Evidence of CFTR Function in Cystic Fibrosis after Systemic Administration of 4-Phenylbutyrate

Zeitlin, Pamela L.; Diener‐West, Marie; Rubenstein, Ronald C.; Boyle, Michael; Lee, Carlton K. K.; Brass-Ernst, Lois

doi:10.1006/mthe.2002.0639

Cited by 177 publications

(133 citation statements)

References 24 publications

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“…31 4-PBA has been demonstrated to reduce the load of mutant or mislocated proteins retained in the ER under conditions associated with cystic fibrosis and liver injury. 25 It is also reported that 4-PBA has a neuroprotective effect on cerebral ischemic injury in a mouse model of ischemia/hypoxia. 27 In the present study, we showed that 4-PBA attenuated hypoxiainduced apoptosis in BSMCs.…”

Section: Discussionmentioning

confidence: 96%

“…A previous report showed that 4-PBA facilitates normal trafficking of mutant proteins from the ER to the plasma membrane. 25 Other reports also showed that 4-PBA has chemical chaperone activity and protects the brain against ischemic injury and ER stress-induced neuronal death in vivo and in vitro. 26,27 Using 4-PBA, we first examined whether ER stress triggered by tunicamycin and thapsigargin, known inducers of ER stress, is attenuated by 4-PBA in BSMCs.…”

Section: Attenuation Of Hypoxia-induced Apoptosis In Vitro and Boo-inmentioning

confidence: 97%

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Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder

Sawada

Yao

Hiramatsu

et al. 2008

Laboratory Investigation

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In bladder outlet obstruction (BOO), mechanical stress and ischemia/hypoxia are implicated in structural and functional alterations of the urinary bladder. Because mechanical stress and hypoxia may trigger endoplasmic reticulum (ER) stress, we examined involvement of ER stress in the damage of the bladder caused by BOO. An experimental model of BOO was established in rats by complete ligature of the urethra for 24 h, and bladders were subjected to northern blot analysis and assessment of apoptosis. Isolated urinary bladders and bladder-derived smooth muscle cells (BSMCs) were also exposed to mechanical strain and hypoxia and used for analyses. To examine involvement of ER stress in the damage of the bladder, the effects of a chemical chaperone 4-phenylbutyrate (4-PBA) were evaluated in vitro and in vivo. Outlet obstruction for 24 h induced expression of ER stress markers, GRP78 and CCAAT/enhancer-binding protein-homologous protein (CHOP), in the bladder. It was associated with induction of markers for mechanical stress (cyclooxygenases 2) and hypoxia (vascular endothelial growth factor and glyceraldehyde-3-phosphate dehydrogenase). When isolated bladders and BSMCs were subjected to mechanical strain, induction of GRP78 and CHOP was not observed. In contrast, when BSMCs were exposed to hypoxic stress caused by CoCl 2 or thenoyltrifluoroacetone (TTFA), substantial upregulation of GRP78 and CHOP was observed, suggesting involvement of hypoxia in the induction of ER stress. In the bladder subjected to BOO, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells increased in the epithelial cells and BSMCs. Similarly, treatment with TTFA or CoCl 2 induced apoptosis of BSMCs, and 4-PBA significantly attenuated ER stress and apoptosis triggered by these agents. Furthermore, in vivo administration with 4-PBA significantly reduced apoptosis in the bladder subjected to BOO. These results suggested that outlet obstruction caused ER stress via hypoxic stress in the bladder and that hypoxia-triggered ER stress may be involved in the induction of apoptosis in BOO.

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Section: Discussionmentioning

confidence: 96%

Section: Attenuation Of Hypoxia-induced Apoptosis In Vitro and Boo-inmentioning

confidence: 97%

Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder

Sawada

Yao

Hiramatsu

et al. 2008

Laboratory Investigation

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“…Butyrate nonspecifically improves ΔF508 CFTR protein expression and function but also promotes expression of many other proteins in the cell. This has led to the development of orally bioavailable sodium 4-phenylbutyrate, which demonstrated borderline promising results in a pilot study involving patients homozygous for ΔF508 CFTR [93]. However, these improvements were not augmented with dose escalation and led to unacceptable adverse effects [93].…”

Section: Restoration Of Cftr Expression or Functionmentioning

confidence: 99%

“…This has led to the development of orally bioavailable sodium 4-phenylbutyrate, which demonstrated borderline promising results in a pilot study involving patients homozygous for ΔF508 CFTR [93]. However, these improvements were not augmented with dose escalation and led to unacceptable adverse effects [93]. A phase II clinical trial is underway in CF patients harboring the G551D CFTR allele, which produces a poorly functional CFTR protein in the cell membrane.…”

