Transcriptional profiling of lipopolysaccharide-induced acute lung injury

被引:156
作者
Jeyaseelan, S
Chu, HW
Young, SK
Worthen, GS
机构
[1] Natl Jewish Med & Res Ctr, Dept Med, Div Resp Infect, Denver, CO 80206 USA
[2] Univ Colorado, Sch Med, Div Pulm Sci & Critical Care Med, Denver, CO 80202 USA
关键词
D O I
10.1128/IAI.72.12.7247-7256.2004
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:7247 / 7256
页数:10
相关论文
共 41 条
[1]   Lipopolysaccharide-induced leukocyte-endothelial cell interactions: A role for CD14 versus toll-like receptor 4 within microvessels [J].
Andonegui, G ;
Goyert, SM ;
Kubes, P .
JOURNAL OF IMMUNOLOGY, 2002, 169 (04) :2111-2119
[2]   Gene expression profiling reveals the mechanism and pathophysiology of mouse liver regeneration [J].
Arai, M ;
Yokosuka, O ;
Chiba, T ;
Imazeki, F ;
Kato, M ;
Hashida, J ;
Ueda, Y ;
Sugano, S ;
Hashimoto, K ;
Saisho, H ;
Takiguchi, M ;
Seki, N .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (32) :29813-29818
[3]   THE AMERICAN-EUROPEAN CONSENSUS CONFERENCE ON ARDS - DEFINITIONS, MECHANISMS, RELEVANT OUTCOMES, AND CLINICAL-TRIAL COORDINATION [J].
BERNARD, GR ;
ARTIGAS, A ;
BRIGHAM, KL ;
CARLET, J ;
FALKE, K ;
HUDSON, L ;
LAMY, M ;
LEGALL, JR ;
MORRIS, A ;
SPRAGG, R ;
COCHIN, B ;
LANKEN, PN ;
LEEPER, KV ;
MARINI, J ;
MURRAY, JF ;
OPPENHEIMER, L ;
PESENTI, A ;
REID, L ;
RINALDO, J ;
VILLAR, J ;
VANASBECK, BS ;
DHAINAUT, JF ;
MANCEBO, J ;
MATTHAY, M ;
MEYRICK, B ;
PAYEN, D ;
PERRET, C ;
FOWLER, AA ;
SCHALLER, MD ;
HUDSON, LD ;
HYERS, T ;
KNAUS, W ;
MATTHAY, R ;
PINSKY, M ;
BONE, RC ;
BOSKEN, C ;
JOHANSON, WG ;
LEWANDOWSKI, K ;
REPINE, J ;
RODRIGUEZROISIN, R ;
ROUSSOS, C ;
ANTONELLI, MA ;
BELOUCIF, S ;
BIHARI, D ;
BURCHARDI, H ;
LEMAIRE, F ;
MONTRAVERS, P ;
PETTY, TL ;
ROBOTHAM, J ;
ZAPOL, W .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1994, 149 (03) :818-824
[4]   Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome [J].
Bhatia, M ;
Moochhala, S .
JOURNAL OF PATHOLOGY, 2004, 202 (02) :145-156
[5]  
BRIGHAM KL, 1986, AM REV RESPIR DIS, V133, P913
[6]   Gene microarray analysis reveals interleukin-5-dependent transcriptional targets in mouse bone marrow [J].
Byström, J ;
Wynn, TA ;
Domachowske, JB ;
Rosenberg, HF .
BLOOD, 2004, 103 (03) :868-877
[7]  
Chabot F, 1998, EUR RESPIR J, V11, P745
[8]  
Chandrasekar B, 2001, CIRCULATION, V103, P2296
[9]   Identification of novel IL-4/Stat6-regulated genes in T lymphocytes [J].
Chen, Z ;
Lund, R ;
Aittokallio, T ;
Kosonen, M ;
Nevalainen, O ;
Lahesmaa, R .
JOURNAL OF IMMUNOLOGY, 2003, 171 (07) :3627-3635
[10]   Neutrophil recruitment and increased permeability during acute lung injury induced by lipopolysaccharide [J].
Chignard, M ;
Balloy, V .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2000, 279 (06) :L1083-L1090