Abstract
Cigarette smoking (CS), the main risk factor for COPD (chronic obstructive pulmonary disease) in developed countries, decreases alveolar macrophages (AM) clearance of both apoptotic cells and bacterial pathogens. This global deficit of AM engulfment may explain why active smokers have worse outcomes of COPD exacerbations, episodes characterized by airway infection and inflammation that carry high morbidity and healthcare cost. When administered as intravenous supplementation, the acute phase-reactant alpha-1 antitrypsin (A1AT) reduces the severity of COPD exacerbations in A1AT deficient (AATD) individuals and of bacterial pneumonia in murine models, but the effect of A1AT on AM scavenging functions has not been reported. Apoptotic cell clearance (efferocytosis) was measured in human AM isolated from patients with COPD, in primary rat AM or differentiated monocytes exposed to CS ex vivo, and in AM recovered from mice exposed to CS. A1AT (100 μg/mL, 16 h) significantly ameliorated efferocytosis (by ~50%) in AM of active smokers or AM exposed ex vivo to CS. A1AT significantly improved AM global engulfment, including phagocytosis, even when cells were simultaneously challenged with apoptotic and Fc-coated (bacteria-like) targets. The improved efferocytosis in A1AT-treated macrophages was associated with inhibition of tumor necrosis factor-α converting enzyme (TACE) activity, decreased mannose receptor shedding, and markedly increased abundance of efferocytosis receptors (mannose- and phosphatidyl serine receptors and the scavenger receptor B2) on AM plasma membrane. Directed airway A1AT treatment (via inhalation of a nebulized solution) restored in situ airway AM efferocytosis after CS exposure in mice. The amelioration of CS-exposed AM global engulfment may render A1AT as a potential therapy for COPD exacerbations.
Highlights
Alveolar macrophages isolated from the lungs of cigarette smokers or those with Cigarette smoking (CS)-related COPD exhibit impaired clearance of pathogens and apoptotic cells [1, 2]
Phorbol 12-myristate 13-acetate (PMA), rabbit anti-MAR antibody, rabbit anti-inducible NO synthase (iNOS) antibody, rabbit polyclonal anti-GAPDH, mouse monoclonal anti-vinculin were from Abcam (Cambridge, MA, USA), rabbit anti-SRB-2 antibody was from Santa Cruz Biotechnology (Dallas, TX, USA), mouse anti-human CD3 was from BD Biosciences (Franklin Lakes, NJ, USA), recombinant rat IL-4 was from ProSpec-Tany TechnoGene (Ness-Ziona, Israel), and TNF-α Protease Inhibitor-1 (TAPI-1) was from ESD Millipore (Billerica, MA, USA)
Primary alveolar macrophages (AM) isolated via bronchoalveolar lavage (BAL) from individuals who were either never smokers or active smokers were tested for efferocytosis by co-incubation with apoptotic targets
Summary
Alveolar macrophages isolated from the lungs of cigarette smokers or those with CS-related COPD exhibit impaired clearance of pathogens (phagocytosis) and apoptotic cells (efferocytosis) [1, 2]. Whereas AM pathogen clearance is important for resolution of airway infection, removal of apoptotic cells ensures resolution of inflammation and repair [1]. The global dysfunction of AM engulfment in smokers and COPD patients may be most damaging during acute infectious exacerbations, episodes of increased airway infection and inflammation during which AM have to scavenge an increased load of both bacterial and apoptotic targets [3]. A protective airway effect of A1AT has been demonstrated in non-AATD experimental model, where A1AT-overexpressing mice had reduced lung tissue damage following lung bacterial infections [9], and A1AT administration suppressed the AM release of proinflammatory mediators in CS-exposed mice [10]. The effect of A1AT on AM engulfment of bacterial or apoptotic targets has not been reported
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