Abstract
BackgroundCigarette smoke has both pro-inflammatory and immunosuppressive effects. Both active and passive cigarette smoke exposure are linked to an increased incidence and severity of respiratory virus infections, but underlying mechanisms are not well defined. We hypothesized, based on prior gene expression profiling studies, that upregulation of pro-inflammatory mediators by short term smoke exposure would be protective against a subsequent influenza infection.MethodsBALB/c mice were subjected to whole body smoke exposure with 9 cigarettes/day for 4 days. Mice were then infected with influenza A (H3N1, Mem71 strain), and analyzed 3 and 10 days later (d3, d10). These time points are the peak and resolution (respectively) of influenza infection.ResultsInflammatory cell influx into the bronchoalveolar lavage (BALF), inflammatory mediators, proteases, histopathology, viral titres and T lymphocyte profiles were analyzed. Compared to smoke or influenza alone, mice exposed to smoke and then influenza had more macrophages, neutrophils and total lymphocytes in BALF at d3, more macrophages in BALF at d10, lower net gelatinase activity and increased activity of tissue inhibitor of metalloprotease-1 in BALF at d3, altered profiles of key cytokines and CD4+ and CD8+ T lymphocytes, worse lung pathology and more virus-specific, activated CD8+ T lymphocytes in BALF. Mice smoke exposed before influenza infection had close to 10-fold higher lung virus titres at d3 than influenza alone mice, although all mice had cleared virus by d10, regardless of smoke exposure. Smoke exposure caused temporary weight loss and when smoking ceased after viral infection, smoke and influenza mice regained significantly less weight than smoke alone mice.ConclusionSmoke induced inflammation does not protect against influenza infection.In most respects, smoke exposure worsened the host response to influenza. This animal model may be useful in studying how smoke worsens respiratory viral infections.
Highlights
Cigarette smoke has both pro-inflammatory and immunosuppressive effects
We have previously shown that tumor necrosis factor-α (TNF-α) mRNA in peripheral fat of smoke exposed mice was unchanged, suggesting that effects of smoke are largely confined to the lung [16]
We have previously found that this short term smoke exposure protocol increased mRNA levels of many proinflammatory mediators in lung and/or alveolar macrophages [12]
Summary
Cigarette smoke has both pro-inflammatory and immunosuppressive effects Both active and passive cigarette smoke exposure are linked to an increased incidence and severity of respiratory virus infections, but underlying mechanisms are not well defined. Cigarette smoke exposure is a major but preventable cause of increased risk of lung infections in children and adults. Exposure to cigarette smoke has similar adverse effects to active smoking on lung infections, with young children at higher risk [1,2]. Half of the world's children breathe cigarette smoke at home [1], and both pre- and post-natal smoke exposure are linked to decreased lung function and increased risk and severity of asthma and respiratory infections [1,2]. The role of inflammation in the resolution of influenza infection remains controversial, with evidence for both immune-mediated amelioration [reviewed in [6]] and worsening [7,8,9] of the host's overall condition
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