Differential effects of simvastatin on IL-13-induced cytokine gene expression in primary mouse tracheal epithelial cellsRespiratory Research - Tập 13 - Trang 1-9 - 2012
Amir A Zeki, Phil Thai, Nicholas J Kenyon, Reen Wu
Asthma causes significant morbidity worldwide in adults and children alike, and incurs large healthcare costs. The statin drugs, which treat hyperlipidemia and cardiovascular diseases, have pleiotropic effects beyond lowering cholesterol, including immunomodulatory, anti-inflammatory, and anti-fibrotic properties which may benefit lung health. Using an allergic mouse model of asthma, we previously demonstrated a benefit of statins in reducing peribronchiolar eosinophilic inflammation, airway hyperreactivity, goblet cell hyperplasia, and lung IL-4 and IL-13 production. In this study, we evaluated whether simvastatin inhibits IL-13-induced pro-inflammatory gene expression of asthma-related cytokines in well-differentiated primary mouse tracheal epithelial (MTE) cell cultures. We hypothesized that simvastatin reduces the expression of IL-13-inducible genes in MTE cells. We harvested tracheal epithelial cells from naïve BALB/c mice, grew them under air-liquid interface (ALI) cell culture conditions, then assessed IL-13-induced gene expression in MTE cells using a quantitative real-time PCR mouse gene array kit. We found that simvastatin had differential effects on IL-13-mediated gene expression (inhibited eotaxin-1; MCP-1,-2,-3; and osteopontin (SPP1), while it induced caspase-1 and CCL20 (MIP-3α)) in MTE cells. For other asthma-relevant genes such as TNF, IL-4, IL-10, CCL12 (MCP-5), CCL5 (RANTES), and CCR3, there were no significant IL-13-inducible or statin effects on gene expression. Simvastatin modulates the gene expression of selected IL-13-inducible pro-inflammatory cytokines and chemokines in primary mouse tracheal epithelial cells. The airway epithelium may be a viable target tissue for the statin drugs. Further research is needed to assess the mechanisms of how statins modulate epithelial gene expression.
Analysis of body mass index, weight loss and progression of idiopathic pulmonary fibrosisRespiratory Research - Tập 21 - Trang 1-11 - 2020
Stéphane Jouneau, Bruno Crestani, Ronan Thibault, Mathieu Lederlin, Laurent Vernhet, Claudia Valenzuela, Marlies Wijsenbeek, Michael Kreuter, Wibke Stansen, Manuel Quaresma, Vincent Cottin
Nintedanib is an approved therapy for idiopathic pulmonary fibrosis (IPF). Some patients treated with nintedanib experience weight loss. Exploratory data suggest that low body mass index or weight loss are associated with worse outcomes in patients with IPF. We investigated whether BMI at baseline or weight loss over 52 weeks was associated with FVC decline, or influenced the effect of nintedanib, in patients with IPF. Using pooled data from the two INPULSIS trials, we analysed the rate of decline in FVC (mL/yr) over 52 weeks in patients treated with nintedanib and placebo in subgroups by baseline BMI (< 25; ≥25 to < 30; ≥30 kg/m2) and by weight loss over 52 weeks (≤5; > 5%) using random coefficient regression. In the placebo group, the mean rate of FVC decline over 52 weeks was numerically greater in patients with lower baseline BMI (− 283.3 [SE 22.4], − 207.9 [20.9] and − 104.5 [21.4] in patients with BMI < 25 kg/m2, ≥25 to < 30 kg/m2 and ≥ 30 kg/m2, respectively). Nintedanib reduced the rate of FVC decline versus placebo in all subgroups by BMI, with a consistent treatment effect across subgroups (interaction p = 0.31). In the placebo group, the mean rate of FVC decline was numerically greater in patients with > 5% than ≤5% weight loss over 52 weeks (− 312.7 [SE 32.2] versus − 199.5 [SE 14.4] mL/year). Nintedanib reduced the rate of FVC decline versus placebo in both subgroups by weight loss, with a greater treatment effect in patients with > 5% weight loss (interaction p = 0.0008). The adverse event profile of nintedanib was similar across subgroups. In patients with IPF, lower BMI and weight loss may be associated with faster decline in FVC. Nintedanib reduces the rate of FVC decline both in patients who lose weight on treatment and those who do not.
ClinicalTrials.gov
; Nos.
NCT01335464
and
NCT01335477
; URL:
www.clinicaltrials.gov
.
Long-acting antimuscarinic therapy in patients with chronic obstructive pulmonary disease receiving beta-blockersRespiratory Research - Tập 22 - Trang 1-10 - 2021
Kenneth R. Chapman, Robert A. Wise, Benjamin M. Scirica, Deepak L. Bhatt, Sami Z. Daoud, Dan Lythgoe, Esther Garcia Gil
Beta-blocker therapies for cardiovascular comorbidities are often withheld in patients with chronic obstructive pulmonary disease (COPD) due to potential adverse effects on airway obstruction. We carried out a post hoc analysis to determine the efficacy and safety of aclidinium in patients with moderate-to-very severe COPD and increased cardiovascular risk receiving beta-blockers at baseline versus non-users. ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients were randomized 1:1 to aclidinium or placebo twice-daily for up to 3 years. Outcomes included risk of (time to first) major adverse cardiovascular events (MACE), all-cause mortality, and lung function over 3 years, and exacerbations over 1 year. Of 3589 patients, 1269 (35.4%) used beta-blockers and 2320 (64.6%) were non-users at baseline. Aclidinium did not statistically increase the risk of MACE (beta-blocker user: hazard ratio 1.01 [95% CI 0.62–1.64]; non-user: 0.80 [0.51–1.24]; interaction P = 0.48) or all-cause mortality (beta-blocker user: 1.13 [0.78–1.64]; non-user: 0.89 [0.62–1.26]; interaction P = 0.35), in patients using beta-blockers. Aclidinium reduced annualized rate of moderate-to-severe COPD exacerbation (beta-blocker user: rate ratio 0.75 [95% CI 0.60–0.94, P = 0.013]; non-user: 0.79 [0.67–0.93, P = 0.005]), delayed time to first exacerbation, and improved lung function versus placebo. There was greater trough FEV1 benefit in beta-blocker users versus non-users (least squares mean difference at 52 weeks: 111 mL [95% CI 74 mL–147 mL] versus 69 mL [42 mL–97 mL]; interaction P = 0.041). This post hoc analysis supports long-acting anti-muscarinic use with concomitant beta-blockers in patients with moderate-to-very severe COPD and cardiovascular comorbidity. Trial registration: ClinicalTrials.gov, NCT01966107, Registered 16 October 2013,
https://clinicaltrials.gov/ct2/show/NCT01966107
.
