluid absorption. Targeted inhibition of sodium absorption by the NHE3 inhibitor tenapanor produced improvements in gastrointestinal transit similar to those produced by linaclotide treatment, suggesting that inhibition of fluid absorption by linaclotide contributes to improved gastrointestinal transit in CF. Our results demonstrate that linaclotide improves gastrointestinal transit in CF mouse models by increasing luminal fluidity through inhibiting NHE3-mediated sodium absorption. Further studies are necessary to assess whether linaclotide could improve CF intestinal pathologies in patients. GCC signaling and NHE3 inhibition may be therapeutic targets for CF intestinal manifestations. NEW & NOTEWORTHY Linaclotide’s primary mechanism of action in alleviating chronic constipation is through cystic fibrosis transmembrane conductance regulator (CFTR), negating its use in patients with cystic fibrosis (CF). For the first time, our findings suggest that in the absence of CFTR, linaclotide can improve fluidity of the intestinal lumen through the inhibition of sodium/hydrogen exchanger 3. These findings suggest that linaclotide could improve CF intestinal pathologies in patients.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00261.2017
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
    detail.hit.zdb_id: 1477329-6
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  • 2
    Online Resource
    Online Resource
    Augmentation of CFTR maturation by S -nitrosoglutathione reductase
    American Physiological Society ; 2016
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 310, No. 3 ( 2016-02-01), p. L263-L270
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 310, No. 3 ( 2016-02-01), p. L263-L270
    Abstract: S-nitrosoglutathione (GSNO) reductase regulates novel endogenous S-nitrosothiol signaling pathways, and mice deficient in GSNO reductase are protected from airways hyperreactivity. S-nitrosothiols are present in the airway, and patients with cystic fibrosis (CF) tend to have low S-nitrosothiol levels that may be attributed to upregulation of GSNO reductase activity. The present study demonstrates that 1) GSNO reductase activity is increased in the cystic fibrosis bronchial epithelial (CFBE41o − ) cells expressing mutant F508del-cystic fibrosis transmembrane regulator (CFTR) compared with the wild-type CFBE41o − cells, 2) GSNO reductase expression level is increased in the primary human bronchial epithelial cells expressing mutant F508del-CFTR compared with the wild-type cells, 3) GSNO reductase colocalizes with cochaperone Hsp70/Hsp90 organizing protein (Hop; Stip1) in human airway epithelial cells, 4) GSNO reductase knockdown with siRNA increases the expression and maturation of CFTR and decreases Stip1 expression in human airway epithelial cells, 5) increased levels of GSNO reductase cause a decrease in maturation of CFTR, and 6) a GSNO reductase inhibitor effectively reverses the effects of GSNO reductase on CFTR maturation. These studies provide a novel approach to define the subcellular location of the interactions between Stip1 and GSNO reductase and the role of S-nitrosothiols in these interactions.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00269.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2016
    detail.hit.zdb_id: 1477300-4
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  • 3
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    Online Resource
    Type II protein kinase A regulates CFTR in airway, pancreatic, and intestinal cells
    American Physiological Society ; 1998
    In:  American Journal of Physiology-Cell Physiology Vol. 274, No. 3 ( 1998-03-01), p. C819-C826
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 274, No. 3 ( 1998-03-01), p. C819-C826
    Abstract: The type of protein kinase A (PKA) responsible for cystic fibrosis transmembrane conductance regulator (CFTR) activation was determined with adenosine 3′,5′-cyclic monophosphate analogs capable of selectively activating type I or type II PKA. The type II-selective pair stimulated chloride efflux in airway, pancreatic, and colonic epithelial cells; the type I-selective pair only stimulated a calcium-dependent efflux in airway cells. The type II-selective analogs activated larger increases in CFTR-mediated current than did the type I-selective analogs. Measurement of soluble PKA activity demonstrated similar levels stimulated by type I- and type II-selective analogs, creating an apparent paradox regarding PKA activity and current generated. Also, addition of forskolin after the type I-selective analogs resulted in an increase in current; little increase was seen after the type II-selective analogs. Measurement of insoluble PKA activity stimulated by the analogs resolved this paradox. Type II-selective analogs stimulated three times as much insoluble PKA activity as the type I-selective pair, indicating that differential activation of PKA in cellular compartments is important in CFTR regulation.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.1998.274.3.C819
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1998
    detail.hit.zdb_id: 1477334-X
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  • 4
    Online Resource
    Online Resource
    Carbonic anhydrase and soluble adenylate cyclase regulation of cystic fibrosis cellular phenotypes
    American Physiological Society ; 2022
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 322, No. 3 ( 2022-03-01), p. L333-L347
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 322, No. 3 ( 2022-03-01), p. L333-L347
    Abstract: Several aspects of the cell biology of cystic fibrosis (CF) epithelial cells are altered including impaired lipid regulation, disrupted intracellular transport, and impaired microtubule regulation. It is unclear how the loss of cystic fibrosis transmembrane conductance regulator (CFTR) function leads to these differences. It is hypothesized that the loss of CFTR function leads to altered regulation of carbonic anhydrase (CA) activity resulting in cellular phenotypic changes. In this study, it is demonstrated that CA2 protein expression is reduced in CF model cells, primary mouse nasal epithelial (MNE) cells, excised MNE tissue, and primary human nasal epithelial cells ( P 〈 0.05). This corresponds to a decrease in CA2 RNA expression measured by qPCR as well as an overall reduction in CA activity in primary CF MNEs. The addition of CFTR-inhibitor-172 to WT MNE cells for ≥24 h mimics the significantly lower protein expression of CA2 in CF cells. Treatment of CF cells with l-phenylalanine (L-Phe), an activator of CA activity, restores endosomal transport through an effect on microtubule regulation in a manner dependent on soluble adenylate cyclase (sAC). This effect can be blocked with the CA2-selective inhibitor dorzolamide. These data suggest that the loss of CFTR function leads to the decreased expression of CA2 resulting in the downstream cell signaling alterations observed in CF.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00022.2021
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 1477300-4
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  • 5
    Online Resource
    Online Resource
    Examining basal chloride transport using the nasal potential difference response in a murine model
    American Physiological Society ; 2001
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 281, No. 5 ( 2001-11-01), p. L1173-L1179
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 281, No. 5 ( 2001-11-01), p. L1173-L1179
    Abstract: Epithelia of humans and mice with cystic fibrosis are unable to secrete chloride in response to a chloride gradient or to cAMP-elevating agents. Bioelectrical properties measured using the nasal transepithelial potential difference (TEPD) assay are believed to reflect these cystic fibrosis transmembrane conductance regulator (CFTR)-dependent chloride transport defects. Although the response to forskolin is CFTR mediated, the mechanisms responsible for the response to a chloride gradient are unknown. TEPD measurements performed on inbred mice were used to compare the responses to low chloride and forskolin in vivo. Both responses show little correlation between or within inbred strains of mice, suggesting they are mediated through partially distinct mechanisms. In addition, these responses were assayed in the presence of several chloride channel inhibitors, including DIDS, diphenylamine-2-carboxylate, glibenclamide, and 5-nitro-2-(3-phenylpropylamino)-benzoic acid, and a protein kinase A inhibitor, the Rp diastereomer of adenosine 3′,5′-cyclic monophosphothioate ( Rp-cAMPS). The responses to low chloride and forskolin demonstrate significantly different pharmacological profiles to both DIDS and Rp-cAMPS, indicating that channels in addition to CFTR contribute to the low chloride response.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.2001.281.5.L1173
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2001
    detail.hit.zdb_id: 1477300-4
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  • 6
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    Online Resource
    Resveratrol restores intracellular transport in cystic fibrosis epithelial cells
    American Physiological Society ; 2020
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 318, No. 6 ( 2020-06-01), p. L1145-L1157
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 318, No. 6 ( 2020-06-01), p. L1145-L1157
