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This Article Full Text Full Text (PDF) All Versions of this Article: 293/2/L336    most recent 00011.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Fang, W.-F. Articles by Douglas, I. S. Search for Related Content PubMed PubMed Citation Articles by Fang, W.-F. Articles by Douglas, I. S.

Lipid A fraction of LPS induces a discrete MAPK activation in acute lung injury

¹Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado; ²Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung U. College of Medicine, Kaohsiung, Taiwan; ³Inha University, Incheon, Republic of Korea; ⁴Department of Respiratory Care, Chang Gung Institute of Technology, Chia-Yi, Taiwan; and ⁵Denver Health Medical Center, Denver, Colorado

Submitted 8 January 2007 ; accepted in final form 6 May 2007

Lipopolysaccharide (LPS) induces acute lung injury (ALI) via Toll-like receptor 4 (TLR4)-mediated MAPK activation. The lipid A fraction of LPS is considered to be the active moiety, but whether the lipid A-TLR4 interaction accounts completely for ALI-associated MAPK activation in vivo has not been determined. The lipid A fraction of LPS induces a discrete MAPK activation pattern in murine ALI. Mice (C57BL/6J, C3H/HeJ) were treated with intratracheal instillations of purified lipid A or LPS (10, 30, and 100 µg per mouse) or vehicle. ALI was assessed by histology. Chromogenic myeloperoxidase (MPO) activity was measured in lung homogenates. MAPK expression was quantified by immunoblotting. In vitro ERK inhibitor studies using thioglycollate-elicited macrophages were also performed. MPO increased in a dose- and time-responsive fashion. Notably, MPO was 2.4-fold greater after lipid A compared with LPS and vehicle at 6 h after instillation (lipid A, 0.88 ± 0.25 vs. LPS, 0.37 ± 0.21 optical density units·min^–1·mg^–1; P < 0.05). However, ALI scores were comparable at 6 and 24 h between LPS and lipid A. MPO was also comparable in vehicle-treated or C3H/HeJ mice treated with LPS or lipid A at 6 and 24 h. Phospho-ERK activation was pronounced at 6 and 24 h after lipid A but not LPS treatment. In vitro studies confirmed the relationship between phospho-ERK activation and cytokine expression in macrophage stimulated with either LPS or lipid A. Compared with whole LPS, the lipid A fraction is associated with amplified whole lung MPO and ERK activation 6 h after intratracheal instillation in mice.

Kdo₂-lipid A; lipopolysaccharide; extracellular signal-regulated kinase p44/42

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