The timing of the observed decrease in neutrophil

The timing of the observed decrease in neutrophil Vorinostat HDAC3 numbers and inflammatory mediators argues against a causal link between decreased inflammation and host protection. Specifically, combined antibiotic treatment reduced the pulmonary bacterial burden as early as at 2 h after initiation of antibiotic treatment, whereas the decreased inflammatory response was also apparent until 6 h post antibiotic treatment. In addition to this discrepancy in timing, there is substantial evidence that the recruitment of neutrophils and regulatory release of proinflammatory mediators are protective against S. pneumoniae-induced mortality. High IL-6 concentrations were found in the lungs of mice infected with SP.

In addition relatively higher serum IL-6 levels has been reported after intravenous injection of wild type SP than after administration of pneumolysin (PLY) negative mutant SP suggesting the induction of an inflammatory response in the pulmonary compartment in the early phase of pneumococcal pneumonia [56]. During lung inflammation in acute phase, damaged alveolar capillary and epithelial membranes by PMN leading to leakage of protein rich edema fluid into the alveolar space, and formation of hyaline membranes which impaired gas exchange have been reported [57]. At early stages of infection the permeability of lung vasculature is increased due to enhanced release of proinflammatory cytokines (TNF-��, IFN-�� and IL-6) [58-60]. Hence, decrease in extravasations after initiation of combined antibiotic therapy after 3 h of post antibiotic treatment may be due to reduced lung TNF-��, IFN-�� and IL-6 level and increased anti-inflammatory cytokine (IL-10), which is sustained until 6 hours post antibiotic treatment.

The inflammatory cytokine response in the lung is characterized by intense elevation IL-6, TNF-�� and IFN-�� which was decreased after combined treatment. A subsequent increase in IL-10 after combinatorial treatment, which is an anti-inflammatory cytokine that inhibits macrophage and neutrophil production, is the beginning of the anti-inflammatory response that prevents an uncontrolled inflammatory response. IL-6 has been considered as a marker for the severity of bacterial challenge represents a relevant marker for the evolution of a host response and high IL-6 concentrations have been found in the lungs of mice infected with SP [61].

Therefore, reduced IL-6 in combined antibiotic treated mice might be responsible for decreased inflammation in mouse lungs along with reduced lung TNF-�� and IFN-�� after antibiotic treatment. We observed that IFN-��, TNF-��, IL-6 but not IL-10 production was increased initially 18 hours post-infection and decreased gradually thereafter Carfilzomib following treatments with AMP and AZM. Therefore, it is likely that increased TNF-�� and IFN-�� released into the circulation after infection by the administration of S. pneumonia cells or their exotoxins demonstrated a detrimental effect on the host.

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