Blockade of p38 map kinase inhibits complement-induced acute lung injury in a murine model

Nash, Steven; Heuertz, Rita M.

doi:10.1016/j.intimp.2005.06.005

Cited by 23 publications

(20 citation statements)

References 29 publications

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“…Therefore, it was worthwhile to test whether p38 inhibitors could exert some inhibitory effects on acrolein-induced inflammatory processes in vivo. Numerous recent studies indicate that SB203580, a specific p38 inhibitor, has potentials to suppress neutrophil influx and migration in models of acute lung injury [17,26,27]. In the mouse model established here by subchronic acrolein exposure, we found that SB203580 significantly reduced the accumulation of neutrophils and macrophages in the BALF, suppressed TNF-α and KC release in both the BALF and lung tissue, and attenuated inflammatory cell infiltration and goblet cell hyperplasia in the airways.…”

Section: Discussionsupporting

confidence: 52%

“…A number of studies have demonstrated that the increase in gene expression of Muc5ac, which is the predominant mucin gene expressed in airway goblet cells, acts mainly through the epidermal growth factor receptor (EGFR)-MAPK pathway [15][16][17]. MAP kinase activation via transactivation of the EGFR is dependent on ectodomain shedding of EGFR ligands by the action of matrix metalloproteinases (MMPs).…”

Section: Introductionmentioning

confidence: 99%

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p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog

Liu

Wang

Han

et al. 2009

International Immunopharmacology

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog

Liu

Wang

Han

et al. 2009

International Immunopharmacology

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“…32 The notion of pharmacologic inhibition of p38 MAPK activity as a possible substitute for glucocorticoid-mediated immunosuppression has been an active area for drug discovery. 52,[54][55][56][57] Our data suggest that glucocorticoids normally impact upon p38 activity for a substantial portion of their therapeutic anti-inflammatory actions, and thus targeting p38 directly is a logical goal. Recent efforts to bring p38 inhibitors into clinical practice have had limited success.…”

Section: Discussionmentioning

confidence: 99%

Macrophage glucocorticoid receptors regulate Toll-like receptor 4–mediated inflammatory responses by selective inhibition of p38 MAP kinase

Bhattacharyya¹,

Brown²,

Brewer³

et al. 2007

Blood

215

186

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To explore the role of glucocorticoids in regulation of kinase pathways during innate immune responses, we generated mice with conditional deletion of glucocorticoid receptor (GR) in macrophages (MGRKO). Activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) caused greater mortality and cytokine production in MGRKO mice than in controls. Ex vivo, treatment with dexamethasone (Dex) markedly inhibited LPS-mediated induction of inflammatory genes in control but not GR-deficient macrophages. We show that Dex inhibits p38 MAPK, but not PI3K/Akt, ERK, or JNK, in control macrophages. Associated with p38 inhibition, Dex induced MAP kinase phosphatase-1 (MKP-1) in control, but not MGRKO, macrophages. Consistent with the ex vivo studies, treatment with a p38 MAPK–specific inhibitor resulted in rescue of MGRKO mice from LPS-induced lethality. Taken together, we identify p38 MAPK and its downstream targets as essential for GR-mediated immunosuppression in macrophages.

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“…and IL-6) and diminished leukocyte responses (40). In a murine model, blockade of p38 MAPK offered a protective effect from C5a-induced acute lung injury (41). More recently, inhibition of the p38 pathway has been shown to reduce dermal inflammation after burn (42).…”

Section: Discussionmentioning

confidence: 99%

The Priming Effect of C5a on Monocytes Is Predominantly Mediated by the P38 Mapk Pathway

Schaeffer

Cuschieri

Garcia

et al. 2007

Shock

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The dysregulation of the inflammatory response after trauma leads to significant morbidity and mortality. Monocytes and macrophages play a central role in the orchestration of the inflammatory response after injury. Serum interleukin-6 (IL-6) concentration correlates with poor outcomes after injury. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that plays a crucial role in the pathogenesis of multiple organ dysfunction syndrome. Furthermore, in the presence of C5a, monocytes and macrophages have potentiated responses, but the mechanisms underlying this response remain largely unknown. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and pretreated with C5a (100 ng/mL) for 1 h before adding lipopolysaccharide (LPS) (10 ng/mL) for up to 20 h. Inhibitors for the mitogen-activated protein kinases (MAPKs) were added 1 h before adding C5a. C5a primes monocytes for LPS-induced IL-6 and TNF-alpha production. Treatment of PBMCs with C5a leads to a rapid activation of the 3 MAPK pathways. SP600125 (inhibitor of c-Jun NH2-terminal kinase MAPK) and PD98059 (inhibitor of extracellular signal-regulated kinase MAPK) did not affect the C5a priming of the LPS-induced IL-6 and TNF-alpha production, whereas SB203580, a specific inhibitor of p38 MAPK, did suppress the C5a priming effect. These results demonstrate that C5a primes adherent PBMCs and modulates LPS-induced IL-6 and TNF-alpha production. Results from extracellular signal-regulated kinase and c-Jun NH2-terminal kinase MAPK blockade suggest that these signaling pathways have minimal or no role in reprogramming LPS-mediated IL-6 and TNF-alpha production. On the contrary, in PBMCs, C5a activates the p38 cascade, and this pathway plays a major role in the C5a enhancement of LPS-induced IL-6 and TNF-alpha production.

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Blockade of p38 map kinase inhibits complement-induced acute lung injury in a murine model

Cited by 23 publications

References 29 publications

p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog

p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog

Macrophage glucocorticoid receptors regulate Toll-like receptor 4–mediated inflammatory responses by selective inhibition of p38 MAP kinase

The Priming Effect of C5a on Monocytes Is Predominantly Mediated by the P38 Mapk Pathway

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