Selective suppression of neutrophil accumulation in ongoing pulmonary inflammation by systemic inhibition of p38 mitogen-activated protein kinase.
The p38 mitogen-activated protein kinase (MAPK) signaling pathway regulates a wide range of inflammatory responses in many different cells. Inhibition of p38 MAPK before exposing a cell to stress stimuli has profound anti-inflammatory effects, but little is known about the effects of p38 MAPK inhibition on ongoing inflammatory responses. LPS-induced activation of p38 MAPK in human neutrophils was inhibited by poststimulation exposure to a p38 MAPK inhibitor (M39). Release of TNF-alpha, macrophage-inflammatory protein (MIP)-2 (MIP-1beta), and IL-8 by LPS-stimulated neutrophils was also reduced by poststimulation p38 MAPK inhibition. In contrast, release of monocyte chemoattractant protein-1 was found to be p38 MAPK independent. Ongoing chemotaxis toward IL-8 was eliminated by p38 MAPK inhibition, although the rate of nondirectional movement was not reduced. A murine model of acute LPS-induced lung inflammation was used to study the effect of p38 MAPK inhibition in ongoing pulmonary inflammation. Initial pulmonary cell responses occur within 4 h of stimulation in this model, so M39 was administered 4 h or 12 h after exposure of the animals to aerosolized LPS to avoid inhibition of cytokine release. Quantities of TNF-alpha, MIP-2, KC, or monocyte chemoattractant protein-1 recovered from bronchial alveolar lavage or serum were not changed. Recruitment of neutrophils, but not other leukocytes, to the airspaces was significantly reduced. Together, these data demonstrate the selective reduction of LPS-induced neutrophil recruitment to the airspaces, independent of suppression of other inflammatory responses. These findings support the feasibility of p38 MAPK inhibition as a selective intervention to reduce neutrophilic inflammation.
Nick
Jerry A
JA
Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA. nickj@njc.org
Young
Scott K
SK
Arndt
Patrick G
PG
Lieber
Jonathan G
JG
Suratt
Benjamin T
BT
Poch
Katie R
KR
Avdi
Natalie J
NJ
Malcolm
Ken C
KC
Taube
Christian
C
Henson
Peter M
PM
Worthen
G Scott
GS
D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000494:pharmacology*; D002464:Cell Migration Inhibition; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004334:Drug Administration Schedule; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D007441:Intubation, Gastrointestinal; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D008168:Lung / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
C119801:5-(2-(1-phenylethylamino)pyridin-4-yl)-1-methyl-4-(3-(trifluoromethyl)phenyl)-2-(4-piperidinyl)imidazole; D000631:Aminopyridines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases