Inhibition of Lipopolysaccharide-Stimulated Chronic Obstructive Pulmonary Disease Macrophage Inflammatory Gene Expression by Dexamethasone and the p38 Mitogen-Activated Protein Kinase Inhibitor N-cyano-N′-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d] pyrimidin-2-yl]amino}ethyl)guanidine (SB706504)

Kent, Lauren; Smyth, Lesley A.; Plumb, Jonathan; Clayton, C. L.; Fox, Steve M.; Ray, David; Farrow, Stuart N.; Singh, Dave

doi:10.1124/jpet.108.142950

Cited by 46 publications

(66 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, overcoming corticosteroid insensitivity by using p38 MAPK inhibitors can be demonstrated in severe asthmatics. Our data are supported by a recent study that reported that a p38 MAPK inhibitor in combination with dexamethasone caused a greater suppression of gene expression induced by LPS in monocyte-derived macrophages or AMs [10]. The p38 MAPK inhibitor, SD282, is an indole-5-carboxamide selective p38a MAPK inhibitor demonstrating a 14.3-fold greater potency for p38a compared with p38b [8,9].…”

Section: Discussionsupporting

confidence: 77%

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Bhavsar¹,

Khorasani²,

Hew³

et al. 2009

Eur Respir J

103

View full text Add to dashboard Cite

Patients with severe asthma respond less well to corticosteroids than those with non-severe asthma. Increased p38 mitogen-activated protein kinase (MAPK) activation in alveolar macrophages (AMs) from severe asthma patients has been associated with a reduced inhibition of cytokine release by dexamethasone.We determined whether p38 MAPK inhibitors would modulate corticosteroid suppression of cytokine release from AMs and peripheral blood mononuclear cells (PBMCs).PBMCs were isolated from venous blood and AMs by bronchoalveolar lavage in severe and non-severe asthma patients. PBMCs and AMs were exposed to lipopolysaccharide (LPS) with and without the p38 MAPK inhibitor, SD282, or dexamethasone. We determined the concentrationdependent effects of another p38 MAPK inhibitor, GW-A, on dexamethasone-induced inhibition of interleukin (IL)-8 release from PBMCs. Cytokines were assayed using an ELISA-based method.

show abstract

Section: Discussionsupporting

confidence: 77%

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Bhavsar¹,

Khorasani²,

Hew³

et al. 2009

Eur Respir J

103

View full text Add to dashboard Cite

show abstract

“…The incomplete suppression of UP-LPS-induced CXCL8, CXCL1, and CCL5 production from COPD alveolar macrophages in the current study was also observed in our previous work (Armstrong et al, 2009;Kent et al, 2009). We now show that the chemokine concentrations in conditioned media present after corticosteroid treatment cause neutrophil chemotaxis to be maintained at a similar level compared with no corticosteroid treatment.…”

Section: Discussionsupporting

confidence: 71%

“…Viable macrophages were isolated and counted using trypan blue exclusion. We have shown that this method results in .90% cells confirmed as macrophages expressing CD68 (Kent et al, 2009;Southworth et al, 2012).…”

Section: Methodsmentioning

confidence: 93%

See 1 more Smart Citation

Neutrophil Chemotaxis Caused by Chronic Obstructive Pulmonary Disease Alveolar Macrophages: The Role of CXCL8 and the Receptors CXCR1/CXCR2

