The effect of long-term doxycycline treatment in a mouse model of cigarette smoke-induced emphysema and pulmonary hypertension

2021 ◽  
Author(s):  
Stefan Hadzic ◽  
Cheng-Yu Wu ◽  
Marija Gredic ◽  
Baktybek Kojonazarov ◽  
Oleg Pak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pulmonary Hypertension ◽  
Mouse Model ◽  
Transgenic Animal ◽  
Airflow Limitation ◽  
Chronic Obstructive ◽  
Preclinical Research ◽  
Doxycycline Treatment ◽  
Expression Modulation

Chronic obstructive pulmonary disease (COPD) is a major cause of death and a still incurable disease, comprising emphysema and chronic bronchitis. In addition to airflow limitation, COPD patients can suffer from pulmonary hypertension (PH). Doxycycline, an antibiotic from the tetracycline family, in addition to its pronounced antimicrobial activity, acts as a matrix metalloproteinase (MMP) inhibitor and has anti-inflammatory properties. Furthermore, doxycycline treatment exhibited a beneficial effect in several preclinical cardiovascular disease models. In preclinical research, doxycycline is frequently employed for gene expression modulation in Tet-On/Tet-Off transgenic animal models. Therefore, it is crucial to know whether doxycycline treatment in Tet-On/Tet-Off systems has effects independent of gene expression modulation by such systems. Against this background, we assessed the possible curative effects of long-term doxycycline administration in a mouse model of chronic CS exposure. Animals were exposed to CS for 8 months and then subsequently treated with doxycycline for additional 3 months in room-air conditions. Doxycycline decreased the expression of MMPs and general pro-inflammatory markers in the lungs from CS-exposed mice. This downregulation was, however, insufficient to ameliorate CS-induced emphysema or PH. Tet-On/Tet-Off induction by doxycycline in such models is a feasible genetic approach to study curative effects at least in established CS-induced emphysema and PH. However, we report several parameters that are influenced by doxycycline, and use of a Tet-On/Tet-Off system when evaluating those parameters should be interpreted with caution.

Lentivirus-Mediated Expression of Human Secreted Amyloid Precursor Protein-Alpha Promotes Long-Term Induction of Neuroprotective Genes and Pathways in a Mouse Model of Alzheimer’s Disease

2020 ◽  
pp. 1-16
Author(s):  
Margaret Ryan ◽  
Valerie T.Y. Tan ◽  
Nasya Thompson ◽  
Diane Guévremont ◽  
Bruce G. Mockett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Integrated Analysis ◽  
Empty Vector ◽  
Mouse Transcriptome

Background: Secreted amyloid precursor protein-alpha (sAPPα) can enhance memory and is neurotrophic and neuroprotective across a range of disease-associated insults, including amyloid-β toxicity. In a significant step toward validating sAPPα as a therapeutic for Alzheimer’s disease (AD), we demonstrated that long-term overexpression of human sAPPα (for 8 months) in a mouse model of amyloidosis (APP/PS1) could prevent the behavioral and electrophysiological deficits that develop in these mice. Objective: To explore the underlying molecular mechanisms responsible for the significant physiological and behavioral improvements observed in sAPPα-treated APP/PS1 mice. Methods: We assessed the long-term effects on the hippocampal transcriptome following continuous lentiviral delivery of sAPPα or empty-vector to male APP/PS1 mice and wild-type controls using Affymetrix Mouse Transcriptome Assays. Data analysis was carried out within the Affymetrix Transcriptome Analysis Console and an integrated analysis of the resulting transcriptomic data was performed with Ingenuity Pathway analysis (IPA). Results: Mouse transcriptome assays revealed expected AD-associated gene expression changes in empty-vector APP/PS1 mice, providing validation of the assays used for the analysis. By contrast, there were specific sAPPα-associated gene expression profiles which included increases in key neuroprotective genes such as Decorin, betaine-GABA transporter, and protocadherin beta-5, subsequently validated by qRT-PCR. An integrated biological pathways analysis highlighted regulation of GABA receptor signaling, cell survival, and inflammatory responses. Furthermore, upstream gene regulatory analysis implicated sAPPα activation of Interleukin-4, which can counteract inflammatory changes in AD. Conclusion: This study identified key molecular processes that likely underpin the long-term neuroprotective and therapeutic effects of increasing sAPPα levels in vivo

scholarly journals The neutrophil-mobilizing cytokine interleukin-26 in the airways of long-term tobacco smokers

