p38 MAPK inhibitors, IKK2 inhibitors, and TNFα inhibitors in COPD
Highlights
► COPD causes significant morbidity and mortality throughout the world. ► Drugs that target inflammation have promise as therapies for COPD. ► TNF alpha, NF kappa B, and p38 MAP kinase may all contribute to COPD pathogenesis. ► Inhibitors of TNF alpha, IKK2 and p38 MAPK may be useful as COPD therapies.
Introduction
Treatments for COPD include inhaled steroids, anticholinergics, and β2-adrenergic receptor agonists. Inhaled long-acting β2-agonists (LABAs) and long acting anticholinergics improve lung function and health-related quality of life [1], while treatment with inhaled steroids decreases the frequency and severity of exacerbations but has little effect on decline in lung function [2]. Many patients however experience morbidity and frequent exacerbations despite therapy with LABAs and inhaled steroids; the molecular mechanisms underlying COPD remain unclear and novel therapeutics to treat inflammation are being examined [3]. With the underlying causes of COPD being diverse, recent approaches attempt to personalize COPD management using novel anti-inflammatory drugs, as seen in Table 1. Multiple basic science studies suggest that the p38 mitogen activated protein kinase (MAPK) inhibitors, TNFα inhibitors, and IKK2 inhibitors may modulate the physiologic changes seen in COPD. In this review, we address signaling pathways that are activated in effector cells in the lungs of COPD patients and identify emerging therapeutics providing targeted bronchodilation and anti-inflammatory therapy.
Section snippets
p38 MAP kinase
Patients with COPD have chronic airway inflammation and suffer from exacerbations, that increase morbidity. The inflammatory mediators involved in COPD are complex, and since relative glucocorticoid insensitivity is a hallmark of COPD, new therapies that target the inflammatory diathesis are being evaluated. The p38 mitogen activated protein kinase (MAPK) family consists of four isoforms of p38 MAPK, α, β, γ, and δ, which are expressed in different tissues and regulate activation of different
