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Departments of
*
Medicine and
Pediatrics, and
Program in Molecular Signal Transduction, National Jewish Medical and Research Center, Denver, CO 80206; and
§
Division of Pulmonary Science and Critical Care Medicine, University of Colorado School of Medicine, Denver, CO 80262
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-
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- and MIP-2. Systemic inhibition of p38 MAPK
resulted in significant decreases in the release of TNF- 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- 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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D. Strassheim, K. Asehnoune, J.-S. Park, J.-Y. Kim, Q. He, D. Richter, K. Kuhn, S. Mitra, and E. Abraham Phosphoinositide 3-Kinase and Akt Occupy Central Roles in Inflammatory Responses of Toll-Like Receptor 2-Stimulated Neutrophils J. Immunol., May 1, 2004; 172(9): 5727 - 5733. [Abstract] [Full Text] [PDF]
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K.-Y. Yang, J. J. Arcaroli, and E. Abraham Early Alterations in Neutrophil Activation Are Associated with Outcome in Acute Lung Injury Am. J. Respir. Crit. Care Med., June 1, 2003; 167(11): 1567 - 1574. [Abstract] [Full Text] [PDF]
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K. C. Malcolm and G. S. Worthen Lipopolysaccharide Stimulates p38-dependent Induction of Antiviral Genes in Neutrophils Independently of Paracrine Factors J. Biol. Chem., April 25, 2003; 278(18): 15693 - 15701. [Abstract] [Full Text] [PDF]
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 C. Stambe, R. C. Atkins, G. H. Tesch, A. M. Kapoun, P. A. Hill, G. F. Schreiner, and D. J. Nikolic-Paterson Blockade of p38{alpha} MAPK Ameliorates Acute Inflammatory Renal Injury in Rat Anti-GBM Glomerulonephritis J. Am. Soc. Nephrol., February 1, 2003; 14(2): 338 - 351. [Abstract] [Full Text] [PDF]
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B. K. Choudhury, J. S. Wild, R. Alam, D. M. Klinman, I. Boldogh, N. Dharajiya, W. J. Mileski, and S. Sur In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma J. Immunol., November 15, 2002; 169(10): 5955 - 5961. [Abstract] [Full Text] [PDF]
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J. A. Nick, S. K. Young, P. G. Arndt, J. G. Lieber, B. T. Suratt, K. R. Poch, N. J. Avdi, K. C. Malcolm, C. Taube, P. M. Henson, et al. Selective Suppression of Neutrophil Accumulation in Ongoing Pulmonary Inflammation by Systemic Inhibition of p38 Mitogen-Activated Protein Kinase J. Immunol., November 1, 2002; 169(9): 5260 - 5269. [Abstract] [Full Text] [PDF]
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N. J. Avdi, K. C. Malcolm, J. A. Nick, and G. S. Worthen A Role for Protein Phosphatase-2A in p38 Mitogen-activated Protein Kinase-mediated Regulation of the c-Jun NH2-terminal Kinase Pathway in Human Neutrophils J. Biol. Chem., October 18, 2002; 277(43): 40687 - 40696. [Abstract] [Full Text] [PDF]
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U. Uhlig, J.J. Haitsma, T. Goldmann, D.L. Poelma, B. Lachmann, and S. Uhlig Ventilation-induced activation of the mitogen-activated protein kinase pathway Eur. Respir. J., October 1, 2002; 20(4): 946 - 956. [Abstract] [Full Text] [PDF]
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Y. Takanami-Ohnishi, S. Amano, S. Kimura, S. Asada, A. Utani, M. Maruyama, H. Osada, H. Tsunoda, Y. Irukayama-Tomobe, K. Goto, et al. Essential Role of p38 Mitogen-activated Protein Kinase in Contact Hypersensitivity J. Biol. Chem., September 27, 2002; 277(40): 37896 - 37903. [Abstract] [Full Text] [PDF]
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J. Arcaroli, K.-Y. Yang, H.-K. Yum, J. Kupfner, T. M. Pitts, J. S. Park, D. Strassheim, and E. Abraham Effects of catecholamines on kinase activation in lung neutrophils after hemorrhage or endotoxemia J. Leukoc. Biol., September 1, 2002; 72(3): 571 - 579. [Abstract] [Full Text] [PDF]
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M. B. Fessler, K. C. Malcolm, M. W. Duncan, and G. S. Worthen A Genomic and Proteomic Analysis of Activation of the Human Neutrophil by Lipopolysaccharide and Its Mediation by p38 Mitogen-activated Protein Kinase J. Biol. Chem., August 23, 2002; 277(35): 31291 - 31302. [Abstract] [Full Text] [PDF]
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N. Beckmann, B. Tigani, R. Sugar, A. D. Jackson, G. Jones, L. Mazzoni, and J. R. Fozard Noninvasive detection of endotoxin-induced mucus hypersecretion in rat lung by MRI Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L22 - L30. [Abstract] [Full Text] [PDF]
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M. D. Lehner, F. Schwoebel, A. Kotlyarov, M. Leist, M. Gaestel, and T. Hartung Mitogen-Activated Protein Kinase-Activated Protein Kinase 2-Deficient Mice Show Increased Susceptibility to Listeria monocytogenes Infection J. Immunol., May 1, 2002; 168(9): 4667 - 4673. [Abstract] [Full Text] [PDF]
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J. Branger, B. van den Blink, S. Weijer, J. Madwed, C. L. Bos, A. Gupta, C.-L. Yong, S. H. Polmar, D. P. Olszyna, C. E. Hack, et al. Anti-Inflammatory Effects of a p38 Mitogen-Activated Protein Kinase Inhibitor During Human Endotoxemia J. Immunol., April 15, 2002; 168(8): 4070 - 4077. [Abstract] [Full Text] [PDF]
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 T ten Hove, B van den Blink, I Pronk, P Drillenburg, M P Peppelenbosch, and S J H van Deventer Dichotomal role of inhibition of p38 MAPK with SB 203580 in experimental colitis Gut, April 1, 2002; 50(4): 507 - 512. [Abstract] [Full Text] [PDF]
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 M. P. Allen, D. A. Linseman, H. Udo, M. Xu, J. B. Schaack, B. Varnum, E. R. Kandel, K. A. Heidenreich, and M. E. Wierman Novel Mechanism for Gonadotropin-Releasing Hormone Neuronal Migration Involving Gas6/Ark Signaling to p38 Mitogen-Activated Protein Kinase Mol. Cell. Biol., January 15, 2002; 22(2): 599 - 613. [Abstract] [Full Text] [PDF]
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D. C. Cara, J. Kaur, M. Forster, D.-M. McCafferty, and P. Kubes Role of p38 Mitogen-Activated Protein Kinase in Chemokine-Induced Emigration and Chemotaxis In Vivo J. Immunol., December 1, 2001; 167(11): 6552 - 6558. [Abstract] [Full Text] [PDF]
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W. H. Chung, B. M. Bennett, W. J. Racz, J. F. Brien, and T. E. Massey Induction of c-jun and TGF-beta 1 in Fischer 344 rats during amiodarone-induced pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1180 - L1188. [Abstract] [Full Text] [PDF]
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 A. M. Reimold, J. Kim, R. Finberg, and L. H. Glimcher Decreased immediate inflammatory gene induction in activating transcription factor-2 mutant mice Int. Immunol., February 1, 2001; 13(2): 241 - 248. [Abstract] [Full Text] [PDF]
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J. Jongstra-Bilen, V. L. Misener, C. Wang, H. Ginzberg, A. Auerbach, A. L. Joyner, G. P. Downey, and J. Jongstra LSP1 modulates leukocyte populations in resting and inflamed peritoneum Blood, September 1, 2000; 96(5): 1827 - 1835. [Abstract] [Full Text] [PDF]
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M. J. Rane, P. Y. Coxon, D. W. Powell, R. Webster, J. B. Klein, W. Pierce, P. Ping, and K. R. McLeish p38 Kinase-dependent MAPKAPK-2 Activation Functions as 3-Phosphoinositide-dependent Kinase-2 for Akt in Human Neutrophils J. Biol. Chem., January 26, 2001; 276(5): 3517 - 3523. [Abstract] [Full Text] [PDF]
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