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Obstructive Lung Diseases |

Antiinflammatory Effect of Roflumilast N-Oxide in Glucocorticoid Insensitive Human Neutrophils From Chronic Obstructive Pulmonary Disease Patients

Javier Milara*, PhD; Javier Lluch, PhD; Patricia Almudever, PhD; Teresa Peiro, PhD; Adela Serrano, PhD; Jose Freire, PhD; Max Qian, PhD; Julio Cortijo, PhD
Author and Funding Information

Dept Pharmacology U Valencia, Fundación de Investigación del Hospital General de Valencia, Valencia, Spain


Chest. 2012;142(4_MeetingAbstracts):663A. doi:10.1378/chest.1388478
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Abstract

SESSION TYPE: COPD Posters II

PRESENTED ON: Wednesday, October 24, 2012 at 01:30 PM - 02:30 PM

PURPOSE: Glucocorticoid function is markedly impaired in patients with chronic obstructive pulmonary disease (COPD). The PDE4 inhibitor roflumilast N-oxide (RNO) is the active metabolite of roflumilast, currently approved as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. This study explored potential complementary/synergistic inhibitory effects of dexamethasone (DEX) and RNO on inflammatory responses in human neutrophils from healthy and COPD patients.

METHODS: Neutrophils from COPD and healthy subjects were incubated with DEX (0.1nM-1μM), RNO (0.1nM-1μM), or with the combination of RNO 1nM plus DEX 10nM for 1h. Neutrophils were stimulated with lipopolysaccharide (LPS; 1μg/ml) or cigarette smoke extract (CSE) 5% for 6h. IL-8, MMP-9 and IL-1β were measured in cell supernatants.

RESULTS: DEX dose-dependently inhibited the LPS-induced IL-8, MMP-9 and IL-1β secretion, reaching a maximal % inhibition of 67.1±11.4%, 96.8±5.1% and 79.6±5.6% in healthy subjects, compared to 15±4.4 % and 8.8±2.5% for IL-8 and MMP-9, and 77.2±5.7% for IL-1β in COPD patients (p<0.05). When CSE was used as stimulus, the maximal % inhibition in healthy subjects was 94.3±21.7% and 83.9±5.8% for IL-8 and MMP-9, versus 20.6±12.1% and 15.4±6.9% in COPD patients (p<0.05). RNO dose-dependently inhibited the LPS-induced IL-8, MMP-9 and IL-1β secretion to similar levels of maximal % inhibition of 40.5±4.5%, 98.9±12.6% and 67.1±6.6% in healthy subjects, and 48.7±5.2%, 94.6±11.8% and 66.7±6.8% in COPD patients. RNO also inhibited the CSE-induced IL-8 and MMP-9 with a similar maximal % inhibition of 90.4±5.4% and 64.8±5.64% in healthy subjects and 88.9±5.6% and 62.6±2.3% in COPD patients. The combination of RNO 1nM and DEX 10nM showed additive effects that nearly abolished the LPS-induced IL-8, MMP-9 and IL-1β, and CSE-induced IL-8 and MMP-9 release in neutrophils from COPD patients.

CONCLUSIONS: Neutrophils from COPD patients are refractory to glucocorticoids but sensitive to RNO. RNO and DEX demonstrated complementary and synergistic anti-inflammatory effects in neutrophils from COPD patients.

CLINICAL IMPLICATIONS: RNO in combination with DEX may be of potential value to address clinical steroid resistance observed in COPD patients.

DISCLOSURE: Javier Milara: Consultant fee, speaker bureau, advisory committee, etc.: Consultant

Javier Lluch: Consultant fee, speaker bureau, advisory committee, etc.: Consultant

Patricia Almudever: Consultant fee, speaker bureau, advisory committee, etc.: Consultant

Teresa Peiro: Consultant fee, speaker bureau, advisory committee, etc.: Consultant

Adela Serrano: Consultant fee, speaker bureau, advisory committee, etc.: Consultant

Jose Freire: Employee: Employee of Forest Research Institute

Max Qian: Employee: Employee of Forest Research Institute

Julio Cortijo: Consultant fee, speaker bureau, advisory committee, etc.: Consultant

No Product/Research Disclosure Information

Dept Pharmacology U Valencia, Fundación de Investigación del Hospital General de Valencia, Valencia, Spain

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