RESUMO
BACKGROUND: The presence of lipids in alveolar macrophages (AMs) may impair their phagocytic response, and determine airway inflammation and obstruction. OBJECTIVE: To determine the factors such as severity of asthma, chronic cough, airway inflammation and obesity that may influence the presence of lipids in lung macrophages. METHODS: Bronchoalveolar lavage fluid (BALF) was obtained from 38 asthmatics (21 severe and 17 mild/moderate), 16 subjects with chronic cough and 11 healthy control subjects. The presence of lipids in macrophages was detected using an Oil-red-O stain and an index of lipid-laden macrophages (LLMI) was obtained. RESULTS: LLMI scores were higher in healthy subjects (median 48 [IQR 10-61]) and the severe asthma group (37 [11.5-61]) compared to mild/moderate asthmatics (7 [0.5-37]; p < 0.05 each). Subjects reporting a history of gastro-oesophageal reflux disease (GORD) had higher LLMI values (41.5 [11.3-138] versus 13 [0-39.3], p = 0.02). There was no significant correlation between LLMI and chronic cough, BAL cell differential counts, FEV1, FEV1/FVC or body mass index (BMI). CONCLUSIONS: The reduced LLMI in mild/moderate asthma may be related to lower incidence of GORD. However, this was not related to the degree of airflow obstruction, obesity or airway inflammation.
Assuntos
Asma/patologia , Líquido da Lavagem Broncoalveolar/química , Tosse/patologia , Lipídeos/análise , Macrófagos Alveolares/química , Adulto , Asma/metabolismo , Índice de Massa Corporal , Líquido da Lavagem Broncoalveolar/citologia , Broncoscopia , Estudos de Casos e Controles , Contagem de Células , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND AND PURPOSE: Corticosteroid insensitivity is a major therapeutic problem for some inflammatory diseases including chronic obstructive pulmonary disease (COPD), and it is known to be induced by reduced histone deacetylase (HDAC)-2 activities via activation of the phosphoinositide 3-kinase (PI3K) pathway. The aim of this study is to evaluate effects of a novel macrolide/fluoroketolide, solithromycin (SOL, CEM-101), on corticosteroid sensitivity induced by oxidative stress. EXPERIMENTAL APPROACH: Corticosteroid sensitivity was determined by IC50/EC50 of dexamethasone (Dex) on TNF-α-induced CXCL8 production in U937 monocytic cell line and peripheral blood mononuclear cells (PBMC) from COPD patients. Activities of HDAC and protein phosphatase 2A (PP2A) were measured by fluorescence-based assay in cells exposed to hydrogen peroxide (H2O2). We also investigated steroid insensitive airway neutrophilia in cigarette smoke exposed mice in vivo. KEY RESULTS: SOL (10 µM) restored Dex sensitivity in PBMC from COPD patients, H2O2-treated U937 cells and phorbol 12-myristate 13-acetate-differentiated U937 cells. In addition, SOL restored HDAC activity with concomitant inhibition of Akt phosphorylation as surrogate marker of PI3K activation. The inhibition of Akt phosphorylation by SOL was due to increased PP2A phosphatase activity, which was reduced in COPD and oxidative stress model. Other known macrolides, such as eryhthromycin, clarithromycin and azithromycin, were significantly less effective in these responses. In cigarette smoke-exposed mice, SOL (100 mg kg(-1), po) showed significant but weak inhibition of neutrophilia, whereas Dex (10 mg kg(-1), p.o.) showed no such effect. However, a combination of SOL and Dex inhibited neutrophilia by over 50%. CONCLUSIONS AND IMPLICATIONS: SOL has potential as novel therapy for corticosteroid-insensitive diseases such as COPD.