Abstract
Influenza A virus (IAV) infection is a common cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Since macrophage inflammatory protein 1 α, a chemokine that acts through CC-chemokine receptor (CCR)-5, appears elevated in COPD patients’ airways, we evaluated whether CCR5 antagonist Maraviroc could inhibit the exacerbated lung inflammatory response noted after IAV H1N1 infection in mice exposed to cigarette smoke (Cs). C57BL/6 mice, subjected or not to Cs inhalation for 11 days, were infected with H1N1 at day 7. Maraviroc (10 mg/kg) or dexamethasone (1 mg/kg) were given in a therapeutic schedule, followed by the analyses of lung function, survival rate, and inflammatory changes. As compared to mice subjected to Cs or H1N1 alone, the insult combination significantly worsened airway obstruction, neutrophil infiltration in the airways, and the survival rate. All changes were sensitive to Maraviroc but not dexamethasone. Maraviroc also reduced the accumulation of neutrophils and macrophages as well as CXCL1 production in the lung tissue, and serum levels of IL-6, whereas comparable viral titers in the lungs were noted in all infected groups. Collectively, these findings suggest that Maraviroc oral treatment could be an effective therapy for controlling acute exacerbations of respiratory diseases such as COPD.
Highlights
Chronic obstructive pulmonary disease (COPD) is a major health problem with increasing prevalence, affecting 216 million people worldwide in 2016 [1]
Macrophage inflammatory protein 1 α (CCL3), a chemokine that acts through CC-chemokine receptor (CCR)-1 and CCR5, appears elevated in COPD patients’ airways [11]
In comparison with mice only infected (H1N1) or with those only exposed to cigarette smoke (Cs), mice subjected to H1N1 infection and Cs exposure (CsH1N1)
Summary
Chronic obstructive pulmonary disease (COPD) is a major health problem with increasing prevalence, affecting 216 million people worldwide in 2016 [1]. Sustained pulmonary inflammation in response to cigarette smoke (Cs) is one of the most recognized causes of COPD pathogenesis leading to chronic bronchitis and emphysema as main clinical manifestations. Lungs of COPD patients present increased levels of pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-8 and IL-1 among others, which mediate a constant influx of leukocytes into the Pharmaceuticals 2021, 14, 620. COPD patients experience acute exacerbations of symptoms (AECOPD) mostly triggered by infections. During AECOPD periods, the production of inflammatory cytokines and chemokines in the lung increases and so does leukocyte migration, with an exacerbated neutrophil activity. AECOPD accelerates lung function deterioration, increases morbidity and mortality of COPD, and represents a major cause of COPD patients’ hospitalization [5,6]. Current pharmacological therapies, including glucocorticoids and bronchodilators, fail to control these exacerbation periods in part due to their low capacity to control non-type 2 pattern of inflammation [7,8,9]
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