Neutrophilic Inflammation In Patients Research Articles

ST2-Mediated Neutrophilic Airway Inflammation: A Therapeutic Target for Patients With Uncontrolled Asthma.

Suppression of tumorigenicity 2 (ST2) has been proposed as the receptor contributing to neutrophilic inflammation in patients with type 2-low asthma. However, the exact role of ST2 in neutrophil activation remains poorly understood. A total of 105 asthmatic patients (classified into 3 groups according to control status: the controlled asthma [CA], partly-controlled asthma [PA], and uncontrolled asthma [UA] groups), and 104 healthy controls were enrolled to compare serum levels of soluble ST2 (sST2) and interleukin (IL)-33. Moreover, the functions of ST2 in neutrophils and macrophages (Mϕ) were evaluated ex vivo and in vivo. Serum sST2 levels were significantly higher in the UA group than in the CA or PA groups (P < 0.05 for all) with a negative correlation between serum sST2 and forced expiratory volume in 1 second % (r = -0.203, P = 0.038). Significantly higher expression of ST2 receptors on peripheral neutrophils was noted in the UA group than in the PA or CA groups. IL-33 exerted its effects on the production of reactive oxygen species, the formation of extracellular traps from neutrophils, and Mϕ polarization/activation. In neutrophilic asthmatic mice, treatment with anti-ST2 antibody significantly suppressed proinflammatory cytokines (tumor necrosis factor-alpha and IL-17A) as well as the numbers of immune cells (neutrophils, Mϕ, and group 3 innate lymphoid cells) in the lungs. These results suggest that IL-33 induces the activation of neutrophils and Mϕ via ST2 receptors, leading to neutrophilic airway inflammation and poor control status of asthma. ST2 could be a therapeutic target for neutrophilic airway inflammation in patients with UA.

Type 17 mucosal-associated invariant T cells contribute to neutrophilic inflammation in patients with nasal polyps

Immune regulation in chronic rhinosinusitis with nasal polyps (CRSwNP) with a neutrophilic endotype remains unclear. Mucosal-associated invariant T (MAIT) cells are tissue-resident innate T lymphocytes that respond quickly to pathogens and promote chronic mucosal inflammation. We investigated the roles of MAIT cells in neutrophilic CRSwNP. Nasal tissues were obtained from 110 CRSwNP patients and 29 control subjects. Peripheral and tissue MAIT cells and their subsets were analyzed by flow cytometry. Polyp derived MAIT cells were analyzed by RNA-sequencing and used to study their effects on neutrophils. Endotypes of CRSwNP were classified into paucigranunlocytic (n=21), eosinophilic (n=29), neutrophilic (n=37), and mixed granulocytic (n=23). Frequencies of MAIT cells were significantly higher in neutrophilic (3.62%) and mixed granulocytic (3.60%) polyps than in control mucosa (1.78%). MAIT cell percentages positively correlated with local neutrophil counts. MAIT cells were more enriched in tissues than in matched PBMCs. The frequencies of MAIT1 subset or IFN-γ+ MAIT cells were comparable among control tissues and CRSwNP subtypes. The proportions of MAIT17 subset or IL-17A+MAIT cells were significantly increased in neutrophilic or mixed granulocytic polyps compared to controls. RNA-sequencing revealed type 17 and pro-neutrophil profiles in neutrophilic polyp derived MAIT cells. In patients with neutrophilic CRSwNP, the proportions of the MAIT and the MAIT17 were positively correlated with local pro-inflammatory cytokines and symptom severity. In vitro experiments demonstrated that neutrophilic polyps derived MAIT cells promoted neutrophil migration, survival, and activation. MAIT cells from neutrophilic CRSwNP present type 17 functional properties and promote neutrophil infiltration in nasal mucosa.

Role of neutrophil interleukin-23 in spondyloarthropathy spectrum disorders.

Neutrophilic inflammation is a pervasive characteristic common to spondyloarthropathies and related disorders. This inflammation manifests as Munro's microabscesses of the skin and osteoarticular neutrophilic inflammation in patients with psoriatic arthritis, intestinal crypt abscesses in patients with inflammatory bowel disease, ocular hypopyon in anterior uveitis, and neutrophilic macroscopic and microscopic inflammation in patients with Behçet's disease. Strong MHC class I associations are seen in these diseases, which represent so-called MHC-I-opathies, and these associations indicate an involvement of CD8 T-cell immunopathology that is not yet well understood. In this Personal View, we highlight emerging data suggesting that the T-cell-neutrophil axis involves both a T-cell-mediated and interleukin (IL)-17-mediated (type 17) recruitment and activation of neutrophils, and also a sequestration of activated neutrophils at disease sites that might directly amplify type 17 T-cell responses. This amplification likely involves neutrophilic production of IL-23 and proteases as well as other feedback mechanisms that could be regulated by local microbiota, pathogens, or tissue damage. This crosstalk between innate and adaptive immunity offers a novel explanation for how bacterial and fungal microbes at barrier sites could innately control type 17 T-cell development, with the aim of restoring tissue homoeostasis, and could potentially explain features of clinical disease and treatment response, such as the fast-onset action of the IL-23 pathway blockade in certain patients. This axis could be crucial to understanding non-response to IL-23 inhibitors among patients with ankylosing spondylitis, as the axial skeleton is a site rich in neutrophils and a site of haematopoiesis with myelopoiesis in adults.