Section: Restoration Of Cftr Expression or Functionmentioning

confidence: 99%

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Campodónico

Gadjeva

Paradis-Bleau

et al. 2008

Trends in Molecular Medicine

100

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Defective expression or function of the cystic fibrosis transmembrane conductance regulator (CFTR) underlies the hypersusceptibility of cystic fibrosis (CF) patients to chronic airway infections, particularly with Pseudomonas aeruginosa. CFTR is involved in the specific recognition of P. aeruginosa, thereby contributing to effective innate immunity and proper hydration of the airway surface layer (ASL). In CF, the airway epithelium fails to initiate an appropriate innate immune response, allowing the microbe to bind to mucus plugs that are then not properly cleared because of the dehydrated ASL. Recent studies have identified numerous CFTR-dependent factors that are recruited to the epithelial plasma membrane in response to infection and that are needed for bacterial clearance, a process that is defective in CF patients hypersusceptible to infection with this organism. Pseudomonas aeruginosa in cystic fibrosisCystic fibrosis (CF) is unique among human genetic disorders in that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a protein whose primary function described to date has been to regulate conductance of ions in and out of cells and intracellular vacuoles, lead to hypersusceptibility to chronic lung infection. Human diseases wherein individuals homozygous for mutant genes are predisposed to infections serve as a firm foundation for understanding the molecular, cellular, physiologic and immunologic aspects of normal and compromised resistance to infection. CF is not just a prime example of how we can learn about normal and pathologic states; it could, in fact, be the only known human genetically determined disease wherein infection with a single pathogen -Pseudomonas aeruginosa -drives the vast majority of morbidity, clinical deterioration and ultimately life-shortening mortality encountered in this disease. In humans with significant compromises to their immune system, such as advanced AIDS, we would normally expect to see a plethora of pathogens take advantage of this debilitated state, but this is not the case in CF.CF is characterized by the emergence and persistence of (and, ultimately, the inability to clear) chronic infection with a variant of P. aeruginosa (mucoid P. aeruginosa) that overproduces a surface polysaccharide known as alginate. The organism undergoes other significant genetic adaptations and selections within the CF lung, and it is the emergence of mucoid P. aeruginosa that is the primary determinant of the clinical course of this disease [1,2]. In those individuals with either an uncommon but fortuitous protective immune response to specific P. aeruginosa antigens [3,4] Histopathologic basis for defining relevant interactions between P.aeruginosa and the CF airway epitheliumAlthough CF is a multisystem disease characterized by GI and nutritional abnormalities, salt loss syndromes and male urogenital abnormalities, the major clinical problem for CF patients is chronic sinopulmonary disease. Therefore, relying on observations made fr...

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“…We have studied potential transnitrosation targets in the CFTR interactome (3,22) of relevance to CFTR trafficking. Here, we report that GSNO S-nitrosylates heat shock protein (Hsp)70/ Hsp90 organizing protein (Hop)-also known as stress-induced phosphoprotein 1 (Stip-1) (23)-decreasing Hop expression and decreasing the association between Hop and maturing CFTR.…”

mentioning

confidence: 99%

Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy

Marozkina¹,

Yemen²,

Borowitz³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The endogenous signaling molecule S-nitrosoglutathione (GSNO) and other S-nitrosylating agents can cause full maturation of the abnormal gene product ΔF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR). However, the molecular mechanism of action is not known. Here we show that Hsp70/Hsp90 organizing protein (Hop) is a critical target of GSNO, and its S-nitrosylation results in ΔF508 CFTR maturation and cell surface expression. S-nitrosylation by GSNO inhibited the association of Hop with CFTR in the endoplasmic reticulum. This effect was necessary and sufficient to mediate GSNO-induced cell-surface expression of ΔF508 CFTR. Hop knockdown using siRNA recapitulated the effect of GSNO on ΔF508 CFTR maturation and expression. Moreover, GSNO acted additively with decreased temperature, which promoted mutant CFTR maturation through a Hop-independent mechanism. We conclude that GSNO corrects ΔF508 CFTR trafficking by inhibiting Hop expression, and that combination therapiesusing differing mechanisms of action-may have additive benefits in treating CF.cystic fibrosis transmembrane conductance regulator | S-nitrosoglutathione corrector | treatment

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Evidence of CFTR Function in Cystic Fibrosis after Systemic Administration of 4-Phenylbutyrate

Cited by 177 publications

References 24 publications

Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder

Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy

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