State of the Art Review: Glucagon-Like Peptide-1 in Obesity-Related Asthma

Lung · 2025-12-01

Inhaled pitavastatin reduces airway hyperresponsiveness and air trapping: implications for the treatment of asthma and COPD

2025-09-27

<bold>Background:</bold> Deep inspiration (DI) helps prevent air trapping, but its bronchodilatory effect is impaired in asthma. We previously showed that salbutamol reduces airway resistance, elastance, and air trapping in ex vivo sheep lungs. This study evaluates the potential of pitavastatin in a large animal model. <bold>Methods:</bold> Ex vivo sheep lungs were ventilated at frequencies of 0.25 and 2 Hz with a transpulmonary pressure of 7.5 cmH₂O. Lung resistance, elastance, and estimated lung volume (based on lateral lung profile) were measured under a small tidal volume (120 mL). Nebulized aerosol pitavastatin (100 μM or 9 mM) was continuously administered via the trachea for approximately 75 minutes with a total solution volume of 15–20 mL. Previously reported salbutamol data (10.4 mM) were used for comparison. Air trapping was induced by 30 minutes of continuous small-tidal-volume ventilation at 0.25 Hz and 7.5 cmH₂O transpulmonary pressure without DI. <bold>Results:</bold> Both salbutamol and pitavastatin significantly reduced relative lung volume after air trapping induction compared with their respective vehicle controls (mean ± SD). Salbutamol reduced lung volume from 200.5 ± 46.4% (vehicle) to 137.2 ± 20.3%. Pitavastatin reduced lung volume to 143.1 ± 29.8% (100 μM) and 131.9 ± 18.4% (9 mM), compared with 189.3 ± 28.5% (vehicle). Both treatments also significantly and independently decreased lung resistance and elastance after 30 minutes of ventilation. <bold>Conclusion:</bold> Inhaled pitavastatin effectively prevents air trapping and reduces lung resistance and elastance. These findings suggest that pitavastatin could serve as a novel inhaled therapy for bronchoconstrictive conditions such as asthma and COPD.

Treating asthma in the time of COVID

UNC Libraries · 2025-04-29

Investigating Asthma After Coccidioidomycosis Among Patients With Commercial Health Insurance, United States, 2017–2022

Mycoses · 2025-02-01 · 2 citations

ABSTRACT Background The relationship between asthma and coccidioidomycosis has not been fully described. We have hypothesised that Coccidioides could trigger inflammatory airway responses, similar to other fungi. Objectives: To estimate the frequency of new‐onset asthma‐related symptoms after coccidioidomycosis and identify potentially associated factors. Patients/Methods We used a large health insurance claims database to identify patients with coccidiomycosis with and without an asthma diagnosis code or a short‐acting β 2 agonist prescription in the year after diagnosis. Results Thirteen per cent of 1657 patients with an asthma diagnosis code or a short‐acting β 2 agonist prescription (median 2.5 months later). Conclusions Increased healthcare provider awareness of asthma as a potential coccidioidomycosis complication could benefit patients, especially female patients and patients with severe pulmonary infection.

Low TET1 Expression Levels in COPD Are Associated With High Numbers of Neutrophils and Surfactant Protein Serum Leakage

American Journal of Respiratory and Critical Care Medicine · 2025-05-01

Abstract Rationale: Emerging evidence supports that epigenetic dysregulation, specifically variations in DNA methylation, is implicated in chronic obstructive pulmonary disease (COPD). Genes related to oxidative stress, mucus production, and epithelial barrier integrity are under strong epigenetic control. Ten-eleven translocation (TET) proteins, known to catalyze the hydroxylation of 5-methylcytosine to 5-hydroxymethylcytosine, may play a significant role but their specific functions in COPD remain underexplored. We aimed to examine the relationship between TET gene expression and COPD clinical phenotypes, with a focus on inflammatory parameters. Methods: RNA-seq data from peripheral blood samples of former smoker COPD patients (n=17; 63-76 yrs old; 40% female) and healthy controls (n=15; 37-43 yrs old, 50% female) was evaluated. Correlations between TET1, TET2, and TET3 expression and immune cell counts, lung function, and COPD severity markers were assessed. Logistic regression and causal inference analyses were used to explore potential associations of TET1 with COPD. Results: TET1 expression was significantly downregulated in peripheral blood mononuclear cells of COPD patients. TET1 showed significant negative correlations with neutrophil counts in sputum and blood as well as with serum SP-D levels, a biomarker linked to COPD severity. Logistic regression indicated that higher TET1 expression was associated with reduced odds of COPD (OR=0.5201). In contrast, blood TET2 and TET3 were positively associated with neutrophil levels, and TET2 was inversely correlated with lung function (FEV1/FVC ratio). Causal inference analysis suggested that TET1's protective effect might be mediated through regulation of neutrophil levels. Conclusion: Our findings highlight a potential protective role for TET1 in COPD through the regulation of neutrophil counts, and serum SP-D, key indicators of airway inflammation severity. TET2 and TET3 on the other hand, were positively associated with inflammatory markers and negatively associated with lung function in COPD. This study suggests that members of the TET family may differentially regulate airway inflammation and may serve as novel epigenetic therapeutic targets in COPD.