Bronchiectasis enters the inflammation era.

Bronchiectasis enters the inflammation era.

Calprotectin as a New Sensitive Marker of Neutrophilic Inflammation in Patients with Bronchiolitis Obliterans.

Introduction Bronchiolitis obliterans (BO) is a chronic disease in which persistent inflammation leads to obstruction and obliteration of the small airways. The aim of this study was to evaluate the value of calprotectin as an inflammatory marker in induced sputum. Methods Twenty-eight patients suffering from BO and 18 healthy controls were examined. Lung function was measured by spirometry, body plethysmography, and lung clearance index (LCI). The induced sputum was obtained, cell counts were performed, and cytokines were measured using cytometric bead array (CBA). Calprotectin was quantified in the sputum and serum samples using commercially available sandwich ELISA. Results Spirometry parameters including forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and maximum expiratory flow rate at 25% vital capacity (MEF25) were significantly lower in BO patients than in healthy controls, whereas the reserve volume (RV), RV to total lung capacity ratio (RV/TLC), and LCI were significantly increased. In sputum, calprotectin levels, neutrophils, and IL-8 were significantly elevated. Calprotectin levels correlated strongly with IL-8 and other biomarkers, neutrophils FEV1 and MEF25. In serum, calprotectin was significantly diminished in BO patients compared to controls. Conclusion Lung function is severely impaired in BO patients. Calprotectin is significantly elevated in the sputum of BO patients and reflects ongoing neutrophilic inflammation.

Charcot-Leyden crystals promote neutrophilic inflammation in patients with nasal polyposis

Charcot-Leyden crystals promote neutrophilic inflammation in patients with nasal polyposis

Inflammatory patterns of antrochoanal polyps in the pediatric age group

BackgroundThe pathogenesis and etiology of antrochoanal polyps (ACPs) remains obscure. This study aimed to characterize the inflammatory profiles and investigate the effect of atopy on the pathogenesis of pediatric ACPs.MethodsThirty-three ACP patients and ten control subjects were enrolled from January to December 2017. The severity of individual nasal symptoms was scored on a visual analogue scale (VAS). The serum total immunoglobulin E (IgE) and cytokines level was measured by multiplexed luminex assay.ResultsThere was no significant difference in VAS scores and counts of inflammatory cells between atopic and nonatopic ACP. No difference in IFNγ, IL-4, IL-5, IL-13, IL-17A and IL-25 was found between control and whole ACP, nonatopic and atopic ACP. Significantly increased levels of IL-6 and IL-10 were found in ACP compared with control. For neutrophil chemotactic factor, significant increases of IL-8 and GRO were observed in ACP, but for eosinophil chemotactic factor, no difference was found in RANTES and GM-CSF. IL-6 level was positively correlated with IL-8, MCP1, and GRO level, and IL-10 level was positively correlated with IL-4 and IL-13 in ACP subjects.ConclusionNasal obstruction was the most common symptom in ACPs in children. Allergic condition may have a poor role in the pathogenesis of ACPs. IL-6 plays a crucial role in the pathogenesis of neutrophilic inflammation in patients with ACPs and may provide a new treatment strategy for ACPs in children. Treg cell associated cytokine IL-10 was involved in the inflammatory pathophysiological process of ACPs and played a certain regulatory role.

Sputum inflammatory profile before and after specific inhalation challenge in individuals with suspected occupational asthma.