    Abstract: We have demonstrated previously that intracellular transport is impaired in cystic fibrosis (CF) epithelial cells. This impairment is related to both growth and inflammatory regulation in CF cell and animal models. Understanding how transport in CF cells is regulated and identifying means to manipulate that regulation are key to identifying new therapies that can address key CF phenotypes. It was hypothesized that resveratrol could replicate these benefits since it interfaces with multiple pathways identified to affect microtubule regulation in CF. It was found that resveratrol treatment significantly restored intracellular transport as determined by monitoring both cholesterol distribution and the distribution of rab7-positive organelles in CF cells. This restoration of intracellular transport is due to correction of both microtubule formation rates and microtubule acetylation in cultured CF cell models and primary nasal epithelial cells. Mechanistically, the effect of resveratrol on microtubule regulation and intracellular transport was dependent on peroxisome proliferator-activated receptor-γ signaling and its ability to act as a pan-histone deacetylase (HDAC) inhibitor. Resveratrol represents a candidate compound with known anti-inflammatory properties that can restore both microtubule formation and acetylation in CF epithelial cells.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00006.2020
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2020
    detail.hit.zdb_id: 1477300-4
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  • 7
    Online Resource
    Online Resource
    CFTR inhibition mimics the cystic fibrosis inflammatory profile
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 292, No. 2 ( 2007-02), p. L383-L395
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 292, No. 2 ( 2007-02), p. L383-L395
    Abstract: Primary airway epithelial cells grown in air-liquid interface differentiate into cultures that resemble native epithelium morphologically, express ion transport similar to those in vivo, and secrete cytokines in response to stimuli. Comparisons of cultures derived from normal and cystic fibrosis (CF) individuals are difficult to interpret due to genetic differences besides CFTR. The recently discovered CFTR inhibitor, CFTR inh -172, was used to create a CF model with its own control to test if loss of CFTR-Cl − conductance alone was sufficient to initiate the CF inflammatory response. Continuous inhibition of CFTR-Cl − conductance for 3–5 days resulted in significant increase in IL-8 secretion at basal ( P = 0.006) and in response to 10 9 Pseudomonas ( P = 0.0001), a fourfold decrease in Smad3 expression ( P = 0.02), a threefold increase in RhoA expression, and increased NF-κB nuclear translocation upon TNF-α/IL-1β stimulation ( P 〈 0.000001). CFTR inhibition by CFTR inh -172 over this period does not increase epithelial sodium channel activity, so lack of Cl − conductance alone can mimic the inflammatory CF phenotype. CFTR inh -172 does not affect IL-8, IL-6, or granulocyte/macrophage colony-stimulating factor secretion in two CF phenotype immortalized cell lines: 9/HTEo − pCEP-R and 16HBE14o − AS, or IL-8 secretion in primary CF cells, and inhibitor withdrawal abolishes the increased response, so CFTR inh -172 effects on cytokines are not direct. Five-day treatment with CFTR inh -172 does not affect cells deleteriously as evidenced by lactate dehydrogenase, trypan blue, ciliary activity, electron micrograph histology, and inhibition reversibility. Our results support the hypothesis that lack of CFTR activity is responsible for the onset of the inflammatory cascade in the CF lung.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00403.2005
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477300-4
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  • 8
    Online Resource
    Online Resource
    Ibuprofen regulation of microtubule dynamics in cystic fibrosis epithelial cells
    American Physiological Society ; 2016
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 311, No. 2 ( 2016-08-01), p. L317-L327
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 311, No. 2 ( 2016-08-01), p. L317-L327
