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CCR5 Antagonist Maraviroc Inhibits Acute Exacerbation of Lung Inflammation Triggered by Influenza Virus in Cigarette Smoke-Exposed Mice.

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.

SUBMITTER: Ferrero MR

PROVIDER: S-EPMC8308708 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In urban areas with a predominance of early to mid-20th century housing stock, islands of children possessing blood lead levels (PbB) in excess of CDC guidelines (>10?g/dL) exist. Many of these children are also exposed to environmental tobacco smoke (ETS). The current study examined the impact of Pb-exposure (PbB levels of 1-55?g/dL) with/without concurrent ETS exposure on immune system function in 318 children aged 6-84 months from the urban area of Springfield-Greene County, MO. In this population, 36.5% of children possessed PbB levels >10?g/dL, 62.9% of children came from smoking homes, 51.9% of children were under 2 years of age, and the population was WIC eligible and predominantly of white, non-Hispanic ethnicity. Multiple immune function markers including cell counts, IgE levels, sCD25 (sIL2R) and IL4 concentrations, and titers to common childhood immunizations were analyzed for correlation with Pb and/or ETS exposure. Increased IgE levels (p<0.01) were found in children with PbB levels within CDC Classes II-IV - this finding was primarily attributable to elevated IgE levels in the subpopulation of children with concurrent Pb and ETS exposure. A trend (0.05<p<0.01) of increases in % total T-cells (p=0.06) was also found in children with concurrent elevated PbB levels and ETS exposure. This trend was not found in the subset of children without ETS exposure nor was it present in the analysis of the entire population set. Conversely, alterations in median values for % lymphocytes, % granulocytes, and % activated T-cells across Pb classes were present in the subpopulation of children expose to Pb alone (without concurrent ETS exposure) though a clear trend was not evident. In the entire population set, a statistically significant correlation between ETS and PbB levels was found. This study indicates that prior reports of a correlation between elevated PbB levels and serum IgE levels may be strongly influenced by exposure to ETS. Findings from this study also indicate that Pb is an immune modulator and PbB levels may be influenced by ETS exposure.

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CCR5 Antagonist Maraviroc Inhibits Acute Exacerbation of Lung Inflammation Triggered by Influenza Virus in Cigarette Smoke-Exposed Mice.

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