Cyclic nucleotide phosphodiesterase inhibitors as therapeutic interventions for cystic fibrosis

Turner, Mark J.; Abbott-Banner, Kathy; Thomas, David Y.; Hanrahan, John W.

doi:10.1016/j.pharmthera.2021.107826

Cited by 14 publications

(13 citation statements)

References 202 publications

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“…In addition, embryonic stem cells-derived AT2 cells also express Cftr [ 58 ]. Persistent loss of this cluster, and thus Cftr expression with hyperoxia would bode poorly for maintenance of normal lung fluid balance and bacterial clearance even in adulthood, which could contribute to sustained tissue damage [ 59 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomics reveals lasting changes in the lung cellular landscape into adulthood after neonatal hyperoxic exposure

et al. 2021

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Ventilatory support, such as supplemental oxygen, used to save premature infants impairs the growth of the pulmonary microvasculature and distal alveoli, leading to bronchopulmonary dysplasia (BPD). Although lung cellular composition changes with exposure to hyperoxia in neonatal mice, most human BPD survivors are weaned off oxygen within the first weeks to months of life, yet they may have persistent lung injury and pulmonary dysfunction as adults. We hypothesized that early-life hyperoxia alters the cellular landscape in later life and predicts long-term lung injury. Using single-cell RNA sequencing, we mapped lung cell subpopulations at postnatal day (pnd)7 and pnd60 in mice exposed to hyperoxia (95% O 2 ) for 3 days as neonates. We interrogated over 10,000 cells and identified a total of 45 clusters within 32 cell states. Neonatal hyperoxia caused persistent compositional changes in later life (pnd60) in all five type II cell states with unique signatures and function. Premature infants requiring mechanical ventilation with different durations also showed similar alterations in these unique signatures of type II cell states. Pathologically, neonatal hyperoxic exposure caused alveolar simplification in adult mice. We conclude that neonatal hyperoxia alters the lung cellular landscape in later life, uncovering neonatal programing of adult lung dysfunction.

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Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomics reveals lasting changes in the lung cellular landscape into adulthood after neonatal hyperoxic exposure

et al. 2021

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“…Another effect of targeting PDE4 is the cAMP/PKA-dependent gating of the CFTR channel, increasing airway surface liquid and facilitating mucus clearance ( 27 ). CFTR functional defects and mucus stasis can be observed in patients with COPD and certain forms of asthma ( 28 ) but are critical in CF ( 2 ).…”

Section: Discussionmentioning

confidence: 99%

A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases

et al. 2022

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Cyclic adenosine 3′,5′-monophosphate (cAMP)–elevating agents, such as β 2 -adrenergic receptor (β 2 -AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by β 2 -ARs in airway structural and inflammatory cells. Displacement of the PI3Kγ-anchored pool of protein kinase A (PKA) by an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited a pool of subcortical PDE4B and PDE4D and safely increased cAMP in the lungs, leading to airway smooth muscle relaxation and reduced neutrophil infiltration in a murine model of asthma. In human bronchial epithelial cells, PI3Kγ MP induced unexpected cAMP and PKA elevations restricted to the vicinity of the cystic fibrosis transmembrane conductance regulator (CFTR), the ion channel controlling mucus hydration that is mutated in cystic fibrosis (CF). PI3Kγ MP promoted the phosphorylation of wild-type CFTR on serine-737, triggering channel gating, and rescued the function of F508del-CFTR, the most prevalent CF mutant, by enhancing the effects of existing CFTR modulators. These results unveil PI3Kγ as the regulator of a β 2 -AR/cAMP microdomain central to smooth muscle contraction, immune cell activation, and epithelial fluid secretion in the airways, suggesting the use of a PI3Kγ MP for compartment-restricted, therapeutic cAMP elevation in chronic obstructive respiratory diseases.

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“…PDE1C inhibition with IBMX (that inhibits all PDEs except PDE8) and PF-04957325 (PDE8 inhibitor) further increased I sc compared to inhibition using IBMX alone, suggesting that CFTR activity is modulated by different PDEs in different cell-types. In fact, other PDE family members, such as PDE3, 4 (see above) and 5, have already been implicated in CFTR regulation and the use of PDE inhibitors has already been proposed as a potential therapy for CF ( Turner et al, 2021 ).…”

Section: Cell Type-specific Regulation Of Cftrmentioning

confidence: 99%

Cell type-specific regulation of CFTR trafficking—on the verge of progress

Farinha,

Santos,

Ferreira

2024

Front. Cell Dev. Biol.

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Trafficking of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is a complex process that starts with its biosynthesis and folding in the endoplasmic reticulum. Exit from the endoplasmic reticulum (ER) is coupled with the acquisition of a compact structure that can be processed and traffic through the secretory pathway. Once reaching its final destination—the plasma membrane, CFTR stability is regulated through interaction with multiple protein partners that are involved in its post-translation modification, connecting the channel to several signaling pathways. The complexity of the process is further boosted when analyzed in the context of the airway epithelium. Recent advances have characterized in detail the different cell types that compose the surface epithelium and shifted the paradigm on which cells express CFTR and on their individual and combined contribution to the total expression (and function) of this chloride/bicarbonate channel. Here we review CFTR trafficking and its relationship with the knowledge on the different cell types of the airway epithelia. We explore the crosstalk between these two areas and discuss what is still to be clarified and how this can be used to develop more targeted therapies for CF.

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Cyclic nucleotide phosphodiesterase inhibitors as therapeutic interventions for cystic fibrosis

Cited by 14 publications

References 202 publications

Single-cell transcriptomics reveals lasting changes in the lung cellular landscape into adulthood after neonatal hyperoxic exposure

Single-cell transcriptomics reveals lasting changes in the lung cellular landscape into adulthood after neonatal hyperoxic exposure

A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases

Cell type-specific regulation of CFTR trafficking—on the verge of progress

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