    Abstract: High-dose ibuprofen, an effective anti-inflammatory therapy for the treatment of cystic fibrosis (CF), has been shown to preserve lung function in a pediatric population. Despite its efficacy, few patients receive ibuprofen treatment due to potential renal and gastrointestinal toxicity. The mechanism of ibuprofen efficacy is also unclear. We have previously demonstrated that CF microtubules are slower to reform after depolymerization compared with respective wild-type controls. Slower microtubule dynamics in CF cells are responsible for impaired intracellular transport and are related to inflammatory signaling. Here, it is identified that high-dose ibuprofen treatment in both CF cell models and primary CF nasal epithelial cells restores microtubule reformation rates to wild-type levels, as well as induce extension of microtubules to the cell periphery. Ibuprofen treatment also restores microtubule-dependent intracellular transport monitored by measuring intracellular cholesterol transport. These effects are specific to ibuprofen as other cyclooxygenase inhibitors have no effect on these measures. Effects of ibuprofen are mimicked by stimulation of AMPK and blocked by the AMPK inhibitor compound C. We conclude that high-dose ibuprofen treatment enhances microtubule formation in CF cells likely through an AMPK-related pathway. These findings define a potential mechanism to explain the efficacy of ibuprofen therapy in CF.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00126.2016
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2016
    detail.hit.zdb_id: 1477300-4
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  • 9
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    Online Resource
    Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 292, No. 2 ( 2007-02), p. L476-L486
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 292, No. 2 ( 2007-02), p. L476-L486
    Abstract: Determining how the regulation of cellular processes is impacted in cystic fibrosis (CF) is fundamental to understanding disease pathology and to identifying new therapeutic targets. In this study, unesterified cholesterol accumulation is observed in lung and trachea sections obtained from CF patients compared with non-CF tissues, suggesting an inherent flaw in cholesterol processing. An alternate staining method utilizing a fluorescent cholesterol probe also indicates improper lysosomal storage of cholesterol in CF cells. Excess cholesterol is also manifested by a significant increase in plasma membrane cholesterol content in both cultured CF cells and in nasal tissue excised from cftr −/− mice. Impaired intracellular cholesterol movement is predicted to stimulate cholesterol synthesis, a hypothesis supported by the observation of increased de novo cholesterol synthesis in lung and liver of cftr −/− mice compared with controls. Furthermore, pharmacological inhibition of cholesterol transport is sufficient to cause CF-like elevation in cytokine production in wild-type cells in response to bacterial challenge but has no effect in CF cells. These data demonstrate via multiple methods in both cultured and in vivo models that cellular cholesterol homeostasis is inherently altered in CF. This perturbation of cholesterol homeostasis represents a potentially important process in CF pathogenesis.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00262.2006
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477300-4
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  • 10
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    Online Resource
    In vivo activation of CFTR-dependent chloride transport in murine airway epithelium by CNP
    American Physiological Society ; 1997
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 273, No. 5 ( 1997-11-01), p. L1065-L1072
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 273, No. 5 ( 1997-11-01), p. L1065-L1072
    Abstract: Inhibitors of guanosine 3′,5′-cyclic monophosphate (cGMP)-inhibited phosphodiesterases stimulate Cl − transport across the nasal epithelia of cystic fibrosis mice carrying the ΔF508 mutation [cystic fibrosis transmembrane conductance regulator (CFTR) (ΔF/ΔF)], suggesting a role for cGMP in regulation of epithelial ion transport. Here we show that activation of membrane-bound guanylate cyclases by C-type natriuretic peptide (CNP) stimulates hyperpolarization of nasal epithelium in both wild-type and ΔF508 CFTR mice in vivo but not in nasal epithelium of mice lacking CFTR [CFTR(−/−)] . With the use of a nasal transepithelial potential difference (TEPD) assay, CNP was found to hyperpolarize lumen negative TEPD by 6.1 ± 0.6 mV in mice carrying wild-type CFTR. This value is consistent with that obtained with 8-bromoguanosine 3′,5′-cyclic monophosphate (6.2 ± 0.9 mV). A combination of the adenylate cyclase agonist forskolin and CNP demonstrated a synergistic ability to induce Cl − secretion across the nasal epithelium of CFTR(ΔF/ΔF) mice. No effect on TEPD was seen with this combination when used on CFTR(−/−) mice, implying that the CNP-induced change in TEPD in CFTR(ΔF/ΔF) mice is CFTR dependent.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.1997.273.5.L1065
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1997
    detail.hit.zdb_id: 1477300-4
    SSG: 12
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