Modulation of lipopolysaccharide-induced gene transcription and promotion of lung injury by mechanical ventilation

被引:124
作者
Altemeier, WA
Matute-Bello, G
Gharib, SA
Glenny, RW
Martin, TR
Liles, WC
机构
[1] Univ Washington, Div Pulm & Crit Care Med, Dept Med, Seattle, WA 98195 USA
[2] Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA
[3] Univ Washington, Dept Pathol, Seattle, WA 98195 USA
[4] Vet Affairs Puget Sound Healthcare Syst Med Res S, Seattle, WA 98195 USA
关键词
D O I
10.4049/jimmunol.175.5.3369
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Mechanical ventilation (MV) with tidal volumes of 10-12 ml/kg is considered safe in the absence of acute lung injury (ALI). However, recent studies show that, when lung injury is already present, tidal volumes of this magnitude increase inflammation and injury in the lungs. We hypothesized that MV with tidal volumes of 10-ml/kg can also function as a cofactor in the initiation of ALI by modulating the transcriptional response to bacterial products. To test this hypothesis, we developed a mouse model in which MV did not independently cause inflammation or injury but augmented the inflammatory response to low-dose aspirated LPS and promoted development of ALI. We analyzed gene expression in lungs from 24 mice assigned to four different groups: control, MV only, intratracheal LPS only, and MV + LPS. There were twice as many differentially regulated genes in the MV + LPS group compared with the LPS-only group and 10 times as many differentially regulated genes compared with the MV-only group. For genes up-regulated by LPS treatment alone, the addition of MV further augmented expression. Cytokine concentrations in bronchoalveolar lavage fluid and tissue distribution of an intracellular protein, GADD45-gamma, correlated with mRNA levels. We conclude that MV with conventional tidal volumes enhanced the transcriptional response to LPS and promoted development of ALI.
引用
收藏
页码:3369 / 3376
页数:8
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