scholarly journals N-Acetylcysteine (NAC) Inhibits Synthesis of IL-18 in Macrophage by Suppressing NLRP3 Expression to Reduce the Production of IFN-γ from NK Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Xiaopeng Liu ◽  
Xufeng Lu ◽  
Zhixiong Hu

Background. N-Acetylcysteine (NAC) had exerted antioxidation and anti-inflammation effects on chronic obstructive pulmonary disease (COPD) patients. However, its effect in regulating interleukin- (IL-) 18 was not fully understood. This study was designed to evaluate the specific mechanism of NAC regulating IL-18. Materials and Methods. A total of 112 COPD patients and 103 health individuals were recruited in the study. Cytokine level in patients’ serum was measured by enzyme-linked immunosorbent assay (ELISA). A COPD mouse model was established by administration of lipopolysaccharide (LPS) and cigarette smoke. The expression of cytokines was measured by ELISA and flow cytometry. Inflammasome-related protein was measured by Western blot. Result. NAC could effectively improve the immune status of COPD patients as well as the COPD mouse model by downregulating proinflammation and inflammation cytokines including IL-1β, interferon- (IFN-) γ, tumor necrosis factor- (TNF-) α, and IL-18. It also had the capability to suppress synthesis of IL-18 in macrophage to inhibit the secretion of IFN-γ from natural killer (NK) cells through influencing the inflammasome-related protein in macrophages. Conclusion. NAC could effectively inhibit the production of IL-18 by suppressing NLRP3 expression in macrophages to reduce the production of IFN-γ in NK cells.

2021 ◽  
Author(s):  
Ayumi Mitsune ◽  
Mitsuhiro Yamada ◽  
Naoya Fujino ◽  
Tadahisa Numakura ◽  
Tomohiro Ichikawa ◽  
...  

Abstract Background: Leukocyte immunoglobulin-like receptor B4 (LILRB4) is one of the inhibitory receptors in various types of immune cells including macrophages. Previous reports suggested that LILRB4 could be involved in a negative feedback system to prevent excessive inflammatory responses. However, its role has been unclear in chronic obstructive pulmonary disease (COPD), in which macrophages play a crucial role in the pathogenesis. In this study, we aimed to examine the changes of LILRB4 on macrophages both in the lung specimens of COPD patients and the lungs of a mouse emphysema model. We then tried to compare the differences in both inflammation and emphysematous changes of the model between wild-type and LILRB4-deficient mice in order to elucidate the role of LILRB4 in the pathogenesis of COPD.Methods: We prepared single-cell suspensions of resected lung specimens of never-smokers (n = 21), non-COPD smokers (n = 16), and COPD patients (n = 14). The identification of LILRB4-expressing cells and the level of LILRB4 expression were evaluated by flow cytometry. We analyzed the relationships between the LILRB4 expression and clinical characteristics including respiratory function. In the experiments using an elastase-induced mouse model of emphysema, we also analyzed the LILRB4 expression on lung macrophages. We compared inflammatory cell accumulation and emphysematous changes induced by elastase instillation between wild-type and LILRB4-deficient mice.Results: The levels of surface expression of LILRB4 are relatively high on monocyte linage cells including macrophages in the human lungs. The percentage of LILRB4+ cells in lung interstitial macrophages was increased in COPD patients compared to non-COPD smokers (p = 0.018) and correlated with the severity of emphysematous lesions detected by CT scan (rs = 0.559, p < 0.001), whereas the amount of smoking showed no correlation with LILRB4 expression. Increased LILRB4 on interstitial macrophages was also observed in elastase-treated mice (p = 0.008). LILRB4-deficient mice showed severer emphysematous lesions with increased MMP-12 expression in the model.Conclusions: LILRB4 on interstitial macrophages was upregulated both in human COPD lungs and in a mouse model of emphysema. This upregulated LILRB4 may have a protective effect against emphysema formation, possibly through decreasing MMP-12 expression in the lungs.


Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1029
Author(s):  
Iva Hlapčić ◽  
Daniela Belamarić ◽  
Martina Bosnar ◽  
Domagoj Kifer ◽  
Andrea Vukić Dugac ◽  
...  