2018 ◽  
Vol 132 (9) ◽  
pp. 959-983 ◽  
Author(s):  
Karlhans Fru Che ◽  
Ellen Tufvesson ◽  
Sara Tengvall ◽  
Elisa Lappi-Blanco ◽  
Riitta Kaarteenaho ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Bronchitis ◽  
Pathogenic Bacteria ◽  
Cell Model ◽  
Water Soluble ◽  
Chronic Obstructive ◽  
Neutrophil Accumulation

Long-term tobacco smokers with chronic obstructive pulmonary disease (COPD) or chronic bronchitis display an excessive accumulation of neutrophils in the airways; an inflammation that responds poorly to established therapy. Thus, there is a need to identify new molecular targets for the development of effective therapy. Here, we hypothesized that the neutrophil-mobilizing cytokine interleukin (IL)-26 (IL-26) is involved in airway inflammation amongst long-term tobacco smokers with or without COPD, chronic bronchitis or colonization by pathogenic bacteria. By analyzing bronchoalveolar lavage (BAL), bronchail wash (BW) and induced sputum (IS) samples, we found increased extracellular IL-26 protein in the airways of long-term smokers in vivo without further increase amongst those with clinically stable COPD. In human alveolar macrophages (AM) in vitro, the exposure to water-soluble tobacco smoke components (WTC) enhanced IL-26 gene and protein. In this cell model, the same exposure increased gene expression of the IL-26 receptor complex (IL10R2 and IL20R1) and nuclear factor κ B (NF-κB); a proven regulator of IL-26 production. In the same cell model, recombinant human IL-26 in vitro caused a concentration-dependent increase in the gene expression of NF-κB and several pro-inflammatory cytokines. In the long-term smokers, we also observed that extracellular IL-26 protein in BAL samples correlates with measures of lung function, tobacco load, and several markers of neutrophil accumulation. Extracellular IL-26 was further increased in long-term smokers with exacerbations of COPD (IS samples), with chronic bronchitis (BAL samples ) or with colonization by pathogenic bacteria (IS and BW samples). Thus, IL-26 in the airways emerges as a promising target for improving the understanding of the pathogenic mechanisms behind several pulmonary morbidities in long-term tobacco smokers.

scholarly journals Integrated Analysis of Prognostic Genes Associated With Ischemia–Reperfusion Injury in Renal Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Di Zhang ◽  
Yicun Wang ◽  
Song Zeng ◽  
Min Zhang ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Transplantation ◽  
Mouse Model ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Therapeutic Targets ◽  
Differentially Expressed ◽  
Novel Genes

