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

Abstract

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 microg 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.

• Authors: Wen-Feng Fang, Jae Hwa Cho, Qianbin He, Meng-Chih Lin, Chao-Chien Wu, Norbert F Voelkel, Ivor S Douglas
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 293 Issue 2 Pg. L336-44 (Aug 2007) ISSN: 1040-0605 [Print] United States
• PMID: 17496062 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Enzyme Inhibitors
• Flavonoids
• Lipid A
• Lipopolysaccharides
• Peroxidase
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• Cytokines (metabolism)
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• Lipid A (pharmacology)
• Lipopolysaccharides (pharmacology)
• Lung (enzymology, immunology)
• MAP Kinase Signaling System (drug effects, immunology)
• Macrophages (drug effects, immunology)
• Male
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, metabolism)
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors, metabolism)
• Peroxidase (metabolism)
• Pneumonia (chemically induced, immunology, metabolism)
• Respiratory Distress Syndrome (immunology, metabolism)