INTRODUCTION:Growth impairment is a known adverse event (AE) of corticosteroids in children. This study aimed to assess the effect of once-daily (QD) inhaled fluticasone furoate (FF) versus placebo on growth velocity over 1 year in prepubertal children with well-controlled asthma. MATERIALS AND METHODS:This randomized, double-blind, parallel-group, placebo-controlled, multicenter study (NCT02889809) included prepubertal children, aged 5 to <9 years (boys), and 5 to <8 years (girls), with ≥6 months' asthma history. Children received inhaled placebo QD plus background open-label montelukast QD for a 16-week run-in period and were then randomized 1:1 to receive inhaled FF 50 μg QD or placebo QD (whilst continuing background open-label montelukast) for a 52-week treatment period. The primary endpoint was the difference in growth velocity (cm/year) over the treatment period. Other growth endpoints were measured, as were incidence of AEs and asthma exacerbation. Growth analyses included all intent-to-treat (ITT) participants with ≥3 post-randomization, on-treatment clinic visit height assessments (GROWTH population). RESULTS:Of 644 children in the run-in period, 477 (mean age 6.2 years, 63% male) entered the 52-week treatment period (ITT population: FF N = 238, placebo N = 239; GROWTH population: N = 457 [FF N = 231; placebo N = 226]). The least-squares mean difference in growth velocity for FF versus placebo was -0.160 cm/year (95% confidence interval: -0.462, 0.142). There were no new safety signals. CONCLUSIONS:Over 1 year, FF 50 μg QD had a minimal effect on growth velocity versus placebo, with no new safety signals.

A dry powder inhaler formulation of the inhaled corticosteroid fluticasone furoate is being evaluated for use in children. We assessed short-term lower leg growth in children with asthma treated with inhaled fluticasone furoate from the ELLIPTA® inhaler versus placebo. Pre-pubertal children with persistent asthma (n=60, aged 5 to <12 years) were recruited into a randomised, double-blind, placebo-controlled, two-way crossover, non-inferiority study. The study consisted of four 2-weeks periods: Run-in, two treatment periods, one wash-out period, and a 1-week follow up period. Interventions were fluticasone furoate 50 μg and placebo once daily in the evening. Lower-leg length was measured by knemometry. Fifty-eight subjects completed both treatment periods. The LS mean growth rate was 0.31 mm/week during treatment with fluticasone furoate and 0.36 mm/week during treatment with placebo. The difference in adjusted LS mean growth rates between fluticasone furoate and placebo was -0.052 mm/week with a 95% confidence interval (CI) of -0.122 to 0.018 mm/week. This was greater than the pre-specified non-inferiority margin of -0.20 mm/week. The overall incidence of adverse events was 35% on placebo and 22% on fluticasone furoate. Inhaled fluticasone furoate 50 μg once daily in the evening was non-inferior to placebo in terms of effects on short-term lower-leg growth in children with asthma. Inhaled fluticasone furoate 50 mg was well tolerated in this study population.

Purpose: A dry powder inhaler formulation of the inhaled corticosteroid fluticasone furoate (FF) is being evaluated for use in children. An important potential risk associated with the use of inhaled corticosteroids in children is growth suppression. Therefore, the aim of this study was to assess the short-term lower leg growth in children with asthma treated for 2 weeks with inhaled FF versus placebo from the ELLIPTA inhaler.Methods: Prepubertal children with persistent asthma (n = 60; aged 5 to <12 years) were recruited into a randomized, double-blind, placebo-controlled, 2-way crossover, noninferiority study. The study consisted of four 2-week periods: run-in, 2 treatment periods, 1 washout period, and a 1-week follow-up period. Interventions were FF 50 jig and placebo once daily in the evening. Lower leg length was measured by using knemometry.Findings: The randomized ITT population comprised 36 boys and 24 girls with a mean age of 8.7 (standard deviation, 1.5; range, 5-11) years; 58% had a duration of asthma >= 5 years. Fifty-eight subjects completed both treatment periods. The least squares mean growth rate was 0.31 mm/week during treatment with FF and 0.36 mm/week during the placebo period. The difference in adjusted least squares mean growth rates between FF and placebo was-0.052 mm/week with a 95% CI of-0.122 to 0.018. This finding was greater than the prespecified noninferiority margin of 0.20 mm/week. The overall incidence of adverse events was 35% with placebo and 22% with FF.Implications: Inhaled FF 50 jig provided once daily for 2 weeks was noninferior to placebo in terms of effects on short-term lower leg growth in children with asthma. To further quantify the risk of growth suppression in children, intermediate-term growth studies should be conducted. Inhaled FF 50 jig was well tolerated in this study population. ClinicalTrials. gov identifier: NCT02502734. (Clin Ther. 2017;39:1191-1199) (C) 2017 The Authors. Published by Elsevier HS Journals, Inc.

The authors regret that a programming error has led to inaccuracies in the adverse event (AE) data. The Reporting and Analysis Plan defined on-treatment AEs as having an onset during the treatment period plus 1 day after the last dose, while post-treatment AEs had an onset of more than 1 day after the last dose (during the wash-out or follow-up periods). The published on-treatment AE data did not reflect the additional 1-day period that was included in the definition. This error has been amended in the text below. The changes do not affect the interpretation of the data or the overall conclusions of the manuscript. On-treatment AEs were reported for 15 (25%) subjects during the placebo period, and for 7 (12%) subjects during treatment with FF 50 µg OD. The most common AE was headache, reported for 8 (13%) subjects taking placebo and for 3 (5%) subjects taking FF 50 µg OD, followed by nasopharyngitis, cough, oropharyngeal pain, and pyrexia. The authors would like to apologize for any inconvenience caused. Knemometry Assessment of Short-term Growth in Children With Asthma Receiving Fluticasone Furoate for 2 Weeks: A Randomized, Placebo-controlled, Crossover TrialClinical TherapeuticsVol. 39Issue 6PreviewA dry powder inhaler formulation of the inhaled corticosteroid fluticasone furoate (FF) is being evaluated for use in children. An important potential risk associated with the use of inhaled corticosteroids in children is growth suppression. Therefore, the aim of this study was to assess the short-term lower leg growth in children with asthma treated for 2 weeks with inhaled FF versus placebo from the ELLIPTA inhaler. Full-Text PDF Open Access

BACKGROUND:Response to inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) combinations varies across ethnic groups.OBJECTIVE:To investigate the efficacy and safety of the ICS/LABA combination fluticasone furoate/vilanterol (FF/VI) 100/25 μg in Asian patients with asthma.METHODS:A randomized (1:1), 12-week, double-blind, placebo-controlled, parallel group, multicenter phase III study of once-daily FF/VI 100/25 μg versus placebo in patients of Asian ancestry ages ≥12 years with asthma, uncontrolled on a low- to mid-strength ICS or low-dose ICS/LABA. The primary end point was the mean change from baseline in the daily evening peak expiratory flow. Secondary end points were the mean change from baseline in percentage rescue-free 24-hour periods, daily morning peak expiratory flow, percentage symptom-free 24-hour periods, Asthma Quality of Life Questionnaire score, adverse events, and severe exacerbations.RESULTS:The intent-to-treat population was 307 patients. There were significant (p < 0.001) improvements from baseline for FF/VI 100/25 μg versus placebo in evening peak expiratory flow (51.0 L/min [95% confidence interval {CI}, 42.2-59.7 L/min]) and all secondary end points (percentage rescue-free 24-hour periods 21.8% [95% CI, 14.6-29.1%]; morning peak expiratory flow 52.9 L/min [95% CI, 44.2-61.6 L/min]; percentage symptom-free 24-hour periods 15.8% [95% CI, 9.4-22.3%]; Asthma Quality of Life Questionnaire score 0.52 [95% CI, 0.28, 0.75]). On-treatment adverse events were 35% with FF/VI (n = 2 [serious]), 31% with placebo; severe exacerbations were FF/VI (n = 1), placebo (n = 7).CONCLUSIONS:In patients of Asian ancestry, once-daily FF/VI 100/25 μg produced statistically and clinically significant improvements in efficacy end points versus placebo, with a generally similar safety profile. Results were consistent with a global phase III study of FF/VI 100/25 μg. Clinicaltrials.gov NCT01498679.

The authors regret that an error occurred in Table 2 in the above-mentioned article. The data on the fourth row of the table, labelled "Morning PEF (l/min): difference in LS mean change from baseline (95% CI) over weeks 1–24", should read as follows:•FF100 μg OD vs. placebo: 12.1 (4.0, 20.2)•FP250 μg BD vs. placebo: 7.6 (−0.5, 15.7) This amendment does not materially affect the findings or interpretations presented in the manuscript. The authors would like to apologise for any inconvenience caused. Efficacy and safety of fluticasone furoate 100 μg once-daily in patients with persistent asthma: A 24-week placebo and active-controlled randomised trialRespiratory MedicineVol. 108Issue 1PreviewInhaled corticosteroids (ICSs) improve asthma disease control; once-daily ICS administration may have advantages for patients. Our objective was to assess the efficacy and safety of the novel ICS fluticasone furoate (FF) over 24 weeks versus placebo. This was a 24-week double-blind, double-dummy, placebo- and active-controlled study ( NCT01159912 ) of 343 asthma patients (≥12 years) not controlled by their current ICS. Patients were randomised (1:1:1) to FF100 μg, placebo (both administered once-daily [OD] via ELLIPTA™ dry powder inhaler in the evening) or fluticasone propionate (FP) 250 μg (administered twice-daily (BD) via DISKUS™/ACCUHALER™). Full-Text PDF Open Access

Background: This study investigated the efficacy and safety of the inhaled corticosteroid (ICS)/long-acting beta(2)-agonist (LABA) combination fluticasone furoate (FF)/vilanterol (VI) in Asian asthma patients.Methods: A 12-week, double-blind, double-dummy, active-comparator, parallel-group, multicenter study. 309 Asian asthma patients (>= 12 years, uncontrolled with high-strength ICS or mid-dose ICS/LABA) were randomized (1: 1) and included in the intent-to-treat population; 155 received once-daily FF/VI 200/25 mcg and 154 received twice-daily fluticasone propionate (FP) 500 mcg. The primary endpoint was change from baseline in daily evening peak expiratory flow (PEF) averaged over 12 weeks. Secondary endpoints were mean change from baseline in % rescue-free 24-h periods, daily morning PEF, % symptom-free 24-h periods, and overall Asthma Quality of Life Questionnaire score. Safety assessments were performed.Results: For change from baseline in daily evening PEF, the adjusted mean treatment difference for FF/VI versus FP of 28.5 L/min (95% confidence interval [CI]: 20.1, 36.9) was clinically and statistically significant (p < 0.001). For change from baseline in % rescue-free 24-h periods, the adjusted mean treatment difference (1.0%; 95% CI: -7.3, 9.2) was not statistically significant (p = 0.821). Statistical significance could not be inferred for the remaining endpoints due to the statistical hierarchy employed. Incidence of on-treatment adverse events was similar with FF/VI (26%; 3% treatment-related; n = 1 serious) and FP (27%; 3% treatment-related; n = 2 serious); none were fatal. No further safety concerns were identified.Conclusions: FF/VI improved evening PEF over 12 weeks versus FP in Asian patients, with a similar safety profile. The results are generally consistent with a global study comparing the same treatments. (C) 2014 Published by Elsevier Ltd.

Inhaled corticosteroids are a mainstay of therapy for persistent asthma, but suboptimal adherence with twice-daily use is widespread. Fluticasone furoate (FF) is a new inhaled corticosteroid (ICS) suitable for once-daily dosing in asthma. This study was performed to descriptively assess the efficacy and safety of two doses of FF, with no planned formal statistical hypothesis testing.

Inhaled corticosteroids (ICSs) improve asthma disease control; once-daily ICS administration may have advantages for patients. Our objective was to assess the efficacy and safety of the novel ICS fluticasone furoate (FF) over 24 weeks versus placebo.This was a 24-week double-blind, double-dummy, placebo- and active-controlled study (NCT01159912) of 343 asthma patients (>= 12 years) not controlled by their current ICS. Patients were randomised (1:1:1) to FF100 mu g, placebo (both administered once-daily [OD] via ELLIPTA (TM) dry powder inhaler in the evening) or fluticasone propionate (FP) 250 14 (administered twice-daily (BD) via DISKUS (TM)/ACCUHALER (TM)). Primary endpoint was change from baseline in pre-dose evening forced expiratory volume in 1s (FEV1) at Week 24; change from baseline in % rescue-free 24-h periods was a powered secondary endpoint. Adverse events (AEs) were assessed.FF100 mu g OD and FP250 mu g BD significantly improved pre-dose evening FEV1 compared with placebo at Week 24 (+146 ml [p = 0.009] and +145 ml [p = 0.011], respectively). Percentage of rescue-free 24-h periods was increased with FF100 mu g OD (+14.8%) and FP250 mu g BD (+17.9%) compared to placebo (both p < 0.001). On-treatment AEs were reported by 53% (FF100 mu g OD), 42% (FP250 mu g BD) and 40% (placebo) of patients. On-treatment severe asthma exacerbations were lower with FF100 mu g OD (3%) and FP250 mu g BD (2%) than placebo (7%). There was significant suppression of urinary cortisol at week 24 with FF100 mu g OD (p = 0.030) and FP250 14 BD (p = 0.036) relative to placebo.FF100 mu g OD, administered in the evening, achieves significant improvements in lung function and rescue inhaler use over 24 weeks, comparable to FP250 mu g BD with similar safety profile. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

Introduction: FF OD is effective in asthma patients (pts) uncontrolled by low-dose ICS (100mcg, 200mcg) or mid-dose ICS (200mcg). Objective: To assess efficacy/safety of two strengths of FF in pts (aged ≥12 years) with moderate-to-severe persistent asthma uncontrolled on a total daily dose of FP >250–1000mcg (or equivalent). Methods: Randomised, double-blind, parallel-group, descriptive (no formal inference was planned) study (N=219; ITT) of FF 100mcg or FF 200mcg OD in the PM via dry powder inhaler for 24 weeks. Endpoints (all Δ baseline [BL]): primary – trough (pre-bronch.) FEV1; secondary/other – %rescue-free 24-h periods (%RF), PM/AM PEF, %symptom-free 24-h periods (%SF), Asthma Control Test (ACT) scores. Safety: AEs, 24-h urine cortisol (UC) excretion, laboratory tests. Results: Data are for FF 100, FF 200. FF increased trough FEV1 (208mL, 284mL), %RF (21.3, 23.1), PM PEF (5.9L/min, 7.2L/min), AM PEF (13.4L/min, 13.2L/min), %SF (17.5, 19.6), ACT score (4.5, 4.9) and %pts ACT score ≥20 (53%, 59%). See Figure for treatment differences. AE profile was broadly similar across groups, except treatment-related AEs (<1%, 5%). No clinically relevant Δ 24-h UC (ratio vs BL: 1.15, 1.09) or laboratory tests. Conclusions: Relative to baseline, FF showed consistent improvements in efficacy (often numerically greater with FF 200mcg) and no safety concerns. Funded by GSK (FFA114496;[NCT01431950][1]). ![Figure][2] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01431950&atom=%2Ferj%2F42%2FSuppl_57%2FP3398.atom [2]: pending:yes

Current guidelines recommend adding a long-acting inhaled β2-agonist (LABA) to inhaled corticosteroids (ICS) in patients with uncontrolled asthma. This study evaluated the novel, once-daily LABA vilanterol trifenatate (VI) in asthma patients who remained symptomatic despite existing ICS therapy.The study involved a randomised, double-blind, placebo-controlled trial of VI (3, 6.25, 12.5, 25 and 50 μg), administered once daily in the evening by dry powder inhaler for 28 days, in asthma patients aged ≥12 yrs symptomatic on current ICS therapy. The primary end-point was trough (24 h post-dose) forced expiratory volume in 1 s (FEV1); secondary end-points were weighted mean FEV1, peak expiratory flow (PEF), symptom-/rescue-free 24-h periods, and safety.A significant relationship was observed between VI dose and improvements in trough FEV1(p=0.037). Statistically significant increases in mean trough FEV1, relative to placebo, were documented for VI 12.5–50 μg (121–162 mL; p≤0.016). Dose-related effects of VI were observed on weighted mean (0–24 h) FEV1, morning/evening PEF, and symptom-/rescue-free 24-h periods. All doses of VI were well tolerated with low incidences of recognised LABA-related adverse events (tremor 0–2%; palpitations 0–2%; glucose effects 0–1%; potassium effects 0–<1%).Once-daily VI 12.5–50 μg resulted in prolonged bronchodilation of at least 24 h with good tolerability in asthma patients receiving ICS. Based on the overall efficacy and adverse event profile from this study, the optimum dose of VI appears to be 25 μg.

Introduction: FF and VI are, respectively, a novel inhaled corticosteroid and long-acting beta2 agonist in development as a combined OD therapy for asthma and COPD. Objectives: To compare the efficacy and safety of FF/VI with FF and fluticasone propionate (FP) in patients (≥12 years old; on ICS) with moderate-to-severe persistent asthma. Methods: Patients (N=586; intent-to-treat) received FF/VI 200/25mcg OD PM, FF 200mcg OD PM or FP 500mcg twice daily (AM/PM) for 24 weeks. Co-primary endpoints were change from baseline in trough (pre-bronchodilator) FEV1 and weighted mean 0–24h serial FEV1. Secondary endpoints were change from baseline in %rescue-free and %symptom-free 24h periods and Asthma Quality of Life Questionnaire (AQLQ) score. Safety assessments included adverse events (AEs), 24h urinary cortisol (UC) excretion, vital signs and ECG. Results: FF/VI improved trough FEV1 (diff. 193mL and 210mL; both p<0.001) and weighted mean serial FEV1 (diff. 136mL [p=0.048] and 206mL [p=0.003]) vs FF and FP. Significantly more %rescue-free (11.7 [p<0.001]) and %symptom-free (8.4 [p=0.01]) 24h periods were reported with FF/VI vs FF. There was no statistical difference between FF/VI and FF in AQLQ score. Incidence of AEs was similar across groups. No clinically significant difference was seen across treatments with respect to 24-h UC excretion, vital signs or ECG. Conclusions: Treatment with FF/VI over 24 weeks was associated with statistically greater improvements in lung function and asthma stability vs FF and FP, and was well tolerated in this asthma population. Funded by GSK (HZA106829; [NCT01134042][1]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01134042&atom=%2Ferj%2F40%2FSuppl_56%2FP1794.atom

printing supported by . Visit Chiesi at Stand B2.10 MONDAY, SEPTEMBER 3RD 2012 correlated with the production of IL-8. In acute (4 day) and sub-chronic (14 day) cigarette smoke-induced murine models of COPD, treatment with either intratracheally delivered RC kinase siRNA or orally administered novel and specific small molecule inhibitors caused a significant reduction in BAL neutrophilia, as well as decreased levels of KC and CCL-20. There was also a marked reduction in the amount of pulmonary inflammation. In a murine adoptive transfer model of idiopathic pulmonary fibrosis, both siRNA and small molecule antagonist treatment significantly inhibited hydroxyproline production, inflammation and cellular and biochemical markers of fibrosis. Taken together, these results strongly suggest that inhibition of RC kinase may provide a novel therapeutic approach for the treatment of COPD and IPF. P2125 Statins worse pulmonary fibrosis through enhancing NLRP3 inflammasome activation Jin-Fu Xu1,2, George R. Washko2, Hui-Ping Li1, Augustine M.K. Choi2, Gary M. Hunninghake2. 1Department of Pulmonary Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; 2Pulmonary and Critical Care Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States The role of statins is controversial. To evaluate the association between statin use and ILD. We used regression analyses to evaluate the association between statin use and interstitial lung abnormalities (ILA) in a large cohort of smokers from COPDGene. Next, we evaluated the effect of statin pretreatment on bleomycin-induced fibrosis in mice and explored the mechanism behind these observations in vitro. In COPDGene, 38% of subjects with ILA were taking statins compared to 27% of subjects without ILA. Statin use was positively associated in ILA (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.03-2.50, P=0.04) after adjustment for covariates including a history of high cholesterol or coronary artery disease. This association was modified by the hydrophilicity of statin and the age of the subject. Next, we demonstrate that statin administration aggravates lung injury and fibrosis in bleomycin-treated mice. Statin pretreatment enhances caspase-1-mediated immune responses in vivo and in vitro; the latter responses were abolished in bone marrow-derived macrophages (BMDM) isolated from Nlrp3-/and Casp1-/mice. Finally, we provide further insights by demonstrating that statins enhance NLRP3-inflammasome activation by increasing mitochondrial reactive oxygen species generation in macrophages. Statin use is associated with ILA among smokers in the COPDGene study and enhances bleomycin-induced lung inflammation and fibrosis in the mouse through a mechanism involving enhanced NLRP3-inflammasome activation. Our findings suggest that clinicians should be aware that radiological evidence of ILD can develop in some COPD patients treated with statins. P2126 Effects of combination of PI3Kγ and δ inhibitors on airway hyperresponsiveness in tobacco smoke-exposed mice Yasuo Kizawa1, Genki Kimura1, Keitaro Ueda1, Yuji Watanabe1, Shouichi Eto1, Tadashi Kusama1, Kazuhiro Ito2. 1Physiology and Anatomy, Nihon University School of Pharmacy, Funabashi, Chiba, Japan; 2Airway Disease Section, NHLI, Imperial College, London, United Kingdom PI3K δ and γ are known to be involved in inflammatory cell functions. We recently found upregulation of PI3Kδ in lung tissue of COPD patients and ability of a PI3Kδ inhibitor on restoration of steroid sensitivity in airway inflammation in tobacco-smoke (TS) exposed mice. Superior effects of combination of PI3Kγ and δ inhibitors to each inhibitor alone on airway inflammation in TS-exposed mice were also observed. The aim of this study is to evaluate role of PI3Kγ and PI3Kδ on airway hyperresponsiveness (AHR) in TS-exposed mice. A/J mice were exposed to TS for 11 days and IC87114 (IC), AS604850 (AS) and/or fluticasone propionate (FP) were administered intranasally twice a day for 3 days after the last TS exposure. Airway responsiveness was determined as the increment of airway resistance ( [sRaw/TV]) before and 1 min after histamine inhalation at 24 h after the last drug dosing. The effects of the PI3K inhibitors on the contractile response to carbachol in guinea-pig tracheal smooth muscle preparation were also evaluated by the isometric tension recording. The concentration-response curve of carbachol was shifted to rightward and reduced the maximal response by AS (10-100 μM), in contrast, the effects of IC (100 μM) was limited in the tracheal smooth muscle. The AHR induced by TS was significantly reduced by AS (4 mg/ml; by 56% inhibition) and IC (4 mg/ml; 43%) alone. The inhibitory effects were enhanced by combination treatment of AS and IC (69%). Moreover, the combination of IC and FP showed stronger inhibition (96%) on the AHR.Considering with our previous findings, the combination of a PI3Kδ or PI3Kγ/δ inhibitor with corticosteroid may offer potential treatment of COPD. P2127 A robust translational model of acute exacerbations in the tobacco-smoke and poly IC treated mouse Vincent Russell, Paul Woodman, Andrew Connolly, Dianne Spicer, Joanna Dlugozima, Alan Young. Pharmacology, Argenta, Stoke Court, Slough, United Kingdom Exposure to tobacco smoke (TS) for 4 days induces steroid-insensitive lung inflammation in mice. The effect of adding the viral mimetic poly IC (PIC) to TS-exposed mice was examined. Methods: Mice were exposed daily to either TS or air for 4d. Saline or PIC was administered intra-nasally. The time course of lung inflammation was examined 4-120hrs after the last exposure and cell numbers measured in the BAL fluid. The acute effects of oral Dexamethasone (DEX 0.3mg/kg) or Roflumilast (ROF 5mg/kg) on the peak inflammation were examined. The effects of DEX on the kinetics of the enhanced inflammation were also examined. Results: TS caused a lung inflammation which was inhibited by ROF but not by DEX. PIC alone induced an inflammation that was not inhibited by DEX or ROF. Dosing PIC