Transcriptional profiling of lipopolysaccharide-induced acute lung injury.
Mortality associated with acute lung injury (ALI) induced by lipopolysaccharide (LPS) remains high in humans, warranting improved treatment and prevention strategies. ALI is characterized by the expression of proinflammatory mediators and extensive neutrophil influx into the lung, followed by severe lung damage. Understanding the pathogenesis of LPS-induced ALI is a prerequisite for designing better therapeutic strategies. In the present study, we used microarrays to gain a global view of the transcriptional responses of the lung to LPS in a mouse model of ALI that mimics ALI in humans. A total of 71 inflammation-associated genes were up-regulated in LPS-treated lungs, including a chemokine, LPS-induced CXC chemokine (LIX), whose role in the induction of ALI is unknown. Most of the inflammatory genes peaked at 2 h post-LPS treatment. Real-time reverse transcription-PCR confirmed the LPS-induced up-regulation of selected genes identified by microarray analysis, including LIX. The up-regulation of LIX, tumor necrosis factor alpha, and macrophage inflammatory protein 2 was confirmed at the protein level by enzyme-linked immunosorbent assays. To determine the role of LIX in the induction of ALI, we used both exogenous LIX and a LIX blocking antibody. Exogenous LIX alone elicited a neutrophil influx in the lungs, and the anti-LIX antibody attenuated the LPS-induced neutrophil accumulation in the lungs. Taken together, the results of our study demonstrate for the first time the temporal expression of inflammatory genes during LPS-induced ALI and suggest that early therapeutic intervention is crucial to attenuate lung damage. Moreover, we identified a role for LIX in the induction of ALI, and therefore LIX may serve as a novel therapeutic target for the minimization of ALI.
Jeyaseelan
Samithamby
S
Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson St., Neustadt D-403, Denver, CO 80206, USA. JeyaseelanS@njc.org
Chu
Hong Wei
HW
Young
Scott K
SK
Worthen
G Scott
GS
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D054365:Chemokine CXCL5; D019743:Chemokines, CXC / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020869:Gene Expression Profiling; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D009504:Neutrophils / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D011971:Receptors, Immunologic / Q000502:physiology; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; C094739:Cxcl5 protein, mouse; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic