Mitogen-Activated Protein Kinases Regulate Susceptibility to Ventilator-Induced Lung Injury

Background: Mechanical ventilation causes ventilator-induced lung injury in animals and humans. Mitogen-activated protein kinases have been implicated in ventilator-induced lung injury though their functional significance remains incomplete. We characterize the role of p38 mitogen-activated protein kinase/mitogen activated protein kinase kinase-3 and c-jun-NH2-terminal kinase-1 in ventilator-induced lung injury and investigate novel independent mechanisms contributing to lung injury during mechanical ventilation. Methodology and Principle Findings: C57/BL6 wild-type mice and mice genetically deleted for mitogen-activated protein kinase kinase-3 (mkk-3-/-) or c-Jun-NH2-terminal kinase-1 (jnk1-/-) were ventilated, and lung injury parameters were assessed. We demonstrate that mkk3-/- or jnk1-/- mice displayed significantly reduced inflammatory lung injury and apoptosis relative to wild-type mice. Since jnk1-/- mice were highly resistant to ventilator-induced lung injury, we performed comprehensive gene expression profiling of ventilated wild-type or jnk1-/- mice to identify novel candidate genes which may play critical roles in the pathogenesis of ventilator-induced lung injury. Microarray analysis revealed many novel genes differentially expressed by ventilation including matrix metalloproteinase-8 (MMP8) and GAFF45α. Functional characterization of MMP8 revealed that mmp8-/- mice were sensitized to ventilator-induced lung injury with increased lung vascular permeability. Conclusion: We demonstrate that mitogen-activated protein kinase pathways mediate inflammatory lung injury during ventilator-induced lung injury. C-Jun-NH2-terminal kinase was also involved in alveolo-capillary leakage and edema formation, whereas MMP8 inhibited alveolo-capillary protein leakage. © 2008 Dolinay et al

Good Efficacy of Artemether-Lumefantrine for Uncomplicated Falciparum Malaria in Eastern Sumba, East Nusatenggara, Indonesia

Aim: to evaluate the safety and efficacy of a fixed combination of artemether-lumefantrine for likely use against failures of the artesunate-amodiaquine first line therapy. Methods: the study was an open label single arm uncontrolled trial. we evaluated the safety and efficacy of standard artemether-lumefantrine therapy in 59 subjects with uncomplicated malaria caused by Plasmodium falciparum on the island of Sumba in eastern Indonesia. No treatment failures occurred up to day 35. One subject had recurrent parasitemia on day 42 that showed a genotype consistent with recrudescence. The efficacy of this therapy was thus estimated to be 98.3% (95% confidence interval=95%-100%). Descriptive analysis was done using the SPSS 12 computer software. Results: two hundred and thirteen P. falciparum patients met the inclusion criteria for in vivo efficacy study, 79 were given artemether-lumefantrine and 134 were treated under another protocol with artesunate-amodiaquine or sulfadoxine-pyrimethamine. Among 79 eligible subjects, 59 successfully completed the 42-day test. As expected, the mean PCT was longer than the mean FCT, i.e. 1.34+-0.67 (95% CI 1.21–1.47) and 1.05+-0.05 (95% CI 0.95–1.15) days, respectively. On day 3 of treatment, both fever and asexual stage of P. falciparum disappeared in all subjects. Observation until Day 35 showed that all of the 59 subjects treated with artemether-lumefantrine were cured. Conclusion: the findings of this uncontrolled study suggest good safety and efficacy of artemether-lumefantrine for treatment of uncomplicated falciparum malaria on Sumba Island in the Lesser Sundas archipelago of eastern Indonesia