Role of p38 mitogen-activated protein kinase in a murine model of pulmonary inflammation

被引:223
作者
Nick, JA
Young, SK
Brown, KK
Avdi, NJ
Arndt, PG
Suratt, BT
Janes, MS
Henson, PM
Worthen, GS
机构
[1] Natl Jewish Med & Res Ctr, Dept Med, Denver, CO 80206 USA
[2] Natl Jewish Med & Res Ctr, Dept Pediat, Denver, CO 80206 USA
[3] Natl Jewish Med & Res Ctr, Program Mol Signal Transduct, Denver, CO 80206 USA
[4] Univ Colorado, Sch Med, Div Pulm Sci & Crit Care Med, Denver, CO 80262 USA
关键词
D O I
10.4049/jimmunol.164.4.2151
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Early inflammatory events include cytokine release, activation, and rapid accumulation of neutrophils, with subsequent recruitment of mononuclear cells, The p38 mitogen-activated protein kinase (MAPK) intracellular signaling pathway plays a central role in regulating a wide range of inflammatory responses in many different cells. A murine model of mild LPS-induced lung inflammation was developed to investigate the role of the p38 MAPK pathway in the initiation of pulmonary inflammation. A novel p38 MAPK inhibitor, M39, was used to determine the functional consequences of p38 MAPK activation. In vitro exposure to M39 inhibited p38 MAPK activity in LPS-stimulated murine and human neutrophils and macrophages, blocked TNF-alpha and macrophage inflammatory protein-2 (MIP-2) release, and eliminated migration of murine neutrophils toward the chemokines MIP-2 and KC. In contrast, alveolar macrophages required a 1000-fold greater concentration of M39 to block release of TNF-alpha and MIP-2 Systemic inhibition of p38 MAPK resulted in significant decreases in the release of TNF-alpha and neutrophil accumulation in the airspaces following intratracheal administration of LPS, Recovery of MIP-2 and KC from the airspaces was not affected by inhibition of p38 MAPK, and accumulation of mononuclear cells was not significantly reduced. When KC was instilled as a proinflammatory stimulus, neutrophil accumulation was significantly decreased by p38 MAPK inhibition independent of TNF-alpha or LPS, Together, these results demonstrate a much greater dependence on the p38 MAPK cascade in the neutrophil when compared with other leukocytes, and suggest a means of selectively studying and potentially modulating early inflammation in the lung.
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页码:2151 / 2159
页数:9
相关论文
共 45 条
[1]  
[Anonymous], [No title captured]
[2]  
Badger AM, 1996, J PHARMACOL EXP THER, V279, P1453
[3]  
BADGER AM, 1989, CIRC SHOCK, V27, P51
[4]  
BOZIC CR, 1995, J IMMUNOL, V154, P6048
[5]   THE PRODUCTION OF CYTOKINES BY POLYMORPHONUCLEAR NEUTROPHILS [J].
CASSATELLA, MA .
IMMUNOLOGY TODAY, 1995, 16 (01) :21-26
[6]   HOW MAP KINASES ARE REGULATED [J].
COBB, MH ;
GOLDSMITH, EJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (25) :14843-14846
[7]  
Detmers PA, 1998, J IMMUNOL, V161, P1921
[8]  
DOHERTY DE, 1994, J IMMUNOL, V153, P241
[9]   RETENTION OF LEUKOCYTES IN CAPILLARIES - ROLE OF CELL-SIZE AND DEFORMABILITY [J].
DOWNEY, GP ;
DOHERTY, DE ;
SCHWAB, B ;
ELSON, EL ;
HENSON, PM ;
WORTHEN, GS .
JOURNAL OF APPLIED PHYSIOLOGY, 1990, 69 (05) :1767-1778
[10]  
FANTONE JC, 1997, CYTOKINES HLTH DIS, P373