Kaur

Singh

2013

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Alveolar macrophages produce neutrophil chemoattractants; this cellular cross-talk contributes to neutrophilic airway inflammation in chronic obstructive pulmonary disease (COPD). We have investigated the chemotaxis cross-talk mechanisms between these cells using COPD alveolar macrophages. Using conditioned media from stimulated COPD alveolar macrophages, we investigated the relative contributions of growthrelated oncogene (CXCL1), interleukin-8 (CXCL8), and regulated on activation normal T cell expressed and secreted (CCL5) to neutrophil chemotaxis and evaluated the effect of blocking the chemokine receptors CXCR1 and CXCR2 on chemotaxis caused by macrophage-conditioned media. Furthermore, we evaluated whether corticosteroid treatment of stimulated alveolar macrophages inhibited the chemotaxis ability of conditioned media. Alveolar macrophages isolated from COPD (n 5 8) and smoker (S) (n 5 8) lungs were treated with ultra-pure lipopolysaccharide in the presence and absence of dexamethasone (1 mM). Supernatants were used for neutrophil chemotaxis assays. SB656933 (2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide) (CXCR2 antagonist) and Sch527123 [1-(2-chloro-3-fluorophenyl)-3-(4-chloro-2-hydroxy-3-piperazin-1-ylsulfonylphenyl)urea, 3-(2-chloro-3-fluoro-phenyl)-1-(4-chloro-2-hydroxy-3-piperazin-1-ylsulfonyl-phenyl)urea] (dual CXCR1 and CXCR2 antagonist) and blocking antibodies for CXCL8, CXCL1, and CCL5 were assessed. Conditioned media caused neutrophil chemotaxis in COPD and smokers (60.5 and 79.9% of total cells, respectively). Dexamethasone did not significantly reduce neutrophil chemotaxis in COPD or S. SB656933 and Sch527123 inhibited chemotaxis in a concentration-dependent manner, with the dual antagonist Sch527123 causing greater inhibition of chemotaxis. CXCL8 antibody inhibited neutrophil chemotaxis to basal levels, although there was no significant effect of blocking either CXCL1 or CCL5 (P . 0.05). CXCL8 plays a major role in neutrophil chemotaxis caused by alveolar macrophage-derived conditioned media, and this is most effectively inhibited by dual antagonism of CXCR1 and CXCR2. Corticosteroids do not inhibit chemotaxis caused by macrophagederived chemokines.

show abstract

“…Alveolar macrophages (AMs) were isolated as previously described (24). Briefly, six smokers (4 men/2 women, mean age 61.7 yr, mean pack-year history 60.3 pack-years) undergoing lung surgery for suspected or confirmed lung cancer, were recruited.…”

Section: Methodsmentioning

confidence: 99%

Cigarette smoke and its component acrolein augment IL-8/CXCL8 mRNA stability via p38 MAPK/MK2 signaling in human pulmonary cells

Moretto

Bertolini

Iadicicco

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

Interleukin-8 (IL-8/CXCL8) is an important neutrophil chemoattractant known to be elevated in the airways of cigarette smokers and in patients with chronic obstructive pulmonary disease (COPD). We examined the acute effect of aqueous cigarette smoke extract (CSE) on IL-8 expression in primary human pulmonary cells, in particular in normal human bronchial smooth muscle cells (HBSMCs). IL-8 mRNA levels increased upon CSE exposure in a concentration- and time-dependent manner, and such an effect was accompanied by IL-8 secretion. CSE-evoked elevation of IL-8 mRNA was mimicked by its component acrolein. Both CSE and acrolein induced p38 mitogen-activated protein kinase (MAPK) phosphorylation, accompanied by the phosphorylation of MAPK-activated kinase 2 (MK2), a known downstream substrate of the p38 MAPK, both in HBSMCs and in human airway epithelial cells. Furthermore, pharmacological inhibition of p38 MAPK or MK2 strongly accelerated the decay of IL-8 mRNA levels upon stimulation with CSE or acrolein and subsequent blockade of mRNA neosynthesis with actinomycin D in pulmonary structural cells (HBSMCs and airways epithelial cells) as well as in human alveolar macrophages. Conversely, pharmacological inhibition of ERK1/2 signaling inhibited CSE-induced steady-state levels of IL-8 mRNA without affecting mRNA stability, thus suggesting inhibition at the transcriptional level. In sum, p38 MAPK/MK2 signaling is an important posttranscriptional mechanism underlying upregulation of IL-8 mRNA levels elicited by CSE and acrolein. Given the pivotal role of IL-8 in neutrophil chemotaxis and activation, our results shed light on the mechanisms through which cigarette smoke can initiate inflammation in the lung.

show abstract

Cited by 46 publications

References 36 publications

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Neutrophil Chemotaxis Caused by Chronic Obstructive Pulmonary Disease Alveolar Macrophages: The Role of CXCL8 and the Receptors CXCR1/CXCR2

Cigarette smoke and its component acrolein augment IL-8/CXCL8 mRNA stability via p38 MAPK/MK2 signaling in human pulmonary cells

Contact Info

Product

Resources

About