An Oral Inhibitor of p38 MAP Kinase Reduces Plasma Fibrinogen in Patients With Chronic Obstructive Pulmonary Disease

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.

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“…Another selective p38 MAPK inhibitor, losmapimod (29), showed to significantly inhibit either CSE-or acrolein-induced (Fig. 3, F and G).…”

Section: -E)mentioning

confidence: 96%

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

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“…tolerance). Oral p38 mitogen-activated protein kinase inhibitors have small effects [158] or no effects [159], and inhaled drugs are in development. Other kinases targeted for COPD include Janus-activated kinase, phosphoinositide-3-kinase, and spleen tyrosine kinase, but no clinical studies have been reported.…”

Section: Novel Pharmacological Therapiesmentioning

confidence: 99%

An official American Thoracic Society/European Respiratory Society statement: research questions in COPD

et al. 2015

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Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) research statement is to describe evidence related to diagnosis, assessment and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management.Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified.Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus.Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ ERS research statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centred outcomes. @ERSpublications ATS/ERS statement: which types of research will have the greatest future impact on patientcentred outcomes in COPD? http://ow.ly/I54Hb

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“…Additionally, p38 MAPK acts post-transcriptionally by stabilising mRNAs, and promotes protein translation [7]. p38 MAPK inhibitors reduce cytokine production from alveolar macrophages [8][9][10][11] and are in clinical development for the treatment of COPD [12,13].…”

Section: Introductionmentioning

confidence: 99%

Increased phosphorylated p38 mitogen-activated protein kinase in COPD lungs

et al. 2012

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The p38 mitogen-activated protein kinase (MAPK) pathway is upregulated in chronic obstructive pulmonary disease (COPD). To date, dual labelling to identify cell-type-specific presence of phosphorylated (phospho-)p38 MAPK has not been carried out.Phospho-p38 MAPK was quantified in a variety of cell types in the lung tissue of 20 COPD patients, 12 smokers and 12 nonsmokers using immunohistochemistry. Paired blood and sputum neutrophils (from seven subjects with COPD), and CD8 and epithelial cells (from three subjects with COPD) were cultured with a p38 MAPK inhibitor. Supernatant tumour necrosis factor-a and CXCL8 levels were analysed by ELISA. Sputum and blood neutrophil cytospins were analysed for phospho-p38 MAPK.Phospho-p38 MAPK was increased in bronchial epithelial cells, macrophages and CD20+ and CD8+ lymphocytes in COPD lungs. Sputum and lung tissue neutrophils were devoid of phospho-p38 in all patient groups. The p38 MAPK inhibitor SB100 attenuated pro-inflammatory mediator release in COPD lung CD8 cells and airway epithelia, but there was no effect on COPD sputum neutrophils.Our data indicate cell-specific anti-inflammatory effects of p38 MAPK inhibition in the lung. @ERSpublications p38 MAPK inhibition causes cell-specific anti-inflammatory effects in the lung

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An Oral Inhibitor of p38 MAP Kinase Reduces Plasma Fibrinogen in Patients With Chronic Obstructive Pulmonary Disease

Cited by 105 publications

References 27 publications

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

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

An official American Thoracic Society/European Respiratory Society statement: research questions in COPD

Increased phosphorylated p38 mitogen-activated protein kinase in COPD lungs

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