Abstract
Respiratory syncytial viral (RSV) infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are a major factor in disease progression and mortality. RSV is able to evade antiviral defenses to persist in the lungs of COPD patients. Though RSV infection has been identified in COPD, its contribution to cigarette smoke-induced airway inflammation and lung tissue destruction has not been established. Here we examine the long-term effects of cigarette smoke exposure, in combination with monthly RSV infections, on pulmonary inflammation, protease production and remodeling in mice. RSV exposures enhanced the influx of macrophages, neutrophils and lymphocytes to the airways of cigarette smoke exposed C57BL/6J mice. This infiltration of cells was most pronounced around the vasculature and bronchial airways. By itself, RSV caused significant airspace enlargement and fibrosis in mice and these effects were accentuated with concomitant smoke exposure. Combined stimulation with both smoke and RSV synergistically induced cytokine (IL-1α, IL-17, IFN-γ, KC, IL-13, CXCL9, RANTES, MIF and GM-CSF) and protease (MMP-2, -8, -12, -13, -16 and cathepsins E, S, W and Z) expression. In addition, RSV exposure caused marked apoptosis within the airways of infected mice, which was augmented by cigarette smoke exposure. RSV and smoke exposure also reduced protein phosphatase 2A (PP2A) and protein tyrosine phosphates (PTP1B) expression and activity. This is significant as these phosphatases counter smoke-induced inflammation and protease expression. Together, these findings show for the first time that recurrent RSV infection markedly enhances inflammation, apoptosis and tissue destruction in smoke-exposed mice. Indeed, these results indicate that preventing RSV transmission and infection has the potential to significantly impact on COPD severity and progression.
Highlights
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US [1] and a foremost cause of morbidity
An exacerbation is a seminal event in the life of a COPD patient that frequently marks the transition from relative stability to a more rapid decline in lung function
It has long been observed that Respiratory syncytial viral (RSV) infections are frequently detected in the lungs of COPD patients during an exacerbation [16]
Summary
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US [1] and a foremost cause of morbidity. Acute exacerbations of COPD, defined as a sudden worsening of COPD symptoms (shortness of breath, quantity and color of phlegm) that typically lasts for several days, are a major contributor to disease morbidity and mortality [4,5] Those with 3 or more exacerbations over a five-year time period had a survival rate of 30% compared to a survival rate of 80% for those without an exacerbation [6]. In the Perception of Exacerbations of Chronic Obstructive Pulmonary Disease (PERCEIVE) survey, 89% of COPD subjects experienced at least one exacerbation in the past year and 21% of these exacerbations resulted in hospital admission [7] These findings show that exacerbations are common in COPD and impact significantly on the natural history of the disease. These studies underscore the importance of determining the etiologic factors underlying COPD exacerbations
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