Our data demonstrate that barrier leakiness in asthmatic patients is induced by T2 cells, IL-4, and IL-13 and HDAC activity. The inhibition of endogenous HDAC activity reconstitutes defective barrier by increasing TJ expression.

Inter-alpha inhibitor protein (IalphaIp) is an endogenous serine protease inhibitor in human plasma. Circulating IalphaIp levels were lower in 51 patients with severe sepsis than in healthy volunteers. Mean levels were 688+/-295 mg/L in patients with severe sepsis who survived (n=32), 486+/-193 mg/L in patients with sepsis who died (n=19), and 872+/-234 mg/L in control subjects (n=25). IalphaIp levels were lower in patients with shock versus those without (540+/-246 [n=33] vs. 746+/-290 [n=18] mg/L; P=.0102). IalphaIp levels were inversely correlated with 28-day mortality rates and Acute Physiology and Chronic Health Evaluation II scores and directly correlated with antithrombin III, protein C, and protein S levels. The administration of IalphaIp (30 mg/kg body weight intravenously) increased the 50% lethal dose in mice by 100-fold after an intravenous challenge of Escherichia coli. Thus, human IalphaIp may be a useful predictive marker and potential therapeutic agent in sepsis.

SUMMARYAcute RSV infection in infancy may produce some asthma-like symptoms and may be followed by a recurrent wheeze later in childhood. It has been proposed that RSV infection stimulates type-2 cytokine responses, resembling those found in atopy and asthma. Peripheral blood cells were obtained from RSVinfected infants (n 30) and healthy controls (n 10). After in vitro restimulation of the cells, intracellular IL-4 and interferon-gamma (IFN-g) were measured by flow cytometry. The cells from RSV-infected infants produced more IL-4 and less IFN-g than those from healthy controls. IL-4 production was more frequent in CD8 than in CD4 cells, and the bias toward IL-4 production was greatest in infants with mild infections, whereas IFN-g production increased with disease severity. Our conclusions are that RSV infection is associated with IL-4 production in peripheral T cells, and that peripheral blood in infants with severe disease may be depleted of cytokine-producing cells.

Inter-alpha inhibitor proteins (IaIp) are serine proteases inhibitors that modulate endogenous protease activity and have been shown to improve survival in adult models of sepsis. We evaluated the effect of IaIp on survival and systemic responses to sepsis in neonatal mice. Sepsis was induced in 2-d-old mice with lipopolysaccharide (LPS), Escherichia coli, and group B Streptococci. Sepsis was associated with 75% mortality. IaIp, given by i.p. administration at doses between 15 and 45 mg/kg from 1 to 6 h after the onset of sepsis, improved survival to ϳ90% (p ϭ 0.0159) in both LPS-induced sepsis and with live bacterial infections. The greatest effect was on reversal of hemorrhagic pneumonitis. The effects were dose and time dependent. Systemic cytokine profile and tissue histology were examined. Survival was compared in IL-10 knock out animals. Systemic cytokine levels including TNF-␣ and IL-10 were increased after induction of sepsis and modulated significantly after IaIp administration. Because the effect of IaIp was still demonstrable in IL-10 deficient mice, we conclude the beneficial effects of IaIp is because of suppression of proinflammatory cytokines such as TNF-␣ rather than augmentation of IL-10. IaIp may offer significant benefits as a therapeutic adjunct to treatment of sepsis in neonates and adults. (Pediatr Res 68: 242-247, 2010)