Discussion Using two different Mtb clinical isolates, which give rise to progressive cavitary disease versus spontan eous clearance of bacilli and establishment of LTBI in rabbit www.selleckchem.com/products/Imatinib(STI571).html lungs, we show that at similar lung bacillary burdens, a clear early difference in leukocyte recruitment and activation was noted. The dif ferential leukocyte infiltration, including a significant dif ference in the accumulation of activated PMN, was associated with striking differences in the activation of gene networks involved in the host inflammatory re sponse, STAT1 Inhibitors,Modulators,Libraries regulation and PMN recruitment, as well as in PMN and macrophage activation. Moreover, we confirmed our hypothesis that the early host immune response determines outcome following Mtb infection, by comparing the differential early response in the lungs to what is seen at 4 weeks of infection.
Similar to 3 hours, we observed Inhibitors,Modulators,Libraries significantly increased induction of Inhibitors,Modulators,Libraries inflammatory responses, activation of STAT1, PMN and macrophages, and fMLP stimulation network gene ex pression profiles at 4 weeks in the lungs of HN878 infected animals, compared to CDC1551 infected rabbit lungs. Based on these findings, we suggest a model for the host response Inhibitors,Modulators,Libraries during early Mtb infection in the rabbit lungs that links specific patterns of macro phage activation in response to phagocytosis of the two Mtb strains, with differential activation of the STAT1 regulated inflammatory response. Accordingly, phagocytosis of HN878 by alveolar macrophages resulted in an early and robust expression of genes coding for pro inflammatory molecules, including TNF, IL 8, IL 15, MCP 1 and CXCL10, that are associated with increased extravasation and activation of PMN in the lungs.
In contrast, CDC1551 infection, which failed to induce the expression of these genes, resulted in less recruitment and reduced activation of PMN. The differential gene expression profile in response to infection with the two clinical Mtb isolates was noted as early as 3 hours. Clearly, the factors that initiate and regulate this Inhibitors,Modulators,Libraries differential response must have been activated even earlier. Some of the earliest mediators of inflammation induced in response to engaging macro phage receptors are the arachidonic acid metabo lites, induced within minutes and shown to peak at 3 hours post LPS stimulation of macrophages. Aderem et al.
showed that LPS primed macrophages demonstrate enhanced production check this of 20 4 upon phago cytosis of zymosan, releasing AA into the extracellu lar milieu at one hour post exposure. Similarly, treatment of J774A. 1 cells with AA or infection with mycobacteria induces NFkB activation and surface ex pression of CD69 within one hour p38 MAP kinase acti vation in these cells is noted by 3 hours. Activation of NFkB and p38 MAP kinase is associated with increased actin polymerization, phagosome maturation and a TNF mediated proinflammatory response.