The effect of inhaled corticosteroids on bronchoalveolar lavage cells and IL-8 levels in stable COPD patients.
Ozol Duygu,Aysan Tulin,Solak Zeynep Aytemur,Mogulkoc Nesrin,Veral Ali,Sebik Filiz
Respiratory medicine
Chronic obstructive pulmonary disease (COPD) is characterised by a chronic inflammatory process in the large and small airways, as well as in the lung parenchyma. Although the role of oral corticosteroids in the management of acute exacerbations of COPD is well documented, its role in stable COPD is not clear. We examined the anti-inflammatory effect of inhaled budesonide on the percentage of neutrophils and on interleukin-8 (IL-8) levels in bronchoalveolar lavage (BAL) and their correlation with spirometry and symptom scores. Twenty-six patients with stable COPD were randomised, in a double-blinded, placebo-controlled trial with either 800 microg of inhaled budesonide or placebo for a 6-month period. The budesonide-treated subjects had significant reductions in IL-8 levels in the BAL after therapy (mean+/-sem, 1.53+/-0.72 at baseline vs. 0.70+/-0.48 ng/ml at 6 months, P=0.004) and a reduction in the mean percentages of neutrophils (17.16+/-2.67% vs. 13.25+/-2.28% P=0.002). The improvement in sputum production was of borderline (P=0.058) significance but there was no improvement in lung function. In stable patients with COPD, treatment with inhaled budesonide for a period of 6 months has a positive effect on markers of lung inflammation, as assessed by reduction in percentage neutrophils and IL-8 concentration in BAL.
10.1016/j.rmed.2005.04.025
Chronic exposure to glucocorticoids shapes gene expression and modulates innate and adaptive activation pathways in macrophages with distinct changes in leukocyte attraction.
van de Garde Martijn D B,Martinez Fernando O,Melgert Barbro N,Hylkema Machteld N,Jonkers René E,Hamann Jörg
Journal of immunology (Baltimore, Md. : 1950)
Glucocorticoids (GCs) have been used for more than 50 y as immunosuppressive drugs, yet their efficacy in macrophage-dominated disorders, such as chronic obstructive pulmonary disease, is debated. Little is known how long-term GC treatment affects macrophage responses in inflammatory conditions. In this study, we compared the transcriptome of human macrophages, matured in the presence or absence of fluticasone propionate (FP), and their ability to initiate or sustain classical activation, mimicked using acute LPS and chronic IFN-γ stimulation, respectively. We identified macrophage gene expression networks, modulated by FP long-term exposure, and specific patterns of IFN-γ- and LPS-induced genes that were resistant, inhibited, or exacerbated by FP. Results suggest that long-term treatment with GCs weakens adaptive immune signature components of IFN-γ and LPS gene profiles by downmodulating MHC class II and costimulatory molecules, but strengthens innate signature components by maintaining and increasing expression of chemokines involved in phagocyte attraction. In a mouse model of chronic obstructive pulmonary disease, GC treatment induced higher chemokine levels, and this correlated with enhanced recruitment of leukocytes. Thus, GCs do not generally suppress macrophage effector functions, but they cause a shift in the innate-adaptive balance of the immune response, with distinct changes in the chemokine-chemokine receptor network.
10.4049/jimmunol.1302138
[Systemic inflammation during exacerbations of chronic obstructive pulmonary disease].
Malo O,Sauleda J,Busquets X,Miralles C,Agustí A G N,Noguera A
Archivos de bronconeumologia
OBJECTIVE:The circulating blood levels of several inflammatory cytokines and acute phase proteins are higher in patients with stable chronic obstructive pulmonary disease (COPD). However, whether or not these inflammatory markers increase during COPD exacerbation or are modified by corticosteroid treatment has not been investigated. The objective of this study was therefore 1) to describe changes in several inflammatory markers in systemic circulation during COPD exacerbation, and 2) to assess the potential effects of corticosteroid treatment during exacerbation. METHODS:Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein (CRP) were determined for 10 patients (65 2 years old) with severe COPD (FEV1 35 4% reference) who were hospitalized for acute respiratory failure (PaO2 57 2 mm Hg; PaCO2 48 3 mm Hg). Blood samples were obtained in the emergency room (before starting intravenous corticosteroid treatment), during the first 24 hours of admission, upon discharge and two months later. Eight healthy non-smokers of a similar age (54 3 years) were also studied as control subjects. RESULTS:The COPD patients had higher concentrations of IL-6 (5.1 1.6 vs. 1.8 0.5 pg/mL, p < 0.05) and CRP (2.2 0.4 vs. 0.6 0.2 mg/dL, p < 0.005) than did controls, but the concentrations of IL-8 were similar (29 11.3 vs. 34.7 10.3 pg/mL, p = ns). No statistically significant changes were seen either during recovery, in spite of intravenous corticosteroid treatment, or two months after discharge.The ELISA test used was unable to detect TNF-alpha in any of the samples obtained from either patients or controls. CONCLUSION:The results show that 1) there is evidence of systemic inflammation during exacerbation of COPD, and 2) such systemic inflammation does not appear to be influenced significantly by intravenous corticosteroid treatment.
Measurement of tumor necrosis factor-alpha, leukotriene B4, and interleukin 8 in the exhaled breath condensate in patients with acute exacerbations of chronic obstructive pulmonary disease.
Ko Fanny W S,Leung Ting-Fan,Wong Gary W K,Ngai Jenny,To Kin W,Ng Susanna,Hui David S C
International journal of chronic obstructive pulmonary disease
BACKGROUND:Assessment of airway inflammation in the clinical course of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) may advance our understanding of the pathogenesis and treatment. OBJECTIVES:To assess airway inflammation in patients during the course of AECOPD by serial analyses of their exhaled breath condensates (EBC). METHODS:Twenty-six patients with AECOPD (22 males, mean[SD] percentage predicted forced expiratory volume in one second (FEV(1)) 44.8 [14.3]), 11 with stable COPD, and 14 age and sex-matched healthy controls were studied. Patients with AECOPD were treated with systemic steroid and antibiotic for 7 days. EBC was collected from each patient with AECOPD on Day 5, 14, 30, and 60 post-hospitalization using EcoScreen (VIASYS Healthcare, USA) during tidal breathing over 10 minutes. Concentrations of tumor necrosis factor-alpha (TNF-alpha), leukotriene B4 (LTB4), and interleukin-8 (IL-8) were measured by enzyme-linked immunosorbent assay. RESULTS:The median (IQR) of TNF-alpha level on Day 5 was 5.08 (3.80-6.32) pg/ml, which was lower than on Day 14 (5.84 [4.91-9.14] pg/ml, p = 0.017), Day 30 (6.14 [3.82-7.67] pg/ml, p = 0.045), and Day 60 (5.60 [4.53-8.80] pg/ml, p = 0.009). On Day 60, subjects receiving inhaled corticosteroid (ICS) had a lower level of TNF-alpha than those who were not (4.82 [4.06-5.65] vs 7.66 [5.48-10.9] pg/ml, p = 0.02). EBC LTB4 level did not change significantly during recovery from AECOPD whereas IL-8 was mostly undetectable. CONCLUSIONS:EBC TNF-alpha level was low in patients receiving systemic steroid and antibiotic therapy for AECOPD. These findings suggest a potential role for serial EBC TNF-alpha for non-invasive monitoring of disease activity.
Compare the efficacy of inhaled budesonide and systemic methylprednisolone on systemic inflammation of AECOPD.
