Project description: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 GADD45a. Functional characterization of MMP8 revealed that mmp8-/- mice were sensitized to ventilator-induced lung injury with increased lung vascular permeability. Conclusions: 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. Keywords: response to injury, genetically modified mouse
Project description:To study the effects of previous exposure to mechanical ventilation may modify the development of Ventilator-induced lung injury, preconditioning was induced by low-pressure ventilation for 90 minutes. After 1 week, intact (sham) and preconditioned mice were sacrificed, the lungs extracted and gene expression measured in order to identify differences responsible for the observed tolerance to ventilator-induced lung injury observed in preconditioned animals. 6 samples were analyzed, from 3 intact (sham) and 3 preconditioned CD1 mice.
Project description:To study the effects of previous exposure to mechanical ventilation may modify the development of Ventilator-induced lung injury, preconditioning was induced by low-pressure ventilation for 90 minutes. After 1 week, intact (sham) and preconditioned mice were sacrificed, the lungs extracted and gene expression measured in order to identify differences responsible for the observed tolerance to ventilator-induced lung injury observed in preconditioned animals.
Project description:WT mice and claudin 4 KO mice were exposed to ventilator-induced lung injury (VILI) for 2 hours. We found that in some Cldn4 KO mice, injury was similar to WT, while in others, injury was higher, as assessed by amount of protein leak into broncho-alveolar lavage fluid. We performed RNAseq to find which genes were responsible for higher injury in Cldn4 KO mice. WT mice and claudin 4 KO mice were exposed to ventilator-induced lung injury (VILI) for 2 hours. RNA were extracted from whole lungs and RNA sequencing was performed. The samples are (all in duplicates): WT no VILI, Cldn4 KO no VILI, WT VILI, Cldn4 KO VILI with similar injury to WT (Cldn4 KOlow), and Cldn4 KO VILI with higher injury than WT (Cldn4 KOhigh)
Project description:This study was undertaken to examine differential gene expression across the whole genome during short-term ventilator-induced lung injury in mice, a commonly used model of acute lung injury, as compared with spontaneous ventilation. Keywords: Disease state analysis