Moreover, LTB4 contributes to the elevated chemo taxis of PMN from the circulation to the infected lungs. Consistent with the results from these studies, we noted in selleck Veliparib the HN878 infected rabbit lungs a signifi cant upregulation of PTGS2, which encodes the prostaglandin synthasecyclooxygenase enzyme involved in AA metabolism and acute inflamma Inhibitors,Modulators,Libraries tion. Moreover, expression of PTGER3, an enzyme involved in prostaglandin metabolism, which mediates an anti inflammatory response, was upregulated in CDC1551 infected lungs. Increased recruitment of PMN to the site of infection is expected to exacerbate the local inflammatory response. For example, stimulation of human PMNs Inhibitors,Modulators,Libraries with LTB4 or fMLP, a proinflammatory chemoattractant produced by activated macrophages in response to Mtb and other ago nists, leads to neutrophil activation, increased cell adhe sion and improved phagocytic activity in these cells.

In Inhibitors,Modulators,Libraries the present study we found upregulation of genes that encode the fMLP receptors in rabbit lungs as early as 3 hours after infection with HN878. This observation is consistent with the profound upregulation of macrophage and PMN activation network genes. Such activation of mature human blood neutrophils has been shown to be associated with an elevated tran scription of STAT1, as well as increased phosphorylation of STAT1 protein. Taken together, these observations support our interpretation of the gene expression patterns observed in the rabbit model of pulmonary TB.

That Inhibitors,Modulators,Libraries is, phagocytosis of selected Mtb strains can be associated with early and robust macrophage activation, leading to a PMN associated inflammatory response that will differen tiate between Inhibitors,Modulators,Libraries phenotypically diverse Mtb strains. The dif ferential macrophage response in the rabbit lungs is similar to the results from our in vitro infection studies using mouse bone marrow derived macrophages infected with HN878 or CDC1551, where expression of inflamma tory genes was significantly upregulated at 6 hours in re sponse to HN878 infection while early immune activation network genes were upregulated in response to CDC1551 infection. The role of PMN in the control of Mtb infection and the pathogenesis of TB is not clearly understood. This is in part due to the short life span of PMN and to the dogma that macrophages, and not PMNs, are the primary habitat of infecting bacilli during chronic, pulmonary TB. More recently, studies using PMN depleted mice highlighted the importance of these cells in the host response to Mtb infection. In mice, antibody mediated neutralization of PMN exacer bated bacillary growth selleck kinase inhibitor in the lung, spleen and liver.