SummarySystemic infection with Streptococcus pneumoniae is associated with a vigorous pro-inflammatory response to structurally complex cell wall fragments (PnCW) that are shed during cell growth and antibiotic-induced autolysis. Consistent with previous studies, inflammatory cytokine production induced by PnCW was dependent on TLR2 but independent of NOD2, a cytoplasmic NLR protein. However, in parallel with the pro-inflammatory response, we found that PnCW also induced prodigious secretion of anti-inflammatory IL-10 from macrophages. This response was dependent on TLR2, but also involved NOD2 as absence of NOD2-reduced IL-10 secretion in response to cell wall and translated into diminished downstream effects on IL-10-regulated target gene expression. PnCWmediated production of IL-10 via TLR2 required RIPK2 a kinase required for NOD2 function, and MyD88 but differed from that known for zymosan in that ERK pathway activation was not detected. As mutations in NOD2 are linked to aberrant immune responses, the temporal and quantitative effects of activation of the TLR2-NOD2-RIPK2 pathway on IL-10 secretion may affect the balance between pro-and anti-inflammatory responses to Gram-positive bacteria.

SUMMARY Incursions of new pathogenic viruses into humans from animal reservoirs are occurring with alarming frequency. The molecular underpinnings of immune recognition, host responses, and pathogenesis in this setting are poorly understood. We studied pandemic influenza viruses to determine the mechanism by which increasing glycosylation during evolution of surface proteins facilitates diminished pathogenicity in adapted viruses. ER stress during infection with poorly glycosylated pandemic strains activated the unfolded protein response, leading to inflammation, acute lung injury, and mortality. Seasonal strains or viruses engineered to mimic adapted viruses displaying excess glycans on the hemagglutinin did not cause ER stress, allowing preservation of the lungs and survival. We propose that ER stress resulting from recognition of non-adapted viruses is utilized to discriminate “non-self” at the level of protein processing and to activate immune responses, with unintended consequences on pathogenesis. Understanding this mechanism should improve strategies for treating acute lung injury from zoonotic viral infections.

Warfarin-related ICH is associated with less early relative edema than non-coagulopathic ICH. This is consistent with the theory that coagulation contributes to early edema. Early edema may be associated with improved functional outcome.

Purpose To investigate the role of ontogeny in sorafenib metabolism to the equipotent active metabolite sorafenib N-oxide. Experimental Design Steady-state pharmacokinetic studies of sorafenib and metabolites were performed in thirty children and young adults (17 males; median age, 9.5 years) receiving sorafenib 150 mg/m2 or 200 mg/m2 twice daily. Sorafenib metabolism was evaluated in vitro at 10 µM using a panel of purified human cytochrome P450 (CYP) enzymes. Sorafenib metabolism and CYP3A4 expression was evaluated in 52 human liver samples from donors ≤ 20 years old. The drug-drug interaction potential between sorafenib and azole antifungal agents was evaluated in vitro and in vivo. Results No age-related differences in sorafenib apparent oral clearance were observed. Mean sorafenib N-oxide metabolite ratio was 0.27±0.14. In children ≤ 10 years of age, boys had approximately 2-fold higher N-oxide ratios than girls (0.40±0.15 versus 0.22±0.12, P = 0.026). Of the CYPs evaluated, sorafenib was exclusively metabolized to sorafenib N-oxide by CYP3A4. A trend for increased N-oxide formation in boys was observed in liver samples, which correlated with CYP3A4 mRNA expression. Posaconazole and voriconazole potently inhibited sorafenib N-oxide formation in vitro, and reduced sorafenib N-oxide formation in 3 children given sorafenib concurrent with azoles. Conclusion We have identified several factors affecting inter-patient variability in sorafenib metabolism to the active N-oxide metabolite including age, sex, and concurrent treatment with azole antifungals. This knowledge may provide important considerations for the clinical use of sorafenib in children and possibly other kinase inhibitors undergoing CYP3A4-mediated metabolism.

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