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Matrix metalloproteinases are important for proper airway matrix structure and wound healing. These enzymes are also implicated in many airway diseases. Previously, chronic ethanol consumption was shown to prolong inflammation and delay viral clearance in respiratory syncytial virus (RSV)-infected mice. We hypothesize that alcohol alters anti-viral immunity by disrupting immune cell chemotaxis in the lung. BALB/c mice were randomly selected to consume 18% alcohol ad libitum for 8 weeks prior to infection with RSV-2A. Bronchoalveolar lavage (BAL) cell populations were measured by flow cytometry, and chemokines were detected by Western blot or ELISA. MMP-9 levels were determined by polymerase chain reaction (PCR) in mouse lungs and in BAL fluid by ELISA. T cells were acquired from the spleens of water-fed, non-infected control mice (CTRL); alcohol-fed, non-infected (ETOH); water-fed, RSV-infected (RSV); or ethanol-fed, RSV-infected (ETOH-RSV) 4 days after RSV infection. T cells were placed in a transmigration system where chemokines had been treated with and without activated MMP-9. Lymphocyte recruitment was significantly reduced in the BAL 4 days after RSV infection in ETOH-RSV mice, whereas chemokine levels were the highest in this group at all experimental time points examined in comparison to RSV (p < 0.05). MMP-9 mRNA and protein were detected at high levels in ETOH-RSV mice compared to RSV. Using ex vivo transmigration to CCL2 and CXCL10, T cell migration was not impaired between any of the treatment groups, yet when CCL2 and CXCL10 were treated with activated MMP-9, significantly fewer T cells migrated across collagen-coated 5-μm membranes (p < 0.05). Immune cell recruitment is necessary for viral clearance. We show that immune cells are decreased in the lungs of ETOH-RSV mice. In contrast to decreased cell recruitment, key inflammatory chemokines were elevated in the lungs of ETOH-RSV mice. These proteins may be prematurely degraded by MMP-9 in the lung, leading to defective immunity and reduced viral clearance. [ABSTRACT FROM AUTHOR]

Background: Agriculture organic dust exposures induce lung disease with lymphoid aggregates comprised of both T and B cells. The precise role of B cells in mediating lung inflammation is unknown, yet might be relevant given the emerging role of B cells in obstructive pulmonary disease and associated autoimmunity.Methods: Using an established animal model, C57BL/6 wild-type (WT) and B-cell receptor (BCR) knock-out (KO) mice were repetitively treated with intranasal inhalation of swine confinement organic dust extract (ODE) daily for 3 weeks and lavage fluid, lung tissues, and serum were collected.Results: ODE-induced neutrophil influx in lavage fluid was not reduced in BCR KO animals, but there was reduction in TNF-α, IL-6, CXCL1, and CXCL2 release. ODE-induced lymphoid aggregates failed to develop in BCR KO mice. There was a decrease in ODE-induced lung tissue CD11c+CD11b+ exudative macrophages and compensatory increase in CD8+ T cells in lavage fluid of BCR KO animals. Compared to saline, there was an expansion of conventional B2-, innate B1 (CD19+CD11b+CD5+/-)-, and memory (CD19+CD273+/-CD73+/-) B cells following ODE exposure in WT mice. Autoreactive responses including serum IgG anti-citrullinated protein antibody (ACPA) and anti-malondialdehyde-acetaldehyde (MAA) autoantibodies were increased in ODE treated WT mice as compared to saline control. B cells and serum immunoglobulins were not detected in BCR KO animals.Conclusions: Lung tissue staining for citrullinated and MAA modified proteins were increased in ODE-treated WT animals, but not BCR KO mice. These studies show that agriculture organic dust induced lung inflammation is dependent upon B cells, and dust exposure induces an autoreactive response. [ABSTRACT FROM AUTHOR]

Alcohol-use disorders (AUD) persist in the United States and are heavily associated with an increased susceptibility to respiratory viral infections. Respiratory syncytial virus (RSV) in particular has received attention as a viral pathogen commonly detected in children and immune-compromised populations (elderly, asthmatics), yet more recently was recognized as an important viral pathogen in young adults. Our study evaluated the exacerbation of RSV-associated illness in mice that chronically consumed alcohol for 6 weeks prior to infection. Prior studies showed that lung viral titers remained elevated in these animals, leading to a hypothesis that T-cell activation and immune specificity were deficient in controlling viral spread and replication in the lungs. Herein, we confirm a reduction in RSV-specific IFNγ production by CD8 T cells and a depolarization of Th1 (CD4+IFNγ+) and Th2 (CD4+IL-4+) T cells at day 5 after RSV infection. Furthermore, over the course of viral infection (day 1 to day 7 after RSV infection), we detected a delayed influx of neutrophils, monocytes/macrophages, and lymphocytes into the lungs. Taken together, the data show that both the early and late adaptive immunity to RSV infection are altered by chronic ethanol consumption. Future studies will determine the interactions between the innate and adaptive immune systems to delineate therapeutic targets for individuals with AUD often hospitalized by respiratory infection. [ABSTRACT FROM AUTHOR]

Agriculture exposures are associated with reducing the risk of allergy and asthma in early life; yet, repeated exposures later in life are associated with chronic bronchitis and obstructive pulmonary diseases. The objective of this study was to investigate the airway inflammatory response to organic dust extract (ODE) in mice with established ovalbumin (OVA)-induced experimental asthma. C57BL/6 mice were either OVA sensitized/aerosol-exposed or saline (Sal) sensitized/aerosol-challenged. Both groups were then subsequently challenged once with intranasal saline or swine confinement ODE to obtain 4 treatment groups of Sal-Sal, Sal-ODE, OVA-Sal, and OVA-ODE. Airway hyper-responsiveness (AHR) to methacholine, bronchiolar lavage fluid, lung tissues, and serum were collected. Intranasal inhalation of ODE in OVA-treated (asthmatic) mice (OVA-ODE) increased AHR and total cellular influx marked by elevated neutrophil and eosinophil counts. Flow cytometry analysis further demonstrated that populations of CD11chi dendritic cells (DC), CD3+ T cells, CD19+ B cells, and NKp46+ group 3 innate lymphoid cells (ILC3) were increased in lavage fluid of OVA-ODE mice as compared to ODE or OVA alone. Alveolar macrophages, DC, and T cells were significantly increased with co-exposure to OVA-ODE as compared to OVA alone. Lung ILC2 and ILC3 were only increased in OVA-Sal mice. Cytokine/chemokine levels varied with exposure to OVA-ODE reflecting an additive mixture of the pro- and allergic-inflammatory profiles. Collectively, ODE increased airway inflammatory cells and chemotactic mediator release in allergic (OVA) sensitized mice to suggest that persons with allergy/asthma be identified and warned prior to the occupational exposure of potentially worsening airway disease. [ABSTRACT FROM AUTHOR]