Tumour necrosis factor-alpha production in human alveolar macrophages: modulation by inhaled corticosteroid

Abstract

Using an ex vivo alveolar macrophage model, the hypothesis that inhaled preparations of corticosteroids might have important anti-inflammatory effects on cells of the peripheral airway was tested.The tumour necrosis factor (TNF)-a-inducing potential of three glycolipid preparations from nonpathogenic (arabinofuranasyl lipoarabinomannan (LAM (Ara-LAM)) and virulent (mannase LAM (ManLAM)) mycobacteria and Gram-negative bacteria (lipopolysaccharide (LPS)), in primary alveolar macrophage preparations was investigated. A novel inhaled chlorofluorocarbon (CFC)-free preparation of beclomethasone dipropionate (hydrofluoroalkane 134a (HFA)-BDP) with increased peripheral lung deposition was investigated for its ability to modulate glycolipidinduced TNF-a production by human alveolar macrophages, in comparison with a CFC-containing preparation and placebo.Compared to the basal TNF-a bioactivity of 0.72 ng . mL -1 (geometric mean), the TNF-a bioactivity in the macrophage preparation increased following incubation with LPS (138 ng . mL -1 , p<0.001), AraLAM (12.6 ng . mL -1 , p<0.001) and ManLAM (1.42 ng . mL -1 , p=0.02). HFA-BDP, administered in vivo, significantly reduced LPS-and ManLAM-induced TNF-a production by alveolar macrophages cultured ex vivo. No change in glycolipid-induced TNF-a production was observed following in vivo administration of CFC-BDP or HFA-placebo. This is the first demonstration of an immunomodulatory effect on alveolar cells of corticosteroid delivered via metered dose inhaler. The present findings suggest that alveolar deposition of beclomethasone dipropionate is capable of modulating the inflammatory potential of the alveolar macrophage population. Eur Respir J 2000; 15: 764±770.

The functional benefit of anti-inflammatory aerosols in the lung periphery

“…10 However, when comparing the effect of half dose HFA-BDP with budesonide delivered from a dry powder inhaler, 6,15 end-expiratory flow improvements were found to be similar for both. Busse et al 16 reported a shift to the left of the HFA-BDP versus the CFC-BDP doseresponse curve for forced expiratory flow between exhalation of 25% and 75% forced vital capacity (FEF 18 have shown a greater potential for an anti-inflammatory effect on an ex vivo alveolar macrophage preparation when inhaled steroids had been delivered via HFA-BDP versus CFC-BDP aerosols, the functional benefit of the acinar airways peripheral to the first 150 mL of conductive airways has never been assessed. With the low resistance of the acinar lung zone impeding conventional spirometry to provide a noninvasive marker of the acinar lung structure, ventilation distribution tests offer a valuable alternative.…”

Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes in an Endotoxin-Induced Lung Inflammation Model

“…Although inhalation of free GC is a promising therapy with less systemic toxicity, the therapeutic efficacy has been ques-tioned with regard to its short half-life (O'Byrne and Pedersen, 1998), potential toxicity at high doses (Foster et al, 2006), and inability to reach alveolar macrophages (Marshall et al, 2000). For these reasons, aerosol drug delivery systems need to be developed.…”

Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: A European consensus

“…Causal relationships between the sites of drug deposition and the patients' response have been established in diseases of the respiratory tract [235], but no data exist for cystic fibrosis. Effective targeting of a given region in the lung, for instance the peripheral airways, has been defined when N 50% of the total drug deposition occurs in that region [197,144].…”