Vandana Gupta

Anti-inflammatory potential of PI3Kδ and JAK inhibitors in asthma patients.

BackgroundPhosphatidylinositol 3-kinase delta (PI3Kδ) and Janus-activated kinases (JAK) are both novel anti-inflammatory targets in asthma that affect lymphocyte activation. We have investigated the anti-inflammatory effects of PI3Kδ and JAK inhibition on cytokine release from asthma bronchoalveolar lavage (BAL) cells and T-cell activation, and measured lung PI3Kδ and JAK signalling pathway expression.MethodCells isolated from asthma patients and healthy subjects were treated with PI3Kδ or JAK inhibitors, and/or dexamethasone, before T-cell receptor stimulation. Levels of IFNγ, IL-13 and IL-17 were measured by ELISA and flow cytometry was used to assess T-cell activation. PI3Kδ, PI3Kγ, phosphorylated protein kinase B (pAKT) and Signal Transducer and Activator of Transcription (STAT) protein expression were assessed by immunohistochemistry in bronchial biopsy tissue from asthma patients and healthy subjects. PI3Kδ expression in BAL CD3 cells was measured by flow cytometry.ResultsJAK and PI3Kδ inhibitors reduced cytokine levels from both asthma and healthy BAL cells. Combining dexamethasone with either a JAK or PI3Kδ inhibitor showed an additive anti-inflammatory effect. JAK and PI3Kδ inhibitors were shown to have direct effects on T-cell activation. Immunohistochemistry showed increased numbers of PI3Kδ expressing cells in asthma bronchial tissue compared to controls. Asthma CD3 cells in BAL expressed higher levels of PI3Kδ protein compared to healthy cells.ConclusionsTargeting PI3Kδ or JAK may prove effective in reducing T-cell activation and the resulting cytokine production in asthma.

Characterization of the inflammatory response to inhaled lipopolysaccharide in mild to moderate chronic obstructive pulmonary disease

AIMSnLipopolysaccharide (LPS) inhalation causes increased airway and systemic inflammation. We investigated LPS inhalation in patients with chronic obstructive pulmonary disease (COPD) as a model of bacterial exacerbations. We studied safety, changes in sputum and systemic biomarkers. We have also investigated interleukin (IL)-17 concentrations in this model.nnnMETHODSnTwelve COPD patients inhaled 5 μg LPS. Safety was monitored over 24 h. Sputum was induced at baseline, 6 and 24 h for cells and IL-8, IL-17, neutrophil elastase, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β) in supernatants. Serum was collected at baseline, 4, 8 and 24 h for IL-6, C-reactive protein (CRP) and Clara cell protein (CC-16) concentrations. Peripheral blood mononuclear cells (PBMCs) were isolated at baseline and 4 h for systemic IL-17 analysis.nnnRESULTSnLPS 5 μg was well tolerated. The greatest FEV1 change was 11.7% (mean) at 1 h (95% CI 5.1-18.2%). There was a large range in maximal fall (2.5-37.7%). Total sputum cell count and neutrophil count significantly increased 6 and 24 h post-LPS. There was no change in sputum supernatant mediators. IL-6, CRP and CC-16 increased post-inhalation, with different temporal patterns. CD4+ and CD8+ cell associated IL-17 significantly increased at 4 h.nnnCONCLUSIONSnInhaled LPS in COPD patients safely causes increased airway and systemic inflammation. This may be a model for studying COPD exacerbations.

Critical assessment of the value of sputum neutrophils

Abstract Neutrophils are central to the pathogenesis of COPD, releasing a range of pro-inflammatory and tissue destructive mediators. Sputum neutrophil numbers are elevated in COPD patients compared to healthy controls. We critically appraise the potential of sputum neutrophils as a biomarker in COPD. We show that there is insufficient evidence to support the use of this biomarker to define a phenotype of patients with more severe disease characteristics or a different prognosis. However, sputum neutrophil measurements can be used to measure the effects of anti-inflammatory drugs for the treatment of COPD.

Characteristics and longitudinal progression of chronic obstructive pulmonary disease in GOLD B patients

BackgroundThe characteristics and natural history of GOLD B COPD patients are not well described. The clinical characteristics and natural history of GOLD B patients over 1 year in a multicentre cohort of COPD patients in the COPDMAP study were assessed. We aimed to identify the subgroup of patients who progressed to GOLD D (unstable GOLD B patients) and identify characteristics associated with progression.MethodsThree hundred seventy COPD patients were assessed at baseline and 12xa0months thereafter. Demographics, lung function, health status, 6xa0min walk tests and levels of systemic inflammation were assessed. Students t tests and Mann Whitney-U tests were used.ResultsOne hundred seven (28.9%) of patients were categorised as GOLD B at baseline. These GOLD B patients had similar FEV1 to GOLD A patients (66% predicted). More GOLD B patients were current smokers (pu2009=u20090.031), had chronic bronchitis (pu2009=u20090.0003) and cardiovascular comorbidities (pu2009=u20090.019) compared to GOLD A. At 12xa0months, 25.3% of GOLD B patients progressed to GOLD D. These patients who progressed (unstable patients) had worse health status and symptoms (SGRQ-C Total, 50.0 v 41.1, pu2009=u20090.019 and CAT, 21.0 v 14.0, pu2009=u20090.006) and lower FEV1 (60% v 69% pu2009=u20090.014) at baseline compared to stable patients who remained in GOLD B.ConclusionsUnstable GOLD B patients who progressed to GOLD D had a higher level of symptoms at baseline. A high symptom burden may predict an increased likelihood of disease progression in GOLD B patients.

Aclidinium bromide for the treatment of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease is characterized by poorly reversible airflow obstruction. Long-acting bronchodilators improve lung function and relieve dyspnea. Aclidinium bromide is a novel long-acting antimuscarinic bronchodilator; Phase III clinical trials have demonstrated that administration of this drug twice per day improves lung function, dyspnea and health-related quality of life. Aclidinium bromide is delivered using the Genuair® device, which is an easy to use multidose dry powder inhaler. Aclidinium bromide is rapidly metabolized in the plasma, so there is low systemic exposure that minimizes the anticholinergic side effects. This new long-acting bronchodilator provides effective bronchodilation with minimal side effects.

M15 Nebulised bronchodilators pre-bronchoscopy in patients with obstructive lung disease: does it help?

Background Patients with Chronic obstructive pulmonary disease (COPD) and asthma may be at higher risk of complications during bronchoscopy. Previous guidelines have recommended that all patients with asthma receive nebulised bronchodilators pre procedure. At our research centre, we changed our practice in January 2012; since this date we administer nebulised salbutamol to all patients with COPD and asthma pre-bronchoscopy. Aims We examined research bronchoscopy records from asthma and COPD patients with and without nebulised bronchodilators to determine tolerance of procedure, complications and adverse events, sedation used and success of obtaining samples. We have also examined the overall safety of research bronchoscopies. Methods A retrospective analysis of case report forms of 140 (65 asthma and 75 COPD) patients who underwent research bronchoscopy at our centre since November 2010. Results See Table 1 for details. Abstract M15 Table 1. Summary of patient demographics, tolerance and saline inserted for BAL. COPD P value Asthma P value No Pre-Procedure Neb (n=38) Pre-Procedure Neb (n=37) No Pre-Procedure Neb (n=32) Pre-Procedure Neb (n=33) Sex(M/F) 22/16 26/11 20/12 18/15 Age(yrs) 63.2 (5.7) 63.0 (6.1) ns 44.3 (12.9) 40.8 (10.8) ns Pack Yrs* 39.9 (10.2 - 82.8) 42.0 (14.5 - 98.8) ns ACQ* 1.3(0.1 - 3.0) 1.4 (0.3 - 4.6) ns FEV1 (L) 1.7(0.4) 1.9 (0.5) 0.07 2.9 (1.0) 2.7 (0.8) ns FEV1 (%) 61.3 (13.5) 63.7 (11.1) ns 83.7 (20.4) 80.7 (20.4) ns Poor Tolerance 7.9% 10.8% ns 6.3% 9.1% ns BAL (ml)* 480.0(240.0 - 480.0) 420.0(0.0 - 480.0) 0.06 480.0(0.0 - 480.0) 480.0(0.0 - 480.0) ns * denotes median (range) Baseline characteristics were the same among COPD and asthma patients who did and did not receive bronchodilators. There was no significant change in procedure tolerance, sedation used, complications or adverse events and samples obtained in patients who received pre-procedure bronchodilators. Mean volume of saline inserted for BAL during bronchoscopy was 414.3 ± 140.5 ml for asthmatics and 392.1 ± 123.5 ml for COPD patients. Overall, serious complications were rare: 2 patients bled during the procedure requiring cold saline and adrenaline, 1 was observed for a few hours due to low saturations, 1 was admitted overnight for hypotension and 1 was admitted with pleuritic chest pain. 41 patients were symptom free at 24 hours and 85 were symptom free at 7 days. The most common mild symptom reported at 24 hours was sore throat, being reported by 50 patients; at 7 days 21 patients reported cough. Conclusion Nebulised bronchodilators pre-bronchoscopy in patients with asthma or COPD appears to have little impact. Overall, research bronchoscopy with significant BAL in these patients appears relatively safe. * The first 2 authors contributed equally to this work.