We (22) as well as others (1) have found that a much higher viral titer is required to infect mice compared with humans

We (22) as well as others (1) have found that a much higher viral titer is required to infect mice compared with humans. expression, and mouse lung macrophages from IL-4 receptor knockout mice showed reduced CCL2 expression in response to HRV, suggesting that exposure to these Th2 cytokines plays a role in the altered HRV response. Finally, bronchoalveolar macrophages from children with asthma elaborated more CCL2 upon ex lover vivo exposure to HRV than cells from nonasthmatic patients. We conclude that CCL2 production by epithelial cells and macrophages contributes to HRV-induced airway hyperresponsiveness and inflammation SGC GAK 1 in a mouse model of allergic airways disease and may play a role SGC GAK 1 in HRV-induced asthma exacerbations. family. HRV serotypes are classified on the basis of their cellular receptors. Major group viruses attach to intercellular adhesion molecule (ICAM)-1, whereas minor group viruses bind to proteins of the low-density lipoprotein receptor (LDL-R) family. The structural similarity of mouse and human LDL-R proteins allows for experimental infection of mice with minor group HRV and in recent years has led to the establishment of mouse models of HRV infection (1, 23). Following experimental infection, HRV is detectable in the lower airways of subjects with asthma (9, 20, 28). Although individuals with asthma are not at greater risk of HRV infection than healthy individuals, the frequency, severity, and duration of lower respiratory tract symptoms in asthmatic patients is increased compared with nonasthmatic subjects (6). According to SGC GAK 1 the current paradigm of asthma exacerbation, viral infection of airway epithelial cells induces production of chemokines, thereby recruiting inflammatory cells to the airways. Inflammatory cells, in turn, elaborate cytokines and mediators capable of increasing airways responsiveness. However, this paradigm fails to explain why asthmatic subjects suffer manifestations of lower airways disease after colds while normal subjects do not. We recently observed that allergen sensitization and challenge alters the polarization state of airway macrophages, resulting in an exaggerated chemokine response to HRV infection (21). The CC chemokines are a class of small (8C10 kDa) chemotactic ligands with two adjacent cysteines near their amino terminus. Recent studies suggest that CC chemokine ligand (CCL)-2/monocyte chemotactic protein (MCP)-1 and its receptor CC chemokine receptor (CCR)-2 play important roles in the pathogenesis of asthma. Studies employing antibody depletion of CCL2 and CCR2-deficient mice demonstrate the requirement of this pathway for allergen-induced airway inflammation and hyperresponsiveness (3, 17). CCR2 blockade prevents and and challenged intranasally with 50 l of a 2 mg/ml solution of OVA or PBS on retinoic acid (5 10?8 M), hydrocortisone (0.5 g/ml), insulin (5 g/ml), transferrin (10 g/ml), epinephrine (0.5 g/ml), triiodothyronine (6.5 ng/ml), gentamycin (50 g/ml), and amphotericin (50 g/ml). In selected experiments, cells were pretreated with 30 ng/ml IL-4 and IL-13 (Peprotech). Analysis SGC GAK 1 of BAL macrophages from children with asthma. BAL macrophages were obtained from children undergoing flexible bronchoscopy at the University of Michigan C.S. Mott Children’s Hospital (Table 1). All procedures were done for clinical indications. Collection of extra BAL fluid was approved by the University of Michigan Institutional Review Board. Ten patients were studied, five with asthma and five with other conditions. BAL cells were seeded in 96-well plates at 1 105 cells/well in 100 l RPMI medium supplemented with 10% fetal bovine serum, l-glutamine, and penicillin/streptomycin (Gibco). Cells were purified by plastic adherence (7, 14), infected with HRV39 (multiplicity Cetrorelix Acetate of infection, 5.0), and cultured for 8 h. CCL2 mRNA was quantified by qPCR. Table 1. Description of human subjects Value*= 5 mice/group. Different from respective sham (*) or PBS (?) group, 0.05, 1-way ANOVA. CCL2 neutralization in vivo. Based on studies implicating CCL2 in human.

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