Interleukin (IL)-1α, IL-1β, IL-6, IL-8 and tumor necrosis factor (TNF)α contribute to inflammation in chronic obstructive pulmonary disease (COPD). We wanted to investigate their interrelations and association with disease severity, as well as to combine them with other inflammation-associated biomarkers and evaluate their predictive value and potential in identifying various patterns of systemic inflammation. One hundred and nine patients with stable COPD and 95 age- and sex-matched controls were enrolled in the study. Cytokines’ concentrations were determined in plasma samples by antibody-based multiplex immunosorbent assay kits. Investigated cytokines were increased in COPD patients but were not associated with disease or symptoms severity. IL-1β, IL-6 and TNFα showed the best discriminative values regarding ongoing inflammation in COPD. Inflammatory patterns were observed in COPD patients when cytokines, C-reactive protein (CRP), fibrinogen (Fbg), extracellular adenosine triphosphate (eATP), extracellular heat shock protein 70 (eHsp70) and clinical data were included in cluster analysis. IL-1β, eATP and eHsp70 combined correctly classified 91% of cases. Therefore, due to the heterogeneity of COPD, its assessment could be improved by combination of biomarkers. Models including IL-1β, eATP and eHsp70 might identify COPD patients, while IL-1β, IL-6 and TNFα combined with CRP, Fbg, eATP and eHsp70 might be informative regarding various COPD clinical subgroups.


2004 ◽  
Vol 48 (8) ◽  
pp. 2897-2904 ◽  
Author(s):  
Ana María Ríos ◽  
Asunción Mejías ◽  
Susana Chávez-Bueno ◽  
Mónica Fonseca-Aten ◽  
Kathy Katz ◽  
...  

ABSTRACT Mycoplasma pneumoniae is a major etiologic agent of acute lower respiratory infections. We evaluated the antimicrobial and immunologic effects of cethromycin (ABT-773), a ketolide antibiotic, for the treatment of M. pneumoniae pneumonia in a mouse model. Eight-week-old BALB/c mice were inoculated intranasally once with 106 CFU of M. pneumoniae on day 0. Treatment was started 24 h after inoculation. Groups of mice were treated subcutaneously with cethromycin at 25 mg/kg of body weight or with placebo daily until sacrifice. Five to ten mice per group were evaluated at days 1, 4, 7, and 10 after inoculation. Outcome variables included bronchoalveolar lavage (BAL) for M. pneumoniae quantitative culture and cytokine and chemokine concentration determinations by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], interleukin-1β [IL-1β], IL-2, IL-4, IL-12, granulocyte-macrophage colony-stimulating factor, IL-8, monocyte chemoattractant protein 1 [MCP-1], and macrophage inflammatory protein 1α [MIP-1α]), histopathologic score of the lungs (HPS), and pulmonary function tests (PFT) using whole-body, unrestrained plethysmography at the baseline and post-methacholine exposure as indicators of airway obstruction (AO) and airway hyperresponsiveness (AHR), respectively. The cethromycin-treated mice had a greater reduction in M. pneumoniae culture titers than placebo-treated mice, reaching statistical significance on days 7 and 10 (P < 0.05). HPS was significantly reduced in cethromycin-treated mice compared with placebo-treated mice on days 4, 7, and 10 (P < 0.05). Cytokine concentrations in BAL samples were reduced in mice that received cethromycin, and the differences were statistically significant for 7 of the 10 cytokines measured (TNF-α, IFN-γ, IL-1β, IL-8, IL-12, MCP-1, and MIP-1α) on day 4 (P < 0.05). PFT values were improved in the cethromycin-treated mice, with AO and AHR significantly reduced on day 4 (P < 0.05). In this mouse model, treatment with cethromycin significantly reduced M. pneumoniae culture titers in BAL samples, cytokine and chemokine concentrations in BAL samples, histologic inflammation in the lungs, and disease severity as defined by AO and AHR.


2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Ying Tang ◽  
Xiaodan Li ◽  
Man Wang ◽  
Qi Zou ◽  
Shasha Zhao ◽  
...  