in addition to TS induced an exaggerated response that was significantly greater than the additive effect of the two stimuli. The enhanced response peaked 24hrs after the last exposure then slowly declined. Neutrophils were predominant over the first 48 hrs. Macrophage numbers increased at 24-72hrs and lymphocyte numbers peaked at 48-72hrs. The peak inflammation after TS/PIC exposure was significantly inhibited by ROF (53%, p<0.05) and DEX (56%, p<0.05), in contrast to the lack of efficacy of DEX against TS or PIC alone. A single dose of DEX after the last exposure reduced the exaggerated response over the entire 120hr study period, but did not fully resolve the inflammation. Conclusions: TS exposure for 4 days induced a steroid-insensitive lung inflammation. Addition of PIC markedly enhanced the inflammatory response which was sensitive to both steroids and roflumilast, mimicking features of human COPD. P2128 Inhaled cationic salts modulate macrophage function to reduce inflammation during LPS induced lung injury S.P. Arold, E.L. Berry, D. Rosa, F.A. Saia, S. Kong, P.L. Wright, R.W. Clarke, D.L. Hava. Research, Pulmatrix, Lexington, MA, United States Pulmatrix is developing PUR118 as a host-targeted, dry powder therapy based on the inhalation of calcium salts for acute exacerbation (AE) control in chronic obstructive pulmonary disease and other inflammatory lung disease. Preclinical data suggest that this approach is effective against an array of pathogens and also reduces inflammation resulting from environmental stimuli such as tobacco smoke. We hypothesized that this treatment could be efficacious in reducing lipopolysaccharide (LPS) induced lung inflammation by modulating the function of pulmonary macrophages. Mice were exposed to nebulized LPS (Pseudomonas aeruginosa) and PUR118, was delivered via whole body exposure 1h post-LPS challenge. Four hours after LPS exposure inflammatory cell counts and chemokine and cytokine concentrations were determined in BAL. PUR118 treatment decreased total inflammatory cell counts and neutrophil counts in the BAL fluid of LPS challenged mice and correlated with reduced KC, IL-6 and TNF-α in BAL fluid. Separately, peritoneal macrophages were isolated from naïve mice and challenged with LPS in media supplemented with calcium to simulate conditions thought to be found in lung fluid lining after PUR118 treatment. Inflammatory mediator secretion and gene expression were determined 2h post LPS exposure. Macrophages stimulated with LPS in the presence of calcium exhibited a dose dependent decrease in KC, IL-6 and TNF-α secretion as well as reduced gene expression for these inflammatory mediators. These data suggest that PUR118 can act through macrophages to reduce lung inflammation and may reduce the risk of AE caused by infections during chronic lung disease. P2129 Inhaled calcium salts reduce expression of inflammatory mediators associated with tobacco smoke exposure to reduce airway inflammation P.L. Wright1, P. Woodman2, D. Spicer2, J. Kenyon1, P. Okerholm1, V. Russell2, R.W. Clarke1, D.L. Hava1. 1Research, Pulmatrix, Lexington, MA, United States; 2Respiratory, Argenta, Slough, United Kingdom PUR118, an inhaled calcium based dry powder (DP) formulation exhibits preclinical anti-inflammatory and anti-infective activity. PUR118 may provide a novel approach for acute exacerbation control in patients with COPD and CF where the combination of underlying inflammation and pathogen infection result in reduced lung function and quality of life. The goal of this study was to evaluate the impact of PUR118 on gene expression in lung samples from a tobacco smoke (TS) exposure model. Mice were exposed to TS for 4d and treated with PUR118 or DP control 1h prior to TS. Mice were euthanized 4h after the last TS exposure and BAL and lung RNA were collected for cell counts, protein levels and QPC