Low TET1 Expression Levels in COPD Are Associated with Airway and Blood Neutrophilia

medRxiv · 2025-04-16

Epigenetic dysregulation, particularly DNA methylation variations, is implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Ten-eleven translocation (TET) proteins (TET1, TET2, and TET3) regulate DNA methylation and gene transcription. Impaired TET1 expression was previously associated with airway inflammation and asthma. Here we investigated TET gene associations with COPD severity. We found that reduced TET1 expression in peripheral blood mononuclear cells was associated with higher sputum and blood neutrophil counts, decreased lung function and increased disease severity in patients. These findings support a potential protective role and warrant further mechanistic investigations into the actions of TET1 in COPD.

The Acute Force Relaxation Effect of Pitavastatin Depends on Cofilin's Rapid Disassembly of F-actin in Human Airway Smooth Muscle

American Journal of Respiratory and Critical Care Medicine · 2025-05-01

Abstract RATIONALE: The 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitor, Pitavastatin, can attenuate ASM contraction within hours via mevalonate (MA)- and geranylgeranyl pyrophosphate (GGPP)-dependent changes in the airway smooth muscle (ASM). Pitavastatin also inhibits ASM contraction within minutes by a MA-independent, filamentous (F)-actin disassembly-dependent mechanism. We now test the hypothesis that this rapid F-actin disassembly depends on cofilin activation. METHODS: Immortalized non-asthmatic human ASM cells were grown to confluence in 10% serum-containing F12 medium, serum-deprived (but insulin-transferrin-selenium (ITS)-supplemented) for an additional 48 hours. We quantified ASM contractile forces using traction force microscopy (TFM). Cells were treated with histamine (1 or 10 uM, 30 minutes) followed by Pitavastatin treatment (100 µM, 10-30 minutes), or no treatment (NT). We then measured Pitavastatin-induced ASM relaxation using TFM with and without the F-actin-stabilizing drug Jasplakinolide (Jasp, 0.1-0.3 µM, 15-30 minutes). We also conducted siRNA knockdown experiments of cofilin and co-treated with and without Pitavastatin (100 µM, 30 minutes). We measured F-actin, G-actin, F/G-actin ratios, phospho-MLC-2, and phospho-cofilin by Western blot using cytochalasin-D and latrunculin as positive controls for F-actin disassembly. We also validated the translational potential of these changes ex vivo in methacholine (MCh)-treated (MCh 10 uM, 30 min) mouse precision-cut lung slices (PCLS) to assess drug efficacy and pharmacokinetic effects. RESULTS: Pitavastatin acutely (within 10-30 minutes), dose-dependently, non-toxically, and significantly reduced histamine-induced ASM contractile force (by 60-90%) as compared to NT or drug vehicle. These relaxation effects were MA-independent and attenuated by Jasp co-treatment, the F-actin stabilizing drug. The knockdown of cofilin completely blocked Pitavastatin's ability to relax ASM over 20 min. Pitavastatin also led to a significant reduction in F-actin while increasing soluble G-actin, thereby significantly reducing the F/G ratio by 44-50% ([asterisk]p&amp;lt;0.05). MLC-2 phosphorylation was similarly significantly reduced by ∼31-33% ([asterisk]p&amp;lt;0.05). This F-actin statin effect was comparable to positive controls latrunculin and cytochalasin-D. In mouse PCLS, Pitavastatin caused rapid onset bronchodilation (25-50% within 5-10 min), with a similar duration of action. Repeated dosing of MCh had no additional bronchoconstricting effects during Pitavastatin treatment. CONCLUSIONS: A dominant mechanism for the acute force relaxation effects of Pitavastatin is due to cofilin-dependent rapid F-actin disassembly. This mechanism likely explains Pitavastatin's acute bronchodilatory effects and its ability to prevent MCh-induced bronchoconstriction. This unique mechanism of action provides a new class of likely inhaled drug therapies for the treatment of bronchoconstriction in obstructive airway diseases. FUNDING: NIH R01HL148715 (A.A.Z., R.K.) supported this study.

Supplementary Table S1 from Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models

2024-05-02

&lt;p&gt;Supplementary Table S1&lt;/p&gt;

Supplementary Fig S4 from Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models

2024-05-02

&lt;p&gt;Supplemental Fig S4&lt;/p&gt;

Supplementary Fig S3 from Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models

2024-05-02

&lt;p&gt;Supplemental Fig S3&lt;/p&gt;