Impact of chronic obstructive pulmonary disease on short-term outcome in patients with ST-elevation myocardial infarction during COVID-19 pandemic: insights from the international multicenter ISACS-STEMI registryRespiratory Research - Tập 23 - Trang 1-9 - 2022
Giuseppe De Luca, Matteo Nardin, Magdy Algowhary, Berat Uguz, Dinaldo C. Oliveira, Vladimir Ganyukov, Zan Zimbakov, Miha Cercek, Lisette Okkels Jensen, Poay Huan Loh, Lucian Calmac, Gerard Roura Ferrer, Alexandre Quadros, Marek Milewski, Fortunato Scotto di Uccio, Clemens von Birgelen, Francesco Versaci, Jurrien Ten Berg, Gianni Casella, Aaron Wong Sung Lung, Petr Kala, José Luis Díez Gil, Xavier Carrillo, Maurits Dirksen, Victor M. Becerra-Munoz, Michael Kang-yin Lee, Dafsah Arifa Juzar, Rodrigo de Moura Joaquim, Roberto Paladino, Davor Milicic, Periklis Davlouros, Nikola Bakraceski, Filippo Zilio, Luca Donazzan, Adriaan Kraaijeveld, Gennaro Galasso, Arpad Lux, Lucia Marinucci, Vincenzo Guiducci, Maurizio Menichelli, Alessandra Scoccia, Aylin Hatice Yamac, Kadir Ugur Mert, Xacobe Flores Rios, Tomas Kovarnik, Michal Kidawa, Josè Moreu, Vincent Flavien, Enrico Fabris, Iñigo Lozano Martínez-Luengas, Marco Boccalatte, Francisco Bosa Ojeda, Carlos Arellano-Serrano, Gianluca Caiazzo, Giuseppe Cirrincione, Hsien-Li Kao, Juan Sanchis Forés, Luigi Vignali, Helder Pereira, Stephane Manzo, Santiago Ordoñez, Alev Arat Özkan, Bruno Scheller, Heidi Lehtola, Rui Teles, Christos Mantis, Ylitalo Antti, João A. Brum Silveira, Rodrigo Zoni, Ivan Bessonov, Stefano Savonitto, George Kochiadakis, Dimitrios Alexopoulos, Carlos E. Uribe, John Kanakakis, Benjamin Faurie, Gabriele Gabrielli, Alejandro Gutierrez Barrios, Juan Pablo Bachini, Alex Rocha, Frankie Chor-Cheung Tam, Alfredo Rodriguez, Antonia Anna Lukito, Veauthyelau Saint-Joy, Gustavo Pessah, Andrea Tuccillo, Giuliana Cortese, Guido Parodi, Mohamed Abed Bouraghda, Elvin Kedhi, Pablo Lamelas, Harry Suryapranata, Monica Verdoia
Chronic obstructive pulmonary disease (COPD) is projected to become the third cause of mortality worldwide. COPD shares several pathophysiological mechanisms with cardiovascular disease, especially atherosclerosis. However, no definite answers are available on the prognostic role of COPD in the setting of ST elevation myocardial infarction (STEMI), especially during COVID-19 pandemic, among patients undergoing primary angioplasty, that is therefore the aim of the current study. In the ISACS-STEMI COVID-19 registry we included retrospectively patients with STEMI treated with primary percutaneous coronary intervention (PCI) between March and June of 2019 and 2020 from 109 high-volume primary PCI centers in 4 continents. A total of 15,686 patients were included in this analysis. Of them, 810 (5.2%) subjects had a COPD diagnosis. They were more often elderly and with a more pronounced cardiovascular risk profile. No preminent procedural dissimilarities were noticed except for a lower proportion of dual antiplatelet therapy at discharge among COPD patients (98.9% vs. 98.1%, P = 0.038). With regards to short-term fatal outcomes, both in-hospital and 30-days mortality occurred more frequently among COPD patients, similarly in pre-COVID-19 and COVID-19 era. However, after adjustment for main baseline differences, COPD did not result as independent predictor for in-hospital death (adjusted OR [95% CI] = 0.913[0.658–1.266], P = 0.585) nor for 30-days mortality (adjusted OR [95% CI] = 0.850 [0.620–1.164], P = 0.310). No significant differences were detected in terms of SARS-CoV-2 positivity between the two groups. This is one of the largest studies investigating characteristics and outcome of COPD patients with STEMI undergoing primary angioplasty, especially during COVID pandemic. COPD was associated with significantly higher rates of in-hospital and 30-days mortality. However, this association disappeared after adjustment for baseline characteristics. Furthermore, COPD did not significantly affect SARS-CoV-2 positivity. Trial registration number: NCT 04412655 (2nd June 2020).