Abstract
We have previously established that a defect in the ability of alveolar macrophages (AM) to phagocytose apoptotic cells (efferocytosis) and pathogens is a potential therapeutic target in COPD. We further showed that levels of mannose binding lectin (MBL; required for effective macrophage phagocytic function) were reduced in the airways but not circulation of COPD patients. We hypothesized that increased oxidative stress in the airway could be a cause for such disturbances. We therefore studied the effects of oxidation on the structure of the MBL molecule and its functional interactions with macrophages. Oligomeric structure of plasma derived MBL (pdMBL) before and after oxidation (oxMBL) with 2,2′-azobis(2-methylpropionamidine)dihydrochroride (AAPH) was investigated by blue native PAGE. Macrophage function in the presence of pd/oxMBL was assessed by measuring efferocytosis, phagocytosis of non-typeable Haemophilus influenzae (NTHi) and expression of macrophage scavenger receptors. Oxidation disrupted higher order MBL oligomers. This was associated with changed macrophage function evident by a significantly reduced capacity to phagocytose apoptotic cells and NTHi in the presence of oxMBL vs pdMBL (eg, NTHi by 55.9 and 27.0% respectively). Interestingly, oxidation of MBL significantly reduced macrophage phagocytic ability to below control levels. Flow cytometry and immunofluorescence revealed a significant increase in expression of macrophage scavenger receptor (SRA1) in the presence of pdMBL that was abrogated in the presence of oxMBL. We show the pulmonary macrophage dysfunction in COPD may at least partially result from an oxidative stress-induced effect on MBL, and identify a further potential therapeutic strategy for this debilitating disease.
Highlights
Chronic obstructive pulmonary disease (COPD), a lung disease mostly associated with cigarette smoking, is predicted to be the third leading cause of death in the world by 2020 [1]
Pre-treatment of human alveolar macrophages with plasma derived MBL (pdMBL) increased efferocytosis of apoptotic bronchial epithelial cells and phagocytosis of non-typeable Haemophilus influenzae (NTHi), a pathogen frequently implicated in exacerbations of COPD. oxMBL did not stimulate but rather showed an inhibitory effect on both phagocytosis of the pathogen and efferocytosis of apoptotic cells (Figure 2A, B)
Similar results were obtained in further experiments in which macrophages derived from THP-1 monocytes were tested for stimulatory effects of pdMBL and inhibitory effects of oxMBL
Summary
Chronic obstructive pulmonary disease (COPD), a lung disease mostly associated with cigarette smoking, is predicted to be the third leading cause of death in the world by 2020 [1]. We have demonstrated impaired phagocytosis of bacteria in COPD; an important finding given the increased bacterial colonization and increased susceptibility to infectious exacerbations in these patients [6,7] These defects are not isolated to COPD, as we have reported increased numbers of apoptotic bronchial epithelial cells and defective efferocytosis in the airways in other chronic lung diseases including severe asthma and chronic lung transplant rejection [8,9]. Nakanishi et al showed that administration of clarithromycin prevented the onset of emphysema in smoke-exposed mice [15] These results are exciting and establish the important biological paradigm that macrophage function can be manipulated for therapeutic gain, the use of long-term antibiotic therapy has obvious drawbacks including the potential emergence of antibiotic-resistant strains of bacteria
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