Effects of pyridinyl imidazole compounds on murine TNF-α production

Olivera, D.L.; Laydon, Jeffrey T.; Hillegass, Leonard M.; Badger, Alison M.; Lee, J. C.

doi:10.1007/bf01972719

Cited by 7 publications

(2 citation statements)

References 6 publications

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“…Initial studies established the ability of p38 MAPK inhibitors to reduce neutrophil influx and cytokine release in models of peritonitis and arthritis in the absence of generalized immunosuppression (37)(38)(39)(40)(41)(42)(43)(44). Early studies predominately used first generation p38 MAPK inhibitors such as the pyridinyl imadazoles SK&F86002 and SB203580 (39,(45)(46)(47)(48). SB203580 has considerable inhibitory effects toward c-Raf and JNK2␣1.…”

Section: Discussionmentioning

confidence: 99%

Selective Suppression of Neutrophil Accumulation in Ongoing Pulmonary Inflammation by Systemic Inhibition of p38 Mitogen-Activated Protein Kinase

Nick

Young

Arndt

et al. 2002

The Journal of Immunology

105

109

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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-α, macrophage-inflammatory protein (MIP)-2 (MIP-1β), 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-α, 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.

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Section: Discussionmentioning

confidence: 99%

Selective Suppression of Neutrophil Accumulation in Ongoing Pulmonary Inflammation by Systemic Inhibition of p38 Mitogen-Activated Protein Kinase

Nick

Young

Arndt

et al. 2002

The Journal of Immunology

105

109

View full text Add to dashboard Cite

show abstract

“…These and other imidazol-like drugs have recently been called "cytokine-suppressing anti-inflammatory drugs" or CSAIDs . Two agents have received careful study for their ability not to affect transcription but rather to inhibit translation (OLIVERA et al 1993;RORDoRFADAM et al 1994). Recent studies suggest that the mechanism by which CSAIDs reduce ILl and TNF translations their ability to bind to and inactivate two related mitogenactivating protein (MAP) kinases .…”

Section: Cytokine-suppressing Anti-inflammatory Drugsmentioning

confidence: 99%