Macrolides inhibit cytokine production by alveolar macrophages in bronchiolitis obliterans organizing pneumonia
Introduction
Bronchiolitis obliterans organizing pneumonia (BOOP) is a distinct clinicopathological entity characterized clinically by subacute illness with flu-like symptoms, radiologically by multiple patchy infiltrates, and histologically by granulation tissue in the alveoli, alveolar ducts and bronchioli (Cordier 2006). Bronchoalveolar lavage (BAL) usually shows increased proportions of lymphocytes, neutrophils and eosinophils (Costabel et al. 1992). BOOP is considered to be an inflammatory rather than a fibrotic lung disease (Cordier 2006), and patients usually respond well to corticosteroid therapy.
The anti-inflammatory properties of macrolides have first been recognized in the treatment of diffuse panbronchiolitis (DPB). Long-term treatment with erythromycin can markedly improve the survival of DPB patients (Kudoh et al. 1998). Therapeutic effects of macrolides have also been observed in bronchiectasis, COPD, cystic fibrosis, bronchiolitis obliterans syndrome (BOS) following lung transplantation or bone marrow transplantation (Crosbie and Woodhead, 2009, Seemungal et al., 2008), and more recently in small case studies of BOOP (Ichikawa et al., 1993, Kastelik et al., 2006, Lee et al., 2011, Radzikowska et al., 2008, Stover and Mangino, 2005).
The mechanisms of action of macrolides in the treatment of chronic inflammatory lung diseases are not fully understood. However, macrolides have been shown to inhibit the activity of nuclear factor kappaB (NF-κB) (Ichiyama et al. 2001) which is an essential protein for gene expression of various inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin 8 (IL-8) and IL-1beta (IL-1β). It is evident that macrolides notably suppress the activation and migration of neutrophils and IL-8 production by inflammatory cells (Tamaoki 2004). In the LPS-treated mouse model macrolide treatment attenuates the neutrophilic alveolitis by inhibiting the production of IL-1β and granulocyte-macrophage colony-stimulating factor (GM-CSF) from alveolar macrophages (AMs) through inhibition of activator protein-1 (Bosnar et al., 2009, Bosnar et al., 2011). Other cell types including pulmonary epithelial cells and peripheral blood monocytes (PBMC) have also been identified as targets of macrolides (Ichiyama et al. 2001). The anti-inflammatory mechanisms for the macrolides include their ability to decrease the generation of cytokines, chemokines, adhesion molecules, elastase activity, and neutrophil oxidation burst, thereby ameliorating inflammatory and fibrotic responses (Ribeiro et al., 2009, Tamaoki, 2004). The immunomodulatory properties of macrolides depend on their molecule structures. The 14- or 15-membered ring macrolides including erythromycin, clarithromycin (CAM) and azithromycin (AZM) seem to be the most effective (Crosbie and Woodhead 2009).
BOOP is predominantly mediated by a T-helper 1 (Th1) response. The cytokine profile in BAL fluid of BOOP is characterized by high levels of IL-12, IL-18 and macrophage inflammatory protein (MIP)-1α and β (Asano et al., 2003, Forlani et al., 2002). AMs derived from BOOP show increased mRNA expression of IL-8, IL-10 and fibronectin, and increased protein production of TNF-α and its soluble receptors sTNFR1/2 (Carre et al., 1994, Martinez et al., 1997, Ye et al., 2011), suggesting that AMs play a critical role in the pathogenesis of BOOP. However, quantitative studies regarding the cytokine production by AMs in BOOP are scanty, and there are no data indicating the effects of macrolides on the cytokine production by AMs in BOOP. Therefore, in this study we aimed to test the hypothesis that AMs in BOOP produce aberrant levels of cytokines. Further, we aimed to investigate the effects of two macrolides, CAM and AZM, in comparison with dexamethasone (DEX), on the spontaneous and lipopolysaccharide (LPS)-stimulated cytokine production by AMs recovered by BAL from patients with BOOP.
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Study population
Six consecutive patients with BOOP (4 idiopathic, 2 secondary) and 8 control subjects were investigated in this study (Table 1). Written informed consent was obtained according to institutional guidelines.
Diagnosis of BOOP was based on the following criteria: (1) acute or subacute onset of a flu-like illness with variable degrees of cough and dyspnea, chills, intermittent fever, and myalgia; (2) radiologic features of areas of airspace consolidation with subpleural or peribronchial
Cytokine production by AMs in BOOP and controls
As shown in Table 2, the spontaneous and LPS-stimulated production of all investigated cytokines by AMs in vitro was significantly increased in BOOP compared to controls (between 3-fold and 40-fold higher in BOOP than in controls). LPS significantly up-regulated the production of all investigated cytokines except IP-10 and CCL18 by AMs in BOOP.
Effects of macrolides and DEX on the spontaneous cytokine production by AMs in BOOP
As illustrated in Table 3 and Fig. 1, CAM and AZM induced a dose-dependent suppression of spontaneous TNF-α, sTNFR2, IL-6, IL-8 and CCL18 production. At
Discussion
The present study showed that the spontaneous and LPS-stimulated production of several proinflammatory cytokines and chemokines by AMs in vitro is increased in BOOP, including TNF-α, sTNFR1, sTNFR2, IL-1β, IL-6, IL-8, IL-10, IP-10 and CCL18. This enhanced cytokine and chemokine production can be partially inhibited by macrolides. CAM and AZM both suppressed TNF-α, sTNFR1 and sTNFR2, IL-6, IL-8 and CCL18, while IL-1β and IL-10 was only affected by CAM. Previous studies with BOOP patients showed
Competing interests
The authors declare that they have no competing interests.
Acknowledgements
This study was supported by the AFPR (Arbeitsgemeinschaft zur Förderung der Pneumologie an der Ruhrlandklinik).
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