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Background Loss of asthma control and asthma exacerbations are associated with increased sputum eosinophil counts. However, whether eosinophils, or the also present neutrophils, actively contribute to the accompanying inflammation has not been extensively investigated. Methods Twenty-three patients with mild to moderate asthma were included in a standardized prospective inhaled corticosteroid (ICS) withdrawal study; 22 of the patients experienced loss of asthma control. The study assessed various immune, inflammatory, and oxidative stress parameters, as well as markers of eosinophil and neutrophil activity, in exhaled breath condensate, plasma, and sputum collected at three phases (baseline, during loss of control, and following recovery). Results Loss of asthma control was characterized by increased sputum eosinophils, whereas no differences were detected between the three phases for most inflammatory and oxidative stress responses. There were also no differences detected for markers of activated eosinophils (eosinophil cationic protein and bromotyrosine) and neutrophils (myeloperoxidase and chlorotyrosine). However, free eosinophilic granules and citrullinated histone H3, suggestive of eosinophil cytolysis and potentially eosinophil extracellular trap formation, were enhanced. Baseline blood eosinophils and changes in asymmetric dimethylarginine (an inhibitor of nitric oxide synthase) in plasma were found to correlate with the decrease in FEV1 percent predicted upon ICS withdrawal (both, rs = 0.46; P = .03). Conclusions The clinical effect in mild to moderate asthma upon interruption of ICS therapy is not related to the classic inflammatory activation of eosinophils and neutrophils. It may, however, reflect another pathway underlying the onset of loss of disease control and asthma exacerbations. Trial Registry The Netherlands Trial Register; No.: NTR3316; URL: trialregister.nl/trial/3172.

PURPOSE OF REVIEW: Asthma is a chronic inflammatory disease in which changes in macrophage polarization have been shown to contribute to the pathogenesis. The present review discusses the contribution of changes in macrophage function to asthma related to polarization changes and elaborates on possible therapeutic strategies targeting macrophage function and polarization. RECENT FINDINGS: Macrophage function alterations were shown to contribute to asthma pathology in several ways. One is by impaired phagocytosis and efferocytosis. Another is by changing inflammation, by altered (anti)inflammatory cytokine production and induction of the inflammasome. Finally, macrophages can contribute to remodeling in asthma, although little evidence is present in humans yet.Novel therapeutic strategies targeting macrophages include dampening inflammation by changing polarization or by inhibiting the NLRP3 inflammasome, and by targeting efferocytosis. However, many of these studies were performed in animal models leaving their translation to the clinic for future research. SUMMARY: The present review emphasizes the contribution of altered macrophage function to asthma, gives insight in possible new therapeutic strategies targeting macrophages, and indicates which knowledge gaps remain open.

Oxidative stress is a common feature of obstructive airway diseases like asthma and chronic obstructive pulmonary disease (COPD). Lung macrophages are key innate immune cells that can generate oxidants and are known to display aberrant polarization patterns and defective phagocytic responses in these diseases. Whether these characteristics are linked in one way or another and whether they contribute to the onset and severity of exacerbations in asthma and COPD remain poorly understood. Insight into oxidative stress, macrophages, and their interactions may be important in fully understanding acute worsening of lung disease. This review therefore highlights the current state of the art regarding the role of oxidative stress and macrophages in exacerbations of asthma and COPD. It shows that oxidative stress can attenuate macrophage function, which may result in impaired responses toward exacerbating triggers and may contribute to exaggerated inflammation in the airways.

Exacerbations of COPD can be triggered by viral infections. Macrophages are involved in airway inflammation in COPD and in limiting inflammatory events in the lung. These opposing tasks are handled by differentially polarized macrophages. MHCII-high expressing macrophages are pro-inflammatory and critical in efficient immune responses against intracellular pathogens, whereas macrophages expressing YM1 are important in healing. To gain more insight into antiviral responses of macrophages in COPD, we studied macrophage responses to X31 influenza in mice after cigarette smoke (CS) exposure as a model of COPD exacerbation. Female BALB/c mice were exposed to CS, each day during 4 weeks. After 3 weeks, mice were exposed to influenza X31. Lung macrophage polarization was measured by flow cytometry. Alveolar macrophages (AM) were defined as CD64+CD68+ SiglecF+CD11c+ and interstitial macrophages (IM) as CD64+CD68+SiglecF-CD11c-. Mice exposed to X31 had more MHCII-high expressing AM than any of the other groups, whereas mice exposed to CS+X31 had more YM1-expressing AM than CS or X31 exposure alone. For IM we found more MHCII-high expressing IM in X31-exposed mice, independent of CS-exposure. In addition, CS+X31 co-exposed mice had higher numbers of YM1-expressing IM than any of the other groups. In summary, AM of CS-exposed mice appear unable to upregulate MHCII during infection with X31 as compared to X31-exposure alone. Together with a polarization shift towards YM1-expression this indicates impaired antigen presentation and defense against intracellular pathogens, which may result in impaired antiviral responses. A role for dysfunctional macrophage polarization in the development of COPD exacerbations is therefore indicated.

Loss of asthma control and asthma exacerbations are predominantly triggered by respiratory viral infections and characterized by eosinophilic airway inflammation and increased oxidative stress. Production of reactive oxygen species is a key feature of activated eosinophils and a link between eosinophils and oxidative stress during exacerbations is thus likely. We investigated whether attenuation of eosinophil numbers and activation using mepolizumab (anti-IL-5) impacts oxidative stress in stable and virus-induced worsening of asthma. Patients with mild asthma received one high dose of mepolizumab or placebo and after two weeks were subjected to rhinovirus 16 (RV16) infection. Exhaled breath condensate (EBC) and plasma was collected at baseline, after treatment and after RV16 challenge and levels of malondialdehyde (MDA), nitrotyrosine, bromotyrosine, chlorotyrosine, dityrosine and asymmetric dimethylarginine (ADMA) were measured using mass spectrometry. Baseline oxidative stress was not significantly different between the mepolizumab and placebo group and did not change upon treatment. EBC MDA near-significantly and nitrotyrosine significantly increased after virus exposure in the placebo group, but not in the mepolizumab group. When stratified for patients with high and low eosinophil counts, MDA levels significantly increased in the high eosinophilic placebo group only. No significant differences were observed after RV16 for any of the biomarkers in plasma. We have demonstrated that in mild asthma eosinophils may contribute to local oxidative stress, but only after RV16-induced loss of asthma control and not in stable disease.