Sun Xuejiao,He Zhiyi,Zhang Jianquan,Deng Jingmin,Bai Jing,Li Meihua,Zhong Xiaoning
Pulmonary pharmacology & therapeutics
BACKGROUND:Corticosteroids have been shown to improve the outcome of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, whether inhaled corticosteroids (IC) alone have similar effects with systemic corticosteroid (SCS) is still unclear. OBJECTIVES:To compare the efficacy of inhaled budesonide and systemic methylprednisolone on systemic inflammation of AECOPD. METHODS:30 AECOPD patients were randomly divided into two group. Budesonide group (15 cases) were treated with inhaled budesonide (3 mg Bid); methylprednisolone group (15 cases) were treated with systemic methylprednisolone (methylprednisolone acetate injectable suspension 40 mg Qd for three days and then methylprednisolone tablets 8 mg Bid). Observe symptoms, lung function, blood gas analysis and adverse effects of the patients in two groups. Peripheral blood samples were collected before and after treatment for 1 day, 4 days and 7 days. Interleukin-8 (IL-8) and TNF-α levels were determined by an enzyme linked immunosorbent assay (ELISA). Hs-CRP levels were detected by automatic biochemical analyzer. Western blotting was used to determine histone deacetylase 2 (HDAC2) protein expression. MEASUREMENTS AND MAIN RESULTS:Symptoms, pulmonary function and blood gas analysis were significantly improved after treatment in the two groups (P < 0.05) and no significant differences between the two groups (P > 0.05). There were no significant differences of IL-8, TNF-α and hs-CRP levels in the two groups (P > 0.05). Besides, the levels of HDAC2 protein expression before treatment were significantly lower comparing to that after treatment for 4 and 7 days. Incidence of adverse events (heart rate, blood pressure, glycemic, sleep condition, gastrointestinal symptoms) in budesonide group was lower than methylprednisolone group (P < 0.05). CONCLUSIONS:Inhaled budesonide and systemic methylprednisolone have the same effects on systemic inflammation of AECOPD. Inhaled corticosteroid alone could instead systemic corticosteroid in AECOPD treatment.
10.1016/j.pupt.2014.09.004
Clinical Significance of Procalcitonin, C-Reactive Protein, and Interleukin-6 in Helping Guide the Antibiotic Use for Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease.
Song Wen,Wang Yue,Tian Fengming,Ge Liang,Shang Xiaoqian,Zeng Qiang,Feng Ning,Fan Jiahui,Wang Jing,Ma Xiumin
Disease markers
Background:Currently, standards of antibiotic use in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients are controversial. Objective:The aim of the present study was to analyze the value of procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6 (IL-6) levels to guide the antibiotic treatment of AECOPD patients. Methods:A total of 371 patients with COPD or AECOPD were included in the study. Clinical and laboratory data were obtained at admission, 325 AECOPD patients and 46 sCOPD patients treated with antibiotics. The receiver operating curve (ROC) was used to evaluate the relationship between CRP, PCT, and IL-6. Results:This study included medical record/case control 1, the COPD group ( = 46) and the AECOPD group ( = 325), and medical record control 2, the nonchanged antibiotic group ( = 203) and the changed antibiotic group ( = 61). In case 1, CRP, PCT, and IL-6 levels in the AECOPD group were higher than that in the control group ( < 0.05), while the result of ROC showed that IL-6 had higher AUC values (0.773) and higher sensitivity (71.7%) than other indicators. The specificity of PCT (93.5%) is higher than other indicators. In case 2, ROC curve results showed that the AUC value of IL-6 (0.771) was slightly higher than PCT and CRP. The sensitivity (85.2%) and specificity (65.5%) of CRP were higher than other indicators. Conclusions:IL-6 and PCT were elevated in AECOPD patients, resulting in a higher diagnostic value for AECOPD. CRP had a higher diagnostic value for antibiotic use in AECOPD patients.
10.1155/2021/8879401
The effect of ventilator mask atomization inhalation of ipratropium bromide and budesonide suspension liquid in the treatment of COPD in acute exacerbation period on circulating levels of inflammation and prognosis.
Jiang D-H,Wang X,Liu L-S,Ji D-D,Zhang N
European review for medical and pharmacological sciences
OBJECTIVE:We investigated the effects of ventilator mask atomization inhalation of ipratropium bromide and budesonide suspension liquid in the treatment of acute exacerbation COPD (AECOPD) on circulating levels of inflammatory factors and prognosis. PATIENTS AND METHODS:A total of 86 cases of patients on ventilator support were randomly divided into control group and observation group with 43 cases each. The control group was administered routine treatment including basic disease treatment, anti-infection, maintenance of a stable internal environment, nutritional support, oxygen inhalation and so on. The control group was administered saline through a ventilator mask. The observation group was treated with atomized inhalation of ipratropium bromide and budesonide suspension and oxygen flow 3-5 L/min, 15-20 min/time and twice a day for 1 week. The treatment effects were compared. RESULTS:Serum TNF-α, IL-6, and CRP levels were decreased in both groups after treatment, but levels in the observation group were significantly lower than those of the control group; differences were statistically significant (p < 0.05). Forced vital capacity (FVC), forced expiratory volume (FEV1), FEV1/FVC and maximal expiratory flow rate in the observation group were significantly higher than those in the control group after treatment (p < 0.05). After treatment, the PaO2, SpO2 and respiratory failure index (RFI) of the observation group were significantly higher than those of the control group. The PaCO2 levels of the observation group were lower than those of the control group. The differences were statistically significant (p < 0.05). The clinical efficacy of the observation group was better than that of the control group; the ventilation time and total treatment time was significantly shorter and the differences were statistically significant (p < 0.05). CONCLUSIONS:The ventilator mask atomizing inhalation of ipratropium bromide and budesonide suspension liquid in the treatment of AECOPD can significantly improve circulating inflammatory reaction, improve lung function and blood gas levels, increase the treatment efficiency, and shorten the treatment time.
10.26355/eurrev_201711_13843
Inhaled and systemic corticosteroids in chronic obstructive pulmonary disease.
Falk Jeremy A,Minai Omar A,Mosenifar Zab
Proceedings of the American Thoracic Society
Systemic and local inflammation is central to the pathophysiology of chronic obstructive pulmonary disease (COPD). Increased levels of inflammation have been linked to a more progressive course in COPD and have been shown to be present during an exacerbation. Decreases in inflammatory cytokines, C-reactive protein, and inflammatory cells have been observed with corticosteroid use, suggesting a possible mechanism for a therapeutic benefit of steroids. No available data support the routine use of systemic corticosteroids in stable COPD; however, short courses during exacerbations are likely to improve length of hospitalization, lung function, and relapse rate. Inhaled corticosteroids (ICS) decrease the rate of exacerbation and may improve the response to bronchodilators and decrease dyspnea in stable COPD. No study shows that ICS reduce the loss of lung function; however, recent data suggest a possible survival benefit when combined with long-acting beta agonists. There are limited data on the use of ICS in the treatment of acute exacerbations of COPD, and its role in this setting must be more clearly defined. The empiric use of systemic corticosteroids perioperatively represents another area of uncertainty. The role of pharmacogenetics in the metabolism of corticosteroids in COPD is evolving but may be partially responsible for the observed variability in patient responsiveness. The potential benefits of systemic or inhaled corticosteroid use must be weighed against the risk of known toxicities.
10.1513/pats.200707-096ET
Melatonin improves influenza virus infection-induced acute exacerbation of COPD by suppressing macrophage M1 polarization and apoptosis.
