OBJECTIVETo monitor the systemic gene expression profile in a murine model of lipopolysaccharide-induced acute lung injury.

METHODSAcute lung injury was induced by intratracheal injection of lipopolysaccharide in 3 mice. Another 3 normal mice receiving same volume of normal saline were taken as the controls. The comprehensive gene expression profile was monitored by the recently modified long serial analysis of gene expression.

RESULTSA total of 24,670 tags representing 12,168 transcripts in the control mice and 26,378 tags representing 13,397 transcripts in the mice with lung injury were identified respectively. There were 11 transcripts increasing and 7 transcripts decreasing more than 10 folds in the lipopolysaccharide-treated mice. The most overexpressed genes in the mice with lung injury included serum amyloid A3, metallothionein 2, lipocalin 2, cyclin-dependent kinase inhibitor 1A, lactate dehydrogenase 1, melatonin receptor, S100 calcium-binding protein A9, natriuretic peptide precursor, etc. Mitogen activated protein kinase 3, serum albumin, complement component 1 inhibitor, and ATP synthase were underexpressed in the lung injury mice.

CONCLUSIONSSerial analysis of gene expression provides a molecular characteristic of acute lung injury.

Animals ; Cyclin-Dependent Kinases ; antagonists & inhibitors ; blood ; DNA-Binding Proteins ; blood ; Disease Models, Animal ; Gene Expression ; genetics ; Gene Expression Profiling ; methods ; Lipopolysaccharides ; Male ; Metallothionein ; blood ; Mice ; Mice, Inbred C57BL ; Neoplasm Proteins ; blood ; Nuclear Proteins ; blood ; Protein Folding ; Reference Values ; Respiratory Distress Syndrome, Adult ; chemically induced ; genetics ; S100 Proteins ; blood ; Serum Amyloid A Protein ; metabolism

Serum amyloid A (SAA) has been regarded as an important mediator of inflammatory responses. The effect of several formyl peptide receptor-like 1 (FPRL1) ligands on the production of IL-8 by SAA was investigated in human neutrophils. Among the ligands tested, LL-37 was found to specifically inhibit SAA-induced IL-8 production in transcriptional and post-transcriptional levels. Since SAA stimulated IL-8 production via ERK and p38 MAPK in human neutrophils, we tested the effect of LL-37 on SAA induction for these two MAPKs. LL-37 caused a dramatic inhibition of ERK and p38 MAPK activity, which is induced by SAA. LL-37 was also found to inhibit SAA-stimulated neutrophil chemotactic migration. Further, the LL-37-induced inhibitory effect was mediated by FPRL1. Our findings indicate that LL-37 is expected to be useful in the inhibition of SAA signaling and for the development of drugs against SAA-related inflammatory diseases.
Animals ; Antimicrobial Cationic Peptides/*pharmacology ; Cell Line, Tumor ; Cell Movement ; Chemotaxis, Leukocyte ; Humans ; Interleukin-8/*biosynthesis ; MAP Kinase Kinase Kinases/metabolism ; Neutrophils/drug effects/*immunology ; Proto-Oncogene Proteins/metabolism ; Rats ; Receptors, Formyl Peptide/metabolism ; Receptors, Lipoxin/metabolism ; Serum Amyloid A Protein/*antagonists & inhibitors ; Signal Transduction ; Transcription, Genetic

Serum amyloid A (SAA) has been regarded as an important mediator of inflammatory responses. The effect of several formyl peptide receptor-like 1 (FPRL1) ligands on the production of IL-8 by SAA was investigated in human neutrophils. Among the ligands tested, LL-37 was found to specifically inhibit SAA-induced IL-8 production in transcriptional and post-transcriptional levels. Since SAA stimulated IL-8 production via ERK and p38 MAPK in human neutrophils, we tested the effect of LL-37 on SAA induction for these two MAPKs. LL-37 caused a dramatic inhibition of ERK and p38 MAPK activity, which is induced by SAA. LL-37 was also found to inhibit SAA-stimulated neutrophil chemotactic migration. Further, the LL-37-induced inhibitory effect was mediated by FPRL1. Our findings indicate that LL-37 is expected to be useful in the inhibition of SAA signaling and for the development of drugs against SAA-related inflammatory diseases.
Animals ; Antimicrobial Cationic Peptides/*pharmacology ; Cell Line, Tumor ; Cell Movement ; Chemotaxis, Leukocyte ; Humans ; Interleukin-8/*biosynthesis ; MAP Kinase Kinase Kinases/metabolism ; Neutrophils/drug effects/*immunology ; Proto-Oncogene Proteins/metabolism ; Rats ; Receptors, Formyl Peptide/metabolism ; Receptors, Lipoxin/metabolism ; Serum Amyloid A Protein/*antagonists & inhibitors ; Signal Transduction ; Transcription, Genetic