Specific inhibitors of p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways block inducible nitric oxide synthase and tumor necrosis factor accumulation in murine macrophages stimulated with lipopolysaccharide and interferon-gamma.

Whether p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase cascades are required for inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF) accumulation in RAW 264.7 murine macrophages exposed to lipopolysaccharide (LPS) plus recombinant interferon-gamma (rIFN-gamma) was investigated. By use of Western blotting for iNOS detection and ELISA for quantitation of TNF secretion, three selective inhibitors of these pathways were tested (the p38 inhibitors SB202190 and SB203580 and the MEK 1,2/ERK inhibitor PD98059). Dose-related inhibition of iNOS production was demonstrated when inhibitors were added 1 h before, simultaneously with, or 1 h after LPS plus rIFN-gamma stimulation. In contrast, inhibition of TNF secretion was observed only when cells were preincubated with these agents. Thus, both the p38 and ERK pathways are involved in the up-regulation of iNOS and TNF production by murine macrophages, and specific inhibitors of these pathways block macrophage iNOS production even when added 1 h after activation of these cells.

Intensive care course and outcome of patients infected with respiratory syncytial virus.

PICU admissions of 97 children positive for respiratory syncytial virus on fluorescent antibody screening were reviewed; 68% of 44 patients without history of preceding disease (Group I) and 79% of 53 patients with preceding pulmonary, cardiac, or other disease (Group II) required ventilation. In Group I ventilated children weighted significantly less (P = 0.001) and were of lower chronological (P = 0.02) and post-conceptional ages (P = 0.02) than those not ventilated. Eighteen infants ventilated for apnea weighted significantly less (P = 0.003), were more often born at less than or equal to 37 weeks gestation (P = 0.001) and were at lower post-conceptional age than 11 infants ventilated for progressive respiratory deterioration. There was no significant difference in mean weight, chronological age, post-conceptional age, CO2, or pH between 12 admissions with BPD who required ventilation for RSV infection and 5 who did not require ventilation. Ribavirin administration to five ventilated patients with BPD did not significantly alter the duration of intubation of PICU stay. Six patients with cardiac disease required longer periods of ventilation than others (Group I, P = 0.001; all others in Group II, P = 0.04). No deaths occurred in Group I, while 6 of 53 (11%) patients in Group II died. In this series immuno compromise placed patients at greatest risk of dying. Mechanical ventilation can be safely managed in previously healthy, RSV infected infants and should be initiated before significant cardiorespiratory compromise arises.