Respiratory research
BACKGROUND:Influenza A viruses (IAV) are extremely common respiratory viruses for the acute exacerbation of chronic obstructive pulmonary disease (AECOPD), in which IAV infection may further evoke abnormal macrophage polarization, amplify cytokine storms. Melatonin exerts potential effects of anti-inflammation and anti-IAV infection, while its effects on IAV infection-induced AECOPD are poorly understood. METHODS:COPD mice models were established through cigarette smoke exposure for consecutive 24 weeks, evaluated by the detection of lung function. AECOPD mice models were established through the intratracheal atomization of influenza A/H3N2 stocks in COPD mice, and were injected intraperitoneally with melatonin (Mel). Then, The polarization of alveolar macrophages (AMs) was assayed by flow cytometry of bronchoalveolar lavage (BAL) cells. In vitro, the effects of melatonin on macrophage polarization were analyzed in IAV-infected Cigarette smoking extract (CSE)-stimulated Raw264.7 macrophages. Moreover, the roles of the melatonin receptors (MTs) in regulating macrophage polarization and apoptosis were determined using MTs antagonist luzindole. RESULTS:The present results demonstrated that IAV/H3N2 infection deteriorated lung function (reduced FEV/FVC), exacerbated lung damages in COPD mice with higher dual polarization of AMs. Melatonin therapy improved airflow limitation and lung damages of AECOPD mice by decreasing IAV nucleoprotein (IAV-NP) protein levels and the M1 polarization of pulmonary macrophages. Furthermore, in CSE-stimulated Raw264.7 cells, IAV infection further promoted the dual polarization of macrophages accompanied with decreased MT1 expression. Melatonin decreased STAT1 phosphorylation, the levels of M1 markers and IAV-NP via MTs reflected by the addition of luzindole. Recombinant IL-1β attenuated the inhibitory effects of melatonin on IAV infection and STAT1-driven M1 polarization, while its converting enzyme inhibitor VX765 potentiated the inhibitory effects of melatonin on them. Moreover, melatonin inhibited IAV infection-induced apoptosis by suppressing IL-1β/STAT1 signaling via MTs. CONCLUSIONS:These findings suggested that melatonin inhibited IAV infection, improved lung function and lung damages of AECOPD via suppressing IL-1β/STAT1-driven macrophage M1 polarization and apoptosis in a MTs-dependent manner. Melatonin may be considered as a potential therapeutic agent for influenza virus infection-induced AECOPD.
10.1186/s12931-024-02815-0
LncRNAs NR-026690 and ENST00000447867 are upregulated in CD4 T cells in patients with acute exacerbation of COPD.
International journal of chronic obstructive pulmonary disease
Objective:The aim of the study was to determine the expression profile of long noncoding RNAs (lncRNAs) in CD4 T cells from COPD patients and explore the clinical value of the lncRNAs. Methods:First, microarray analysis was performed. Differentially expressed lncRNAs were validated by quantitative real-time reverse transcription-PCR (qRT-PCR) in samples from 56 patients with acute exacerbations of COPD (AECOPD), 56 patients with stable COPD, and 35 healthy controls. Meanwhile, the clinical value was tested by receiver operating characteristic curve analysis. The functions of lncRNAs were analyzed by the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes database. The potential target genes that might be regulated by NR-026690 and ENST00000447867 were identified by the lncRNA-mRNA network and competing endogenous RNA network. The transcriptional expression level of rap guanine nucleotide exchange factor 3 (RAPGEF3) was tested by qRT-PCR. The correlation of the expression between NR-026690, ENST00000447867, and RAPGEF3 was analyzed by Spearman's correlation test. Results:We found that the relative expression levels of ENST00000447867 and NR-026690 in the CD4 T cells of AECOPD patients were significantly higher than in the stable COPD patients and control subjects by microarray and qRT-PCR validation. The transcriptional expression level of RAPGEF3 in the CD4 T cells was significantly higher in the AECOPD group compared to the control group (<0.01) and the stable COPD group (<0.05). RAPGEF3 expression was positively associated with NR-026690 (=0.4925, <0.01) and ENST00000447867 (=0.4065, <0.01). Conclusion:NR-026690 and ENST00000447867 might be potential biomarkers for COPD. They might affect RAPGEF3 as miRNA sponges to regulate COPD development.