BackgroundThe aim of this study was to establish the sputum inflammatory profile and changes in levels of leukotriene B4 (LTB4) and a panel of Th1/Th2 cytokines in subjects with suspected occupational asthma (OA) following specific inhalation challenge (SIC) to high-molecular-weight (HMW) and low-molecular-weight (LMW) agents.Material and MethodsFifty-one consecutive subjects undergoing SIC for suspected OA were enrolled. Sputum induction was performed the day before and 24 h after exposure to the offending agent. Total and differential cell counts were assessed. LTB4 and a 10 Th1/Th2 cytokines were measured in sputum supernatant.ResultsThirty-four patients tested positive to SIC and were diagnosed with OA (in 10 due to HMW agents and in 24 to LMW agents). SIC was negative in 17 subjects. As compared to baseline an increase was found in the percentage of sputum eosinophils and neutrophils, and in IL-10 concentration after SIC (p = 0.0078, p = 0.0195, and p = 0.046, respectively), and a decrease was seen in LTB4 level (p = 0.0078) in patients with OA due to HMW agents. An increase in the percentage of sputum neutrophils after SIC (p = 0.0040) was observed in subjects without OA exposed to LMW agents. IL-8 levels after SIC were higher in patients without OA compared with patients with OA (p = 0.0146).ConclusionWhen conducting airway inflammation studies in OA, patients should be divided according to the causal agent (HMW or LMW). In OA patients exposed to HMW agents, an increase in the number of neutrophils can be found in parallel to the increase of eosinophils, although this does not contradict an IgE-mediated mechanism. Exposure to LMW agents can result in increased neutrophilic inflammation in patients with airway diseases unrelated to OA. There is variability in the responses observed in patients with OA exposed to LMW agents.

Local and systemic neutrophilic inflammation in patients with lung cancer and chronic obstructive pulmonary disease

BackgroundRecent investigations suggest that neutrophils play an important role in the immune response to lung cancer as well as chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the amount of neutrophils and markers of their activity in lung cancer and COPD and in coexistence of these two diseases.MethodsIn total, 267 persons were included in the study: 139 patients with lung cancer, 55 patients with lung cancer and COPD, 40 patients with COPD, and 33 healthy subjects. Peripheral blood and BAL fluid samples were obtained for cell count analysis and determination of NE, MPO levels and ROS production. NE and MPO levels in the serum and BAL fluid were determined by ELISA. ROS production was analyzed by flow cytometer.ResultsThe percentage, cell count of neutrophils and neutrophil to lymphocyte ratio in the peripheral blood were significantly higher in lung cancer patients with or without COPD compared to COPD patients or healthy individuals (P < 0.05). The percentage and cell count of neutrophils in BAL fluid were significantly lower in patients with lung cancer with or without COPD than in patients with COPD (P < 0.05). However, BAL fluid and serum levels of both NE and MPO were significantly higher in patients with lung cancer than COPD patients or healthy individuals (P < 0.05). Neutrophils produced higher amounts of ROS in patients with lung cancer with or without COPD compared with COPD patients or healthy individuals (P < 0.05).ConclusionsThe results from this study demonstrate higher degree of local and systemic neutrophilic inflammation in patients with lung cancer (with or without COPD) than in patients with COPD.

Assessment of Pulmonary Neutrophilic Inflammation in Emphysema by Quantitative Positron Emission Tomography

Neutrophilic inflammation is understood to be of pathogenetic importance in chronic obstructive pulmonary disease (COPD) and may be quantified using 18-fluorodeoxyglucose positron emission tomography-computed tomography ((18)FDG PET-CT) as a noninvasive, spatially informative biomarker. To assess the potential usefulness of (18)FDG PET-CT as a surrogate measure of pulmonary neutrophilic inflammation in patients with usual COPD and α(1)-antitrypsin deficiency (AATD). (18)FDG PET-CT imaging was performed in 10 patients with usual COPD, 10 patients with AATD, and 10 healthy control subjects. Pulmonary (18)FDG uptake was estimated by three-dimensional Patlak graphical analysis as an indicator of pulmonary neutrophilic glycolytic activity. Patients with AATD were treated with 12 weekly intravenous infusions of AAT augmentation therapy before repeat imaging. (18)FDG uptake, lung physiology, lung density, and systemic markers of inflammation were compared for all groups at baseline and, in patients with AATD, at baseline and on treatment. (18)FDG uptake in the upper lung of patients with usual COPD was greater compared with the healthy control group (P = 0.009) and correlated with measures of disease severity (FEV(1)% predicted, r = -0.848, P = 0.001; FEV(1)/FVC, r = -0.918, P < 0.001; Kco% predicted, r = -0.624, P = 0.027; 15th percentile point, r = -0.709, P = 0.011). No significant difference was observed between measurements at baseline and on treatment in patients with AATD. Quantitative (18)FDG PET-CT has a potential role as an imaging biomarker in mechanistic and interventional studies in patients with usual COPD. The data support previous evidence of distinct functional characteristics of neutrophils in COPD. Clinical trial registered with https://eudract.ema.europa.eu/index.html (EudraCT 2007-004869-18).

Neutrophilic Inflammation and CXC Chemokines in Patients with Refractory Asthma

Background: There is evidence that eosinophils and neutrophils are simultaneously increased in the airways of some patients with chronic refractory asthma. The mechanisms by which neutrophils accumulate in the airways of asthmatics remain to be elucidated, however, chemoattractants for neutrophils such as CXC chemokines may affect either the accumulation or functional status of neutrophils in such patients. The objective of the present study was to identify the CXC chemokine responsible for the neutrophilic and possibly eosinophilic inflammation observed in the airways of patients with refractory asthma. Methods: Following the inhalation of hypertonic saline, induced sputum was obtained from 14 healthy controls, 16 patients with mild well-controlled nonrefractory asthma, and 14 patients with refractory asthma. Concentrations of CXC chemokines and differential inflammatory cell counts were determined. Results: The percentages of induced sputum eosinophils were significantly higher both in patients with nonrefractory asthma and in patients with refractory asthma. On the other hand, the percentages of neutrophils were increased only in sputum from patients with refractory asthma. The concentration of IL-8, but not ENA-78 or GRO-α, was also significantly increased in induced sputum from patients with refractory asthma. The concentration of IL-8 correlated significantly with the percentages of neutrophils. Conclusions: The results of the present study suggest that IL-8, but not ENA-78 or GRO-α, may contribute to the observation of neutrophilic inflammation in patients with refractory asthma.

Induced sputum in interstitial lung diseases

Induced sputum is a particularly useful procedure since it provides information on the cellular and molecular constituents in inflammation. Extensive work has demonstrated the application of induced sputum in the management of asthma, chronic obstructive pulmonary disease and chronic bronchitis, but less attention has been paid to its efficacy in diagnosing interstitial lung diseases. This review analyzes the applications of induced sputum in the assessment of sarcoidosis, nongranulomatous interstitial lung diseases, occupational lung diseases and other systemic diseases with or without lung involvement. T cell subsets in induced sputum in combination with pulmonary function testing can serve as predictors with high specificity and sensitivity in diagnosing sarcoidosis, using multivariate logistic regression models which can be easily implemented in clinical practice. Differential cell counts in induced sputum are as useful as bronchoalveolar lavage for identifying neutrophilic inflammation in patients with nongranulomatous interstitial lung diseases (e.g. idiopathic pulmonary fibrosis) and detecting chronic rejection in bronchiolitis obliterans syndrome. Sputum analysis has also been shown to be a useful tool for diagnosing, assessing and monitoring occupational lung disorders. We suggest integrating induced sputum technology to the well-established criteria for the diagnosis of interstitial lung diseases, especially when there are clinical contraindications for performing bronchoscopy or when tissue confirmation is absent for any reason.

Inhaled Corticosteroids May Reduce Neutrophilic Inflammation in Patients with Stable Chronic Obstructive Pulmonary Disease

Background: Although both inhaled and oral corticosteroids have anti-inflammatory effects causing improvement in clinical symptoms and spirometry in the treatment of asthma, the role of corticosteroids in the management of chronic obstructive pulmonary disease (COPD) is controversial. Objective: To evaluate the effects of inhaled corticosteroids on sputum neutrophilia in clinically stable COPD patients. Methods: In total, 18 patients were enrolled in the study. During 2 months, 9 patients in group A inhaled fluticasone propionate (FP) 500 μg 3 times daily. In group B 9 patients received placebo. All of the patients continued to inhale both salbutamol and ipratropium bromide. In 9 patients, sustained-released theophylline was also administered. Blood samples, spirometric tests, blood gas analyses, and either spontaneous or induced sputum cultures were evaluated on entry into the study, after a 2 months of treatment and following the 6-week washout period. Results: After the 2-month FP treatment, no significant changes in the number of peripheral blood neutrophils, blood gas and spirometry data were observed in both groups. In group A, the total cell number and the number of neutrophils decreased from a mean of 3.4 ± 1.3 × 10⁶ cells/g and 0.6 ± 0.3 × 10⁶ neutrophils/g on entry into study to 1.9 ± 0.6 × 10⁶ cells/g and 0.02 ± 0.01 × 10⁶ neutrophils/g after 8-week treatment with FP, returning to 3.3 ± 1.1 × 10⁶ cells/g and 0.5 ± 0.3 × 10⁶ neutrophils/g following the washout period. The percentages of neutrophils were 55.6 and 77.9% in groups A and B after 2 months of FP treatment. There was no significant change in group B values during the study. Conclusion: These data suggest that neutrophilic inflammation in sputum may be decreased by inhaled corticosteroids in clinically stable COPD patients.