T cells and B cells participate in the pathogenesis of COPD. Currently, NK cells and NKT cells have gained increasing attention. In the present study, 19 COPD patients and 12 healthy nonsmokers (HNS) were recruited, and their pulmonary function was assessed. The frequencies of CD3+T, CD4+T, CD8+T, B, NK, and NKT-like cells were determined using flow cytometry. The frequencies of spontaneous and inducible IFN-γ+or CD107a+NK and NKT-like cells as well as activating or inhibitory receptors were also detected. The potential association of lymphocyte subsets with disease severity was further analyzed. Significantly decreased numbers of CD3+and CD4+T cells, and the CD4+/CD8+ratio, but increased numbers of CD3−CD56+NK and CD3+CD56+NKT-like cells were observed in COPD patients compared to HNS. The frequencies of inducible IFN-γ-secreting NK and NKT-like cells were less in COPD patients. The frequencies of CD158a and CD158b on NK cells and CD158b on NKT-like cells were greater. The frequency of CD158b+NK cells was negatively correlated with FEV1% prediction and FEV1/FVC. Our data indicate that COPD patients have immune dysfunction, and higher frequencies of inhibitory NK cells and NKT-like cells may participate in the pathogenesis of COPD.


2019 ◽  
Vol 7 (14) ◽  
pp. 2298-2304
Author(s):  
Muhammad Ilyas ◽  
Agussalim Agussalim ◽  
Megawati Megawati ◽  
Nasrum Massi ◽  
Irawaty Djaharuddin ◽  
...  

Background: Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory disease and disturbed bacterial clearance. Vitamin D deficiency is sometimes observed in COPD patients and as significant roles in increasing inflammation of airway obstruction and systemic obstruction, increasing proinflammatory cytokine including TNF-α, reduction of bacterial clearance and increase exacerbation risk due to infection. Also, vitamin D plays significant roles in the metabolism of calcium and mineralization of bones and regulation system of immune. TNF-α also has essential roles in pathogenesis and inflammation of COPD.  Several studies that investigate the relationship between vitamin D level and serum TNF-α concentration in COPD patients are relatively uncommon, including in Indonesia. For that reason, this study aimed to assess the relationship between vitamin D level and TNF-α concentration in patients on the severity of the chronic obstructive pulmonary disease. Methods This study was a hospital-based descriptive cross-sectional study. Total samples were 50 COPD patients with the average age of older than 60 years during their enrollments at the Department of Pulmonology and Respiratory Medicine of the Dr.Wahidin Sudirohusodo General hospital  Makassar in September 2018-January 2019. All procedures of the present study were reviewed and approved by the Research Ethics Committee of Medicine Faculty of Hasanuddin University. The severity of COPD was assessed according to the combination of COPD assessment stages that referred to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guideline 2015 that consisted of the combination of scoring COPD Assessment Test (CAT), the modified Medical Research Council (mMRC) questionnaire and results of the spirometric measurement. Assessment of airway obstruction levels referred to the GOLD spirometric criteria. Determination of thoracic photographs was conducted to verify the COPD diagnosis of the severity of COPD. Determination of serum TNF-α concentration and vitamin D3 [1,25(OH)2D3] level used the ELISA method. Results  The majority of COPD patients were observed in the category of older than 60 years old accounted for 34 COPD patients (68%), and the majority of COPD patients were males accounted for 47 males with COPD (94%). The majority of COPD patients were observed in the group of D (38%). All the study subjects observed in this study were smokers, and 82% of them were in the category of heavy smokers. 21 study subjects had higher concentration of serum TNF-α  (tertile 3 = 0.21-1.83 pg/dl), 20 study subjects  and lower level of vitamin D (tertile 1 = 182.1-364.5 pg/dl). The majority of the study subjects (38%) were in the category of severe COPD (category D of the severity of COPD at the tertile 3) according to the GOLD Combine Assessment. In view of the relationship between vitamin D level and serum TNF-α concentration on the airway obstruction, there were significant positive correlations between the increase of vitamin D levels and the increase of serum TNF-α concentrations on airway obstruction. In view of the relationship between vitamin D level and serum TNF-α concentration on the severity of COPD, there were significant positive correlations between the increase of vitamin D levels (tertiles 1, 2 and 3) and the increase of serum TNF-α concentrations on the severity of COPD at p-value<0.05. Overall, there were non-linear relationships between vitamin D level and serum TNF-α concentration on the severity of COPD. Conclusions: Serum TNF-α concentration was positively associated with airway obstruction level and severity of COPD. Low level of vitamin D was negatively associated with airway obstruction level and severity of COPD. Vitamin D3 level (1,25(OH)2D) was negatively associated with serum TNF-α concentration and airway obstruction level and severity of COPD.


2020 ◽  
Vol 2020 ◽  
pp. 1-6 ◽  
Author(s):  
Margarita Y. Pervakova ◽  
Alexandra V. Mazing ◽  
Sergey V. Lapin ◽  
Olga Y. Tkachenko ◽  
Anna I. Budkova ◽  
...  

Chronic obstructive pulmonary disease (COPD) is multifactorial disease, which is characterized by airflow limitation and can be provoked by genetic factors, including carriage of the PiZ allele of the protease inhibitor (Pi) gene, encoding alpha-1 antitrypsin (A1AT). Both homozygous and heterozygous PiZ allele carriers can develop COPD. It was found recently that normal A1AT regulates cytokine levels, including IL-17, which is involved in COPD progression. The aim of this study was to determine whether homozygous or heterozygous PiZ allele carriage leads to elevated level of IL-17 and other proinflammatory cytokines in COPD patients. Materials and Methods. Serum samples and clinical data were obtained from 44 COPD patients, who included 6 PiZZ, 8 PiMZ, and 30 PiMM A1AT phenotype carriers. Serum concentrations of IL-17, IL-6, IL-8, IFN-γ, and TNF-α were measured by the enzyme-linked immunosorbent assay (ELISA). All A1AT phenotypes were verified by narrow pH range isoelectrofocusing with selective A1AT staining. A turbidimetric method was used for quantitative A1AT measurements. Results. COPD patients with both PiZZ and PiMZ phenotypes demonstrated elevated IL-17 and decreased IFN-γ levels in comparison to patients with the PiMM phenotype of A1AT. Thereafter, the ratio IL-17/IFN-γ in PiZZ and PiMZ groups greatly exceeded the values of the PiMM group. Homozygous PiZ allele carriers also had significantly higher levels of IL-6 and lower levels of IL-8, and IL-6 values correlated negatively with A1AT concentrations. Conclusions. The presence of the PiZ allele in both homozygous and heterozygous states is associated with altered serum cytokine levels, including elevated IL-17, IL-17/IFN-γ ratio, and IL-6 (only PiZZ), but lower IFN-γ and IL-8.


2020 ◽  
Vol 19 ◽  
pp. 153303382095180
Author(s):  
Jian Chen ◽  
Xincai Li ◽  
ChaoLin Huang ◽  
Ying Lin ◽  
Qingfu Dai

Objective: This study aimed to investigate the serum inflammatory cytokines levels in patients with COPD, pneumonia and lung cancer, and assess the correlation between the levels of inflammatory cytokines levels and development of these diseases. Methods: Two hundred thirty-two patients including 114 patients with pneumonia, 76 patients with chronic obstructive pulmonary disease (COPD) and 42 patients with lung cancer, and 62 age-matched healthy volunteers as controls were enrolled. The pro-inflammatory cytokine IL-6, IL-2, IFN-γ, TNF-α, anti-inflammatory cytokines IL-4 and IL-10 in serum were analyzed by flow cytometry microsphere array (CBA). Results: We found that the levels of TNF-α and IL-10 in patients with lung cancer, COPD and pneumonia were significantly higher than control group. The IL-6 in the lung cancer group were significantly increased compared with the controls and COPD group, pneumonia group. IFN-γ and IL-2 levels were lower in lung cancer compared with controls and COPD group, pneumonia group. TNF-α, IL-4 and IL-10 levels were increased in patients with COPD and pneumonia compared with controls. In addition, the concentrations of IFN-γ and IL-6 were increased in acute exacerbation COPD (AECOPD) group compared with stable COPD group. Conclusion: In conclusion, elevated TNF-α and IL-10 levels in serum may be related with lung diseases including lung cancer, COPD and pneumonia. Additionally, IFN-γ and IL-6 might be potential biomarkers for the further deterioration of lung disease patients. The increased concentrations of IFN-γ and IL-6 might be used to predict the exacerbation of COPD.


2021 ◽  
Vol 8 ◽  
Author(s):  
Zhu-Xia Tan ◽  
Lin Fu ◽  
Wen-Jing Wang ◽  
Ping Zhan ◽  
Hui Zhao ◽  
...  

Background: Cysteine-rich 61 (CYR61) and inflammation was upregulated in the lungs of patients with chronic obstructive pulmonary disease (COPD). However, the association between CYR61 and inflammation was unclear in COPD patients. This study aimed to analyze the association of serum CYR61 with pulmonary inflammation and lung function indexes in COPD patients.Methods: One hundred and fifty COPD patients and 150 control subjects were enrolled. Serum and pulmonary CYR61 was detected. Lung function indexes were evaluated in COPD patients.Results: Serum CYR61 level was elevated and pulmonary CYR61 expression was upregulated in COPD patients. An increased CYR61 was associated with decreased pulmonary function indexes in COPD patients. Further analyses showed that nuclear factor-kappa B (NF-κB) p65-positive nuclei was elevated in the lungs of COPD patients with high level of CYR61. Accordingly, serum monocyte chemotactic protein (MCP)-1 and tumor necrosis factor α (TNF-α), two downstream inflammatory cytokines of NF-κB pathway, were increased in parallel with CYR61, among which serum MCP-1 and TNF-α were the highest in COPD patients with high level of CYR61. Moreover, a positive correlation, determined by multivariate regression that excluded the influence of age, gender and smoking, was observed between serum CYR61 and inflammatory cytokines in COPD patients.Conclusion: These results provide evidence that an increased CYR61 is associated with pulmonary inflammation and COPD progression. Inflammatory cytokines may be the mediators between CYR61 elevation and COPD progression.


Author(s):  
Mathanraj S. ◽  
Vysak Kumar ◽  
Yuvarajan S. ◽  
Vikram Reddy

Background: Tumor necrosis factor alpha (TNF α) is the most widely studied cytokine of TNF super family. TNF α plays a significant role in many inflammatory diseases affecting the lung, such as chronic bronchitis (CB), chronic obstructive pulmonary disease (COPD), asthma, acute lung injury (ALI) and acute respiratory distress syndrome. Elevated levels of TNF-alpha are seen in COPD patients. An increased level of TNF-α has been found in induced sputum or lung biopsy of COPD patients. 14-16 This study includes correlation of level of TNF α with severity and characterization of individuals with COPD. There are only limited numbers of studies being conducted regarding this topic in the world, including India. Objectives of present study were to measure the TNF-α level in patients with chronic obstructive pulmonary disease and to correlate TNF α level with severity of chronic obstructive pulmonary disease.Methods: The study was conducted on one hundred and eight (108) patient’s COPD patients attending the Pulmonary medicine department of Sri Manakula Vinayagar Medical College and Hospital Puducherry, who are aged above forty years, with a duration of 18 months, starting from the date of getting approval from the Ethics Committee. The subjects were analysed on their TLC, DLC was done to rule out any co-existing infections. Spirometry was done to confirm the diagnosis of COPD. Blood was taken from the confirmed COPD patients after getting their approval, for the estimation of serum TNF α level.Results: The Serum TNF alpha levels increases according to the COPD severity. The mean serum TNF alpha level in patients with mild obstruction, moderate obstruction, severe and very severe obstruction were 9.91+2.9, 21.25+4.8, 32.4+8.2 and 39.2+3.1pg/dl respectively. Mean TNF alpha value was 26.7pg/dl. The values of TNF α increases with the stages of COPD which is statistically significant with p value of 0.0001.Conclusions: The present study showed that serum TNF alpha level correlates with severity of airway obstruction in spirometry among the COPD patients. It also correlates with the disease severity as per the different stages of COPD patients (GOLD COPD staging 2016). Thus, serum TNF alpha is a useful marker to monitor the disease severity in addition to spirometric parameters like FVC, FEV1 and FEV1/FVC. However, further studies are needed with larger sample size.


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