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1.
Sci Rep ; 13(1): 12272, 2023 07 28.
Article in English | MEDLINE | ID: mdl-37507487

ABSTRACT

Microtubule dysfunction has been implicated as a mediator of inflammation in multiple diseases such as disorders of the cardiovascular and neurologic systems. Tubulin polymerization promoting protein (Tppp) facilitates microtubule elongation and regulates tubulin acetylation through inhibition of cytosolic deacetylase enzymes. Pathologic alterations in microtubule structure and dynamics have been described in cystic fibrosis (CF) and associated with inflammation, however the causality and mechanism remain unclear. Likewise, Tppp has been identified as a potential modifier of CF airway disease severity. Here we directly assess the impact of microtubule dysfunction on infection and inflammation by interrogating wild type and a Tppp knockout mouse model (Tppp - / -). Mice are challenged with a clinical isolate of Pseudomonas aeruginosa-laden agarose beads and assessed for bacterial clearance and inflammatory markers. Tppp - / - mouse model demonstrate impaired bacterial clearance and an elevated inflammatory response compared to control mice. These data are consistent with the hypothesis microtubule dysregulation is sufficient to lead to CF-like airway responses in mice.


Subject(s)
Cystic Fibrosis , Nerve Tissue Proteins , Tubulin , Animals , Mice , Cystic Fibrosis/metabolism , Microtubules/metabolism , Nerve Tissue Proteins/metabolism , Polymerization , Tubulin/metabolism
4.
Am J Physiol Lung Cell Mol Physiol ; 311(2): L317-27, 2016 08 01.
Article in English | MEDLINE | ID: mdl-27317686

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.


Subject(s)
Cyclooxygenase Inhibitors/pharmacology , Cystic Fibrosis/drug therapy , Epithelial Cells/metabolism , Ibuprofen/pharmacology , Microtubules/metabolism , Acetylation , Adenylate Kinase , Cell Line , Cystic Fibrosis/pathology , Drug Evaluation, Preclinical , Enzyme Activation , Epithelial Cells/drug effects , Guanine Nucleotide Exchange Factors/metabolism , Humans , Primary Cell Culture , Protein Multimerization , Protein Processing, Post-Translational , Shelterin Complex , Telomere-Binding Proteins/metabolism
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