10.2147/COPD.S191815
Immunophenotype in acute exacerbation of chronic obstructive pulmonary disease: a cross-sectional study.
Respiratory research
BACKGROUND:Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, and the immune inflammatory response is thought to play an important role in pathogenesis. However, the immunophenotype of patients with COPD is unknown. Herein, we evaluated the immunophenotype of patients with acute exacerbation of COPD (AECOPD). METHODS:A cross-sectional study was conducted in West China Hospital from September 2018 to October 2019. The proportion of CD4 + T lymphocyte subtypes (Th1, Th2, Th17 and Treg) and levels of serum cytokines in the peripheral blood of patients with AECOPD, stable COPD (SCOPD), healthy smokers (HSs)and healthy controls (HCs) were evaluated. RESULTS:A total of 15 HCs, 19 HSs, 42 patients with SCOPD, and 55 patients with AECOPD were included. Compared to patients with SCOPD, Th1 cells, Th17 cells, Treg cell ratio, Th1/Th2 cell ratio, and the levels of C-reactive protein, interleukin (IL)-6, and IL-10 were significantly increased in patients with AECOPD (P < 0.001), while the proportion of Th2 cells was significantly reduced (P < 0.01). The proportion of Th17 cells was positively correlated with COPD Assessment Test score (r = 0.266, P = 0.009), modified Medical Research Council dyspnea score (r = 0.858, P < 0.0001), and Th1 cell ratio (r = 0.403, P < 0.0001) and negatively correlated with forced vital capacity (r = - 0.367, P = 0.009) and proportion of Th2 cells (r = - 0.655, P < 0.0001). CONCLUSIONS:The immunophenotype of patients with AECOPD shows abnormal activation of Th1, Th17, and Treg cells. There is a correlation between the proportion of Th17 cells and the severity of COPD; therefore, this may represent a novel index for the evaluation of COPD severity. TRIAL REGISTRATION:China Clinical Trials Registry, ChiCTR1800018452, registered 19 September 2018, https://www.chictr.org.cn/index.aspx .
10.1186/s12931-022-02058-x
Preclinical studies and the function of IL-17 cytokines in COPD.
Ritzmann Felix,Beisswenger Christoph
Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft
Chronic obstructive pulmonary disease (COPD) is among the leading causes of death worldwide and imposes a high economic burden to the health systems. COPD is characterized by chronic inflammation of the lung leading to airflow limitation, alveolar tissue destruction, and emphysema. Therefore, anti-inflammatory therapies for the treatment of COPD are of interest. In this review, we focus on the function of the IL-17 cytokines IL-17A and IL-17C, both known to mediate the recruitment of inflammatory cells, in the pathogenesis of COPD. We highlight that the expression of IL-17A and IL-17C is induced by pathogens frequently found in lungs of COPD patients and that targeting IL-17-signaling is an interesting option for the treatment of acute exacerbation of COPD.
10.1016/j.aanat.2021.151729
Targeting cytokines to treat asthma and chronic obstructive pulmonary disease.
Barnes Peter J
Nature reviews. Immunology
Cytokines play a key role in orchestrating and perpetuating the chronic airway inflammation in asthma and chronic obstructive pulmonary disease (COPD), making them attractive targets for treating these disorders. Asthma and some cases of COPD are mainly driven by type 2 immune responses, which comprise increased airway eosinophils, T helper 2 (T2) cells and group 2 innate lymphoid cells (ILC2s) and the secretion of IL-4, IL-5 and IL-13. Clinical trials of antibodies that block these interleukins have shown reduced acute exacerbations and oral corticosteroid use and improvements in lung function and symptoms in selected patients. More recent approaches that block upstream cytokines, such as thymic stromal lymphopoietin (TSLP), show promise in improving patient outcome. Importantly, the clinical trials in cytokine blockade have highlighted the crucial importance of patient selection for the successful use of these expensive therapies and the need for biomarkers to better predict drug responses.
10.1038/s41577-018-0006-6