BackgroundIschemia–reperfusion injury (IRI) remains an inevitable and major challenge in renal transplantation. The current study aims to obtain deep insights into underlying mechanisms and seek prognostic genes as potential therapeutic targets for renal IRI (RIRI).MethodsAfter systematically screening the Gene Expression Omnibus (GEO) database, we collected gene expression profiles of over 1,000 specimens from 11 independent cohorts. Differentially expressed genes (DEGs) were identified by comparing allograft kidney biopsies taken before and after reperfusion in the discovery cohort and further validated in another two independent transplant cohorts. Then, graft survival analysis and immune cell analysis of DEGs were performed in another independent renal transplant cohort with long-term follow-ups to further screen out prognostic genes. Cell type and time course analyses were performed for investigating the expression pattern of prognostic genes in more dimensions utilizing a mouse RIRI model. Finally, two novel genes firstly identified in RIRI were verified in the mouse model and comprehensively analyzed to investigate potential mechanisms.ResultsTwenty DEGs upregulated in the process of RIRI throughout different donor types (living donors, cardiac and brain death donors) were successfully identified and validated. Among them, upregulation of 10 genes was associated with poor long-term allograft outcomes and exhibited strong correlations with prognostic immune cells, like macrophages. Furthermore, certain genes were found to be only differentially expressed in specific cell types and remained with high expression levels even months after RIRI in the mouse model, which processed the potential to serve as therapeutic targets. Importantly, two newly identified genes in RIRI, Btg2 and Rhob, were successfully confirmed in the mouse model and found to have strong connections with NF-κB signaling.ConclusionsWe successfully identified and validated 10 IRI-associated prognostic genes in renal transplantation across different donor types, and two novel genes with crucial roles in RIRI were recognized for the first time. Our findings offered promising potential therapeutic targets for RIRI in renal transplantation.

scholarly journals Cardiovascular comorbidity in patients with chronic obstructive pulmonary disease: echocardiography changes and their relation to the level of airflow limitation

2019 ◽  
Vol 7 (21) ◽  
pp. 3568-3573
Author(s):  
Daniela Buklioska Ilievska ◽  
Jordan Minov ◽  
Nade Kochovska Kamchevska ◽  
Biljana Prgova Veljanova ◽  
Natasha Petkovikj ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Hypertension ◽  
Pulmonary Disease ◽  
Doppler Echocardiography ◽  
Mean Value ◽  
Airflow Limitation ◽  
Left Ventricular Ejection ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

Objective. To compare frequency of echocardiographic changes in patients with chronic obstructive pulmonary disease (COPD) and non-COPD controls and to assess their relation to the level of airflow limitation. Methods. Study population included 120 subjects divided in two groups. Group 1 included 60 patients with COPD (52 male and 8 female, aged 40 to 80 years) initially diagnosed according to the actual recommendations. Group 2 included 60 subjects in whom COPD was excluded serving as a control. The study protocol consisted of completion of a questionnaire , pulmonary evaluation (dyspnea severity assessment, baseline and post-bronchodilator spirometry, gas analyses, and chest X-ray) and two dimensional (2D) Doppler echocardiography. Results. We found significantly higher mean right ventricle end-diastolic dimension (RVEDd) in COPD patients as compared to its dimension in controls (28.0 ± 4.8 vs. 24.4 ± 4.3; P = 0.0000). Pulmonary hypertension (PH) was more frequent in COPD patients than in controls (28.0 ± 4.8 vs. 24.4 ± 4.3; P = 0.0000) showing linear relationship with severity of airflow limitation. The mean value of left ventricular ejection fraction (LVEF%) was significantly lower in COPD patients than its mean value in controls (57.4 ± 6.9% vs. 64.8 ± 2.7; P = 0.0000) with no correlation with severity of airflow limitation.       Conclusion. Frequency of echocardiographic changes in COPD patients was significantly higher as compared to their frequency in controls in the most cases being significantly associated with severity of airflow limitation. Echocardiography enables early, noninvasive, and accurate diagnosis of cardiac changes in COPD patients giving time for early intervention. Key words: airflow limitation, chronic obstructive pulmonary disease, Doppler echocardiography, pulmonary hypertension, ventricular dysfunction.  

scholarly journals Long-term outcomes after percutaneous transluminal pulmonary angioplasty for chronic thromboembolic pulmonary hypertension

2019 ◽  
Vol 16 (4) ◽  
pp. 27-32 ◽  
Author(s):  
Madina B Karabasheva ◽  
Nikolai M Danilov ◽  
Olesia V Sagaidak ◽  
Yurii G Matchin ◽  
Irina E Chazova
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Treatment Method ◽  
Classical Type ◽  
Chronic Obstructive ◽  
Clinical Effects ◽  
Long Term Outcomes ◽  
Thromboembolic Pulmonary Hypertension

Introduction. Chronic thromboembolic pulmonary hypertension is a precapillary form of pulmonary hypertension that develops due to thrombotic mass obstruction of the pulmonary arteries. Balloon pulmonary angioplasty (BPA) is a new, alternative treatment method for inoperable chronic thromboembolic pulmonary hypertension (CTEPH), which demonstrated good hemodynamic and clinical effects. In this article we studied the long-term outcomes results after BPA. Material and methods. The study included 22 patients with inoperable CTEPH who were treated by BPA 6 (5; 8) interventions per patient. The results of the procedure were evaluated 2 months and 18 (12; 18) months after the last BPA. Results. A significant decrease in all important hemodynamic parameters was noted. There no difference between the date immediately after the operation and the long term period. However, the division of patients into groups with and without disease progression allow us to identify factors affecting the effectiveness of BPA (weight, the number of BPA procedures per patient, the total number of treated segmental arteries, the presence of coronary heart disease and chronic obstructive pulmonary disease, not the appointment of a concomitant pathogenetic pulmonary arterial hypertension (PAH) therapy. Conclusion. BPA is an effective method of treating patients with inoperable CTEPH, which demonstrates a good, sustainable long-term result. Patients with classical type 4 pulmonary hypertension receiving PAH-specific therapy are best responders to BPA.

Hepatic gene expression profiles in a long-term high-fat diet-induced obesity mouse model

Gene ◽  
2004 ◽  
Vol 340 (1) ◽  
pp. 99-109 ◽  
Author(s):  
Sujong Kim ◽  
Insuk Sohn ◽  
Joon-Ik Ahn ◽  
Ki-Hwan Lee ◽  
Yeon Sook Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
High Fat Diet ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Hepatic Gene Expression ◽  
High Fat ◽  
Diet Induced Obesity

scholarly journals Lung cancer resection and postoperative outcomes in COPD: A single-center experience

2020 ◽  
Vol 17 ◽  
pp. 147997312092543
Author(s):  
Emma Roy ◽  
Justine Rheault ◽  
Marc-Antoine Pigeon ◽  
Paula Antonia Ugalde ◽  
Christine Racine ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Postoperative Complications ◽  
Lung Cancer Surgery ◽  
Cancer Surgery ◽  
Airflow Limitation ◽  
Chronic Obstructive ◽  
Term Survival ◽  
Long Term Survival ◽  
Cancer Resection

Chronic obstructive pulmonary disease (COPD) increases postoperative morbidity and is associated with diminished long-term survival after lung cancer resection. Whether this is also true for mild-to-moderate COPD is uncertain. We conducted a retrospective analysis of all the patients who underwent lung cancer surgery between 2002 and 2012 in a university-affiliated hospital. The severity of airflow limitation was stratified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) from stage 1 to 4. Data from 1456 cases of lung cancer surgery were reviewed and 1126 patients were included in the study: 672 (59.7%) patients had COPD (GOLD 1, n = 340; GOLD 2, n = 282; GOLD 3, n = 50) and 454 patients had a normal spirometry (controls). Following lung cancer resection, patients with COPD had a higher rate of postoperative morbidities of any kind ( p < 0.0001), in particular, pneumonia (7.0% vs. 3.7%; p = 0.0251) and prolonged air leak (17.0% vs. 8.2%; p < 0.0001) than controls. In-hospital mortality was increased in GOLD 3 COPD but the incidence of other postoperative complications was not influenced by COPD severity. Neither COPD nor its severity influenced long-term survival in this population. To conclude, patients with COPD undergoing lung cancer surgery were at higher risk of postoperative complications than patients with normal respiratory function but the procedure was considered safe. The presence of COPD itself did not influence long-term survival. The results of our study apply mainly to patients with a GOLD 1 and 2 COPD since only a small number of patients with GOLD 3 COPD were involved.

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