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1.
Acta Pharm Sin B ; 14(4): 1726-1741, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38572107

RESUMO

Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A-D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

2.
Mol Cell Proteomics ; : 100770, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38641226

RESUMO

Inhalation of crystalline silica dust induces incurable lung damage, silicosis and pulmonary fibrosis. However, the mechanisms of the lung injury remain poorly understood, with limited therapeutic options aside from lung transplantation. Post-translational modifications can regulate the function of proteins and play an important role in studying disease mechanisms. To investigate changes in post-translational modifications of proteins in silicosis, combined quantitative proteome, acetylome, and succinylome analyses were performed with lung tissues from silica-injured and healthy mice using liquid chromatography-mass spectrometry. Combined analysis was applied to the three omics datasets to construct a protein landscape. The acetylation and succinylation of the key transcription factor STAT1 were found to play important roles in the silica-induced pathophysiological changes. Modulating the acetylation level of STAT1 with geranylgeranylacetone (GGA) effectively inhibited the progression of silicosis. This report revealed a comprehensive landscape of post-translational modifications in silica-injured mouse, presented a novel therapeutic strategy targeting the post-translational level for silica-induced lung diseases.

3.
Quant Imaging Med Surg ; 14(3): 2590-2602, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38545067

RESUMO

Background: Single-photon emission computed tomography (SPECT) ventilation perfusion imaging is the main imaging method for the diagnosis of pulmonary embolism, and its application in the diagnosis and efficacy evaluation of chronic thromboembolic pulmonary hypertension (CTEPH) has been paid more and more attention. In recent years, with the development of computer software technology, ventilation/perfusion (V/Q) imaging quantitative analysis technology has become more and more mature. The objective of this study was to investigate the utility of quantitative analysis of pulmonary V/Q scintigraphy in evaluating the efficacy of balloon pulmonary angioplasty (BPA) in patients with CTEPH. Methods: In this retrospective analysis, we collected data of patients diagnosed with CTEPH who underwent BPA at the China-Japan Friendship Hospital from April 2018 to September 2020. The sample consisted of 23 males and 28 females, with an average age of 55.1±12.7 years. All patients underwent V/Q scintigraphy within one week before surgery, and we reviewed the pulmonary angiography within 1-3 months following the last BPA procedure. We repeated V/Q scintigraphy within 1 week before or after the pulmonary angiography, at the time of collecting clinical and hemodynamic parameters of these patients. We divided the patients into two groups based on the presence of residual pulmonary hypertension post-surgery and compared the pre- and post-operative quantitative pulmonary perfusion defect percentage scores (PPDs%) using the t-test. Results: In all, 102 V/Q scintigraphy scans were performed in 51 patients. The quantitative PPDs% were positively correlated with the hemodynamic indexes mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and mean right ventricular pressure (RVP) (r=0.605, 0.391, and 0.464, respectively, all P<0.001) and negatively correlated with the 6-minute walking distance (6MWD) (r=-0.254, P=0.010). The average preoperative quantitative PPDs% were (49.0±15.6)% which significantly decreased to (33.5±13.9)% after surgery (t=11.249, P<0.001). The preoperative quantitative PPDs% were (54.7±15.7)% and (44.0±13.8)% in the residual pulmonary hypertension group and the non-residual pulmonary hypertension group, respectively (t=2.599, P=0.012). The postoperative quantitative PPDs% were (41.5±12.5)% and (26.3±11.0)%, in the residual pulmonary hypertension group and the non-residual pulmonary hypertension group, respectively (t=4.647, P<0.001). Conclusions: In this study, we found that quantitative analysis of SPECT pulmonary V/Q scintigraphy adequately reflected the pulmonary artery pressure and clinical status in patients with CTEPH. Our results demonstrate its definite utility in predicting residual pulmonary hypertension and in evaluating the postoperative efficacy of BPA in patients with CTEPH.

4.
Thromb J ; 22(1): 17, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317247

RESUMO

Patients with venous thromboembolism (VTE) comorbid renal insufficiency (RI) are at higher risk of bleeding and thrombosis. Recommendations in guidelines on anticoagulation therapy for those patients remain ambiguous. The goal of this study is to compare the efficacy and safety between different anticoagulant regimens in VTE patients comorbid RI at different stages of treatment and prophylaxis. We performed English-language searches of Pubmed, EMBASE, and Web of Science (inception to Nov 2022). RCTs evaluated anticoagulants for VTE treatment at the acute phase, extension phase, and prophylaxis in patients with RI and reported efficacy and safety outcomes were selected. The methodological quality of the studies was assessed at the outcome level using the risk-of-bias assessment tool developed by the Cochrane Bias Methods Group. A meta-analysis of twenty-five RCTs was conducted, comprising data from twenty-three articles, encompassing a total of 9,680 participants with RI. In the acute phase, the risk of bleeding was increased with novel oral anticoagulants (NOACs) compared to LMWH (RR 1.29, 95% CI 1.04-1.60). For the prophylaxis of VTE, NOACs were associated with an elevated risk of bleeding compared with placebo (RR 1.31, 95%CI 1.02-1.68). In comparison to non-RI patients, both NOACs and vitamin K antagonists (VKA) could increase the risk of bleeding among RI patients (RR 1.45, 95%CI 1.14-1.84 and RR 1.53, 95%CI 1.25-1.88, respectively) during acute phase, while NOACs may increase the incidence of VTE in RI population (RR 1.74, 95%CI 1.29-2.34). RI patients who are under routine anticoagulation have a significantly higher risk of adverse outcomes. LMWH is the most effective and safe option for VTE treatment or prophylaxis in patients with RI.

5.
iScience ; 27(2): 108930, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38333700

RESUMO

Determining novel biomarkers for early identification of chronic thromboembolic pulmonary hypertension (CTEPH) could improve patient outcomes. We used the isobaric tag for relative and absolute quantitation approach to compare the serum protein profiles between CTEPH patients and the controls. Bioinformatics analyses and ELISA were also performed. We identified three proteins including heparanase (HPSE), gelsolin (GSN), and secreted protein acidic and rich in cysteine (SPARC) had significant changes in CTEPH. The receiver operating characteristic curve analysis showed that the areas under the curve of HPSE in CTEPH diagnosis were 0.988. Furthermore, HPSE was correlated with multiple parameters of right ventricular function. HPSE concentrations were significantly higher in patients with a low TAPSE/sPAP ratio (≤0.31 mm/mmHg) (65.4 [60.5,68.0] vs. 59.9 [35.9,63.2] ng/mL, p < 0.05). The CTEPH patients treated by balloon pulmonary angioplasty had significantly lower HPSE levels. The study demonstrates that HPSE may be a promising biomarker for noninvasive detection of CTEPH.

6.
Circulation ; 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38314588

RESUMO

BACKGROUND: Pulmonary hypertension (PH) is a progressive cardiopulmonary disease with a high mortality rate. Although growing evidence has revealed the importance of dysregulated energetic metabolism in the pathogenesis of PH, the underlying cellular and molecular mechanisms are not fully understood. In this study, we focused on ME1 (malic enzyme 1), a key enzyme linking glycolysis to the tricarboxylic acid cycle. We aimed to determine the role and mechanistic action of ME1 in PH. METHODS: Global and endothelial-specific ME1 knockout mice were used to investigate the role of ME1 in hypoxia- and SU5416/hypoxia (SuHx)-induced PH. Small hairpin RNA and ME1 enzymatic inhibitor (ME1*) were used to study the mechanism of ME1 in pulmonary artery endothelial cells. Downstream key metabolic pathways and mediators of ME1 were identified by metabolomics analysis in vivo and ME1-mediated energetic alterations were examined by Seahorse metabolic analysis in vitro. The pharmacological effect of ME1* on PH treatment was evaluated in PH animal models induced by SuHx. RESULTS: We found that ME1 protein level and enzymatic activity were highly elevated in lung tissues of patients and mice with PH, primarily in vascular endothelial cells. Global knockout of ME1 protected mice from developing hypoxia- or SuHx-induced PH. Endothelial-specific ME1 deletion similarly attenuated pulmonary vascular remodeling and PH development in mice, suggesting a critical role of endothelial ME1 in PH. Mechanistic studies revealed that ME1 inhibition promoted downstream adenosine production and activated A2AR-mediated adenosine signaling, which leads to an increase in nitric oxide generation and a decrease in proinflammatory molecule expression in endothelial cells. ME1 inhibition activated adenosine production in an ATP-dependent manner through regulating malate-aspartate NADH (nicotinamide adenine dinucleotide plus hydrogen) shuttle and thereby balancing oxidative phosphorylation and glycolysis. Pharmacological inactivation of ME1 attenuated the progression of PH in both preventive and therapeutic settings by promoting adenosine production in vivo. CONCLUSIONS: Our findings indicate that ME1 upregulation in endothelial cells plays a causative role in PH development by negatively regulating adenosine production and subsequently dysregulating endothelial functions. Our findings also suggest that ME1 may represent as a novel pharmacological target for upregulating protective adenosine signaling in PH therapy.

7.
Eur J Intern Med ; 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38350784

RESUMO

BACKGROUND: The performance of existing prognostic scores including the simplified Pulmonary Embolism Severity Index (sPESI) for short-term mortality of non-high-risk PE in Chinese population has not been widely validated. METHODS: Non-high-risk patients were included from the prospective cohort of the China pUlmonary Thromboembolism REgistry Study (CURES). The sPESI, RIETE, Geneva, modified FAST, and Bova score were validated. The discriminatory performance was measured by the area under the curve (AUC). We also compared the sensitivity, odds ratio, specificity, positive predictive value and negative predictive value of these scores. RESULTS: A total of 6,873 non-high-risk patients with acute PE were included and 241 (3.5 %) patients died within 30 days. Compared to the Geneva, modified FAST, and Bova score, the AUCs for predicting 30-day death of sPESI and RIETE score were higher at 0.712 (95 % CI, 0.680, 0.743) and 0.723 (95 % CI, 0.691, 0.755) respectively. The sPESI demonstrated the highest sensitivity at 0.809, while the RIETE score, Geneva, Modified FAST and BOVA score showed sensitivities of 0.622, 0.568, 0.477 and 0.502 respectively. A sPESI ⩾1 point was associated with a 4.7-fold increased risk of 30-day all-cause mortality (95 % CI, 3.427, 6.563, p < 0.001), while a RIETE score of ⩾1 point was associated with a 4.5-fold increased risk (95 % CI, 3.127, 6.341, p < 0.001). The Geneva score, modified FAST and Bova score showed inferior performance. CONCLUSIONS: The implementation of the fewer-parameter, easier-to-calculate sPESI in Chinese patients with PE can help to discriminate patients with extremely low risk of short-term mortality for home treatment or early discharge.

10.
J Hum Genet ; 68(12): 805-812, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37537391

RESUMO

Genome-wide association studies (GWAS) have identified numerous risk loci for venous thromboembolism (VTE), but it is challenging to decipher the underlying mechanisms. We employed an integrative analytical pipeline to transform genetic associations to identify novel plasma proteins for VTE. Proteome-wide association studies (PWAS) were determined by functional summary-based imputation leveraging data from a genome-wide association analysis (14,429 VTE patients, 267,037 controls), blood proteomes (1348 cases), followed by Mendelian randomization, Bayesian colocalization, protein-protein interaction, and pathway enrichment analysis. Twenty genetically regulated circulating protein abundances (F2, F11, ABO, PLCG2, LRP4, PLEK, KLKB1, PROC, KNG1, THBS2, SERPINA1, RARRES2, CEL, GP6, SERPINE2, SERPINA10, OBP2B, EFEMP1, F5, and MSR1) were associated with VTE. Of these 13 proteins demonstrated Mendelian randomized correlations. Six proteins (F2, F11, PLEK, SERPINA1, RARRES2, and SERPINE2) had strong support in colocalization analysis. Utilizing multidimensional data, this study suggests PLEK, SERPINA1, and SERPINE2 as compelling proteins that may provide key hints for future research and possible diagnostic and therapeutic targets for VTE.


Assuntos
Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Proteoma/genética , Estudo de Associação Genômica Ampla/métodos , Análise da Randomização Mendeliana , Teorema de Bayes , Serpina E2/genética , Proteínas Sanguíneas/genética , Polimorfismo de Nucleotídeo Único , Proteínas da Matriz Extracelular/genética
11.
Lancet Reg Health West Pac ; 39: 100848, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37565068

RESUMO

Background: Serum uric acid (SUA) levels have been associated with an increased risk and recurrence of venous thromboembolism (VTE) in European populations, but the potential causal relationship remains unclear. Large-scale studies on the association between SUA and VTE in East Asian populations are lacking, despite the high prevalence of hyperuricemia in this region. To address this, we conducted a cohort analysis and a two-sample Mendelian randomization (MR) study in East Asian populations. Methods: We collected data on VTE patients from the China Pulmonary Thromboembolism Registry Study (CURES) and compared them to controls obtained from the China Health and Retirement Longitudinal Survey (CHARLS). Propensity score matching (PSM) and cubic-spline models were applied to assess the effect of SUA on VTE risk while adjusting for multiple covariates. We also performed two-sample MR analyses to infer potential causality based on summary statistics from Genome-wide Association Studies (GWAS) of SUA and VTE in the East Asian population. Findings: We found that the SUA levels were higher in VTE patients (317.95 mmol/L) compared to the general population (295.75 mmol/L), and SUA ≥ 325 mmol/L was associated with an increased risk of VTE recurrence (P-value = 0.0001). The univariable MR suggested a causal relationship between elevated SUA and higher VTE risk (Pinverse variance weighted < 0.05), and multivariable MR showed that elevated SUA levels continued to promote the development of VTE after adjusting for multiple covariates (Pmultivariable residual < 0.05). Sensitivity analyses produced similar results for these estimations. Interpretation: Our study provides evidence supporting a robust positive association between SUA and VTE in the East Asian population, and MR analyses suggest that this association is likely to be causal. Our findings underscore the importance of monitoring SUA levels in VTE prevention and call for urgent action to address the growing burden of hyperuricemia in the Asia-Pacific region. Funding: This research was funded by Beijing Nova Program (No. Z211100002121057), National Natural Science Foundation of China (No. 82100065 and No. 62350004), CAMS Innovation Fund for Medical Sciences (No. 2021-I2M-1-061 and No. 2021-1-I2M-001), Elite Medical Professionals project of China-Japan Friendship Hospital (No. ZRJY2021-QM12), National Key Research and Development Project (No. 2021YFF1201200 and No. 2022YFC3341004).

13.
J Funct Biomater ; 14(4)2023 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-37103310

RESUMO

BACKGROUND: Autogenous tooth bone graft material (AutoBT) has been advocated as a bone substitute when conducting alveolar ridge preservation. This study is aimed at using a radiomics approach in order to evaluate and testify whether AutoBT can stimulate bone growth during socket preservation in severe periodontal cases. MATERIALS AND METHODS: For this study, 25 cases with severe periodontal diseases were selected. The patients' AutoBTs were inserted into the extraction sockets and covered with Bio-Gide® collagen membranes. 3D CBCT scans and 2D X-rays were taken of the patients before surgery and after 6 months post-surgery. For the retrospective radiomics analysis, the maxillary and mandibular images were compared in different groups. Maxillary bone height was analyzed at the buccal, middle, and palatal crest sites, while the mandibular bone height was compared at the buccal, center, and lingual crest sites. RESULTS: In the maxilla, the alveolar height was increased by -2.15 ± 2.90 mm at the buccal crest; -2.45 ± 2.36 mm at the center of the socket, and -1.62 ± 3.19 mm at the palatal crest, while the height of the buccal crest was increased by 0.19 ± 3.52 mm, and the height at the center of the socket was increased by -0.70 ± 2.71 mm in the mandible. The three-dimensional radiomics analysis demonstrated significant bone growth in the local alveolar height and high density. CONCLUSION: Based on clinical radiomics analysis, AutoBT could be used as an alternative bone material in socket preservation after tooth extraction in patients with severe periodontitis.

14.
BMC Med ; 21(1): 153, 2023 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-37076872

RESUMO

BACKGROUND: A large proportion of pulmonary embolism (PE) heritability remains unexplained, particularly among the East Asian (EAS) population. Our study aims to expand the genetic architecture of PE and reveal more genetic determinants in Han Chinese. METHODS: We conducted the first genome-wide association study (GWAS) of PE in Han Chinese, then performed the GWAS meta-analysis based on the discovery and replication stages. To validate the effect of the risk allele, qPCR and Western blotting experiments were used to investigate possible changes in gene expression. Mendelian randomization (MR) analysis was employed to implicate pathogenic mechanisms, and a polygenic risk score (PRS) for PE risk prediction was generated. RESULTS: After meta-analysis of the discovery dataset (622 cases, 8853 controls) and replication dataset (646 cases, 8810 controls), GWAS identified 3 independent loci associated with PE, including the reported loci FGG rs2066865 (p-value = 3.81 × 10-14), ABO rs582094 (p-value = 1.16 × 10-10) and newly reported locus FABP2 rs1799883 (p-value = 7.59 × 10-17). Previously reported 10 variants were successfully replicated in our cohort. Functional experiments confirmed that FABP2-A163G(rs1799883) promoted the transcription and protein expression of FABP2. Meanwhile, MR analysis revealed that high LDL-C and TC levels were associated with an increased risk of PE. Individuals with the top 10% of PRS had over a fivefold increased risk for PE compared to the general population. CONCLUSIONS: We identified FABP2, related to the transport of long-chain fatty acids, contributing to the risk of PE and provided more evidence for the essential role of metabolic pathways in PE development.


Assuntos
População do Leste Asiático , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Embolia Pulmonar , Humanos , China/epidemiologia , População do Leste Asiático/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Polimorfismo de Nucleotídeo Único/genética , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/etnologia , Embolia Pulmonar/genética , Fatores de Risco
15.
Am J Respir Cell Mol Biol ; 68(2): 213-227, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36227848

RESUMO

Progressive fibrosing interstitial lung diseases (PF-ILDs) result in high mortality and lack effective therapies. The pathogenesis of PF-ILDs involves macrophages driving inflammation and irreversible fibrosis. Fc-γ receptors (FcγRs) regulate macrophages and inflammation, but their roles in PF-ILDs remain unclear. We characterized the expression of FcγRs and found upregulated FcγRIIB in human and mouse lungs after exposure to silica. FcγRIIB deficiency aggravated lung dysfunction, inflammation, and fibrosis in silica-exposed mice. Using single-cell transcriptomics and in vitro experiments, FcγRIIB was found in alveolar macrophages, where it regulated the expression of fibrosis-related genes Spp1 and Ctss. In mice with macrophage-specific overexpression of FcγRIIB and in mice treated with adenovirus by intratracheal instillation to upregulate FcγRIIB, silica-induced functional and histological changes were ameliorated. Our data from three genetic models and a therapeutic model suggest that FcγRIIB plays a protective role that can be enhanced by adenoviral overexpression, representing a potential therapeutic strategy for PF-ILDs.


Assuntos
Doenças Pulmonares Intersticiais , Pneumonia , Humanos , Animais , Camundongos , Adenoviridae/genética , Adenoviridae/metabolismo , Pneumonia/genética , Inflamação/genética , Inflamação/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Fibrose , Dióxido de Silício
16.
Front Cardiovasc Med ; 9: 1023282, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36457807

RESUMO

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) patients may present with atherosclerotic lesions in their pulmonary arteries, but their clinical characteristics remain unclear. The metabolic pathways associated with the atherosclerotic lesions may explain their occurrence and have implications for interventions, but they have not been investigated. Methods: We collected pulmonary endarterectomy (PEA) samples of CTEPH patients from December 2016 to August 2021. Following a detailed pathological examination of the PEA specimen, the patients were divided into those with and without lesions, and age- and sex matching were performed subsequently using propensity score matching (n = 25 each). Metabolomic profiling was used to investigate the metabolites of the proximal lesions in the PEA specimens. Results: In our study population, 27.2% of all PEA specimens were found to contain atherosclerotic lesions. CTEPH patients with atherosclerotic lesions were more likely to have a history of symptomatic embolism and had a longer timespan between embolism and surgery, whereas the classic risk factors of systemic and coronary circulation could not distinguish CTEPH patients with or without atherosclerotic lesions. Metabolomic profiling revealed that the formation of atherosclerotic lesions in CTEPH was closely related to altered glycine, serine, and threonine metabolic axes, possibly involved in cellular senescence, energy metabolism, and a proinflammatory microenvironment. Conclusion: The occurrence of atherosclerotic lesions in the pulmonary arteries of CTEPH was associated with symptomatic thromboembolic history and prolonged disease duration. The results revealed a new link between atherosclerotic lesions and aberrant amino acid metabolism in the context of CTEPH for the first time. This study has characterized the clinical and metabolic profiles of this distinct group of CTEPH patients, providing new insights into disease pathogenesis and potential interventions.

17.
Comput Biol Med ; 151(Pt A): 106187, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36327882

RESUMO

Blood leukocyte counts (e.g., eosinophil count) are important biomarkers for the onset, classification, and exacerbation of chronic obstructive pulmonary disease (COPD). The causal relationships between them are necessary for the development of COPD treatment strategy, but remain unclear. Here, we implement two-sample bi-directional univariable Mendelian Randomization (MR) and multivariable MR to investigate the causal relationships. Univariable MR find that elevated blood eosinophil count significantly increases the risk of COPD (odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.14-1.30, P = 1.54 × 10-09) and COPD-related hospitalization (OR = 1.44, 95% CI: 1.15-1.80, P = 1.36 × 10-03). Besides, it also significantly decreases the ratio of forced expiratory volume in the first second over forced vital capacity (FEV1/FVC ratio) (OR = 0.942, 95% CI: 0.914-0.971, P = 1.02 × 10-04). These findings are fully supported by multivariate MR results. Interestingly, univariable MR reveals a weak causal relationship between elevated blood eosinophil count and COPD risk in younger people (<65 years) (OR = 1.39, 95% CI: 1.10-1.75, P = 5.52 × 10-03), but not older individuals (OR = 1.20, 95% CI: 0.926-1.55, P = 0.17). Finally, reverse univariable MR reveals the onset of COPD and the decreased FEV1/FVC ratio both lead to increased blood neutrophil count (OR = 1.03, 95% CI: 1.01-1.05, P = 3.40 × 10-03 and OR = 0.947, 95% CI: 0.91-0.986, P = 8.75 × 10-03 respectively). In summary, this MR study demonstrates that high blood eosinophil count is an independent causal mediator of COPD risk, FEV1/FVC decline, and COPD-related hospitalization. The increase in neutrophil count is induced by COPD onset or FEV1/FVC decline. This suggests eosinophil, but not neutrophil, may be used as a therapeutic target for preventing the onset and exacerbation of COPD and FEV1/FVC decline. Therefore, a non-neutrophil-targeted therapeutic strategy for neutrophilic COPD is required in the future.


Assuntos
Análise da Randomização Mendeliana , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/genética , Volume Expiratório Forçado , Capacidade Vital , Contagem de Leucócitos
18.
J Clin Med ; 11(22)2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36431142

RESUMO

The pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH) is largely unknown. Although pulmonary endarterectomy (PEA) is potentially curative, inoperable patients and persistent pulmonary hypertension (PH) following surgery remain a significant problem. In this study, we aim to describe the histopathological characteristics of CTEPH and explore the potential relationship between pulmonary arterial lesions, radiological parameters, and clinical manifestations. Endarterectomized tissues from 81 consecutive patients of CTEPH were carefully collected, sectioned, and examined by experienced pathologists. Pertinent clinical and radiological data were obtained from medical records and operative reports. Neointima, fresh/organized thrombi, recanalized regions, and atherosclerotic lesions were microscopically examined as previously described. Thrombi and atherosclerosis were dominant in UCSD classification level I PEA materials, while recanalized neo-vessels were more frequently observed in UCSD classification level III cases. Degenerative changes of the extracellular matrix were also noticed in the vascular bed. Atherosclerotic lesions were more frequently observed in cases with higher ratio of the pulmonary artery diameter to ascending aorta diameter (PA/AA) reflected by computed tomographic pulmonary arterial scanning. Furthermore, the removal of pulmonary artery complex lesions (with the combination of three to four types of lesions) by PEA was associated with lower postoperative mean pulmonary arterial pressure (mPAP) and decreased incidences of persistent PH. Our study demonstrates that the histopathological features of CTEPH are strongly linked with clinical manifestations and the postoperative outcome after PEA. These data may provide possible evidence for further studies in searching for appropriate causal factors underlying this disease.

19.
Front Cardiovasc Med ; 9: 990207, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36237910

RESUMO

Background: Oxygen pathway limitation exists in chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA) are two effective interventions for CTEPH, but their effects and comparison of these two interventions on the oxygen pathway are not well demonstrated. Methods: CTEPH patients with available pulmonary function test, hemodynamics, and blood gas analysis before and after the interventions were included for comparison of oxygen pathway in terms of lung ventilation, lung gas exchange, oxygen delivery, and oxygen extraction between these two interventions. Results: The change in the percentage of the predicted forced expiratory volume in the 1 s (-3.4 ± 12.7 vs. 3.8 ± 8.7%, P = 0.006) and forced vital capacity (-5.5 ± 13.0 vs. 4.2 ± 9.9%, P = 0.001) among the PEA group (n = 24) and BPA group (n = 46) were significantly different. Patients in the PEA group had a significant increase in their arterial oxygen saturation (from 92.5 ± 3.6 to 94.6 ± 2.4%, P = 0.022), while those in the BPA group had no change, which could be explained by a significant improvement in ventilation/perfusion (-0.48 ± 0.53 vs. -0.17 ± 0.41, P = 0.016). Compared with patients post-BPA, patients post-PEA were characterized by higher oxygen delivery (756.3 ± 229.1 vs. 628.8 ± 188.5 ml/min, P = 0.016) and higher oxygen extraction (203.3 ± 64.8 vs. 151.2 ± 31.9 ml/min, P = 0.001). Conclusion: Partial amelioration of the oxygen pathway limitations could be achieved in CTEPH patients treated with PEA and BPA. CTEPH patients post-PEA had better performance in lung gas exchange, oxygen delivery, and extraction, while those post-BPA had better lung ventilation. Cardiopulmonary rehabilitation may assist in improving the impairment of the oxygen pathway.

20.
Ecotoxicol Environ Saf ; 244: 114043, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36087468

RESUMO

Silicosis is one of the most important occupational diseases worldwide, caused by inhalation of silica particles or free crystalline silicon dioxide. As a disease with high mortality, it has no effective treatment and new therapeutic targets are urgently needed. Recent studies have identified FCER1A, encoding α-subunit of the immunoglobulin E (IgE) receptor FcεRI, as a candidate gene involved in the biological pathways leading to respiratory symptoms. FcεRI is known to be important in allergic asthma, but its role in silicosis remains unclear. In this study, serum IgE concentrations and FcεRI expression were assessed in pneumoconiosis patients and silica-exposed mice. The role of FcεRI was explored in a silica-induced mouse model using wild-type and FcεRI-deficient mice. The results showed that serum IgE concentrations were significantly elevated in both pneumoconiosis patients and mice exposed to silica compared with controls. The mRNA and protein expression of FcεRI were also significantly increased in the lung tissue of patients and silica-exposed mice. FcεRI deficiency significantly attenuated the changes in lung function caused by silica exposure. Silica-induced elevations of IL-1ß, IL-6, and TNF-α were significantly attenuated in the lung tissue and bronchoalveolar lavage fluid (BALF) of FcεRI-deficient mice compared with wild-type controls. Additionally, FcεRI-deficient mice showed a significantly lower score of pulmonary fibrosis than wild-type mice following exposure to silica, with significantly lower hydroxyproline content and expression of fibrotic genes Col1a1 and Fn1. Immunofluorescent staining suggested FcεRI mainly on mast cells. Mast cell degranulation took place after silica exposure, as shown by increased serum histamine levels and ß-hexosaminidase activity, which were significantly reduced in FcεRI-deficient mice compared with wild-type controls. Together, these data showed that FcεRI deficiency had a significant protective effect against silica-induced pulmonary inflammation and fibrosis. Our findings provide new insights into the pathophysiological mechanisms of silica-induced pulmonary fibrosis and a potential target for the treatment of silicosis.


Assuntos
Pneumonia , Fibrose Pulmonar , Silicose , Animais , Fibrose , Histamina/metabolismo , Histamina/toxicidade , Hidroxiprolina/metabolismo , Hidroxiprolina/farmacologia , Hidroxiprolina/uso terapêutico , Imunoglobulina E , Interleucina-6/metabolismo , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , RNA Mensageiro/metabolismo , Receptores de IgE/genética , Receptores de IgE/metabolismo , Receptores de IgE/uso terapêutico , Dióxido de Silício/toxicidade , Silicose/genética , Silicose/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , beta-N-Acetil-Hexosaminidases/metabolismo , beta-N-Acetil-Hexosaminidases/farmacologia , beta-N-Acetil-Hexosaminidases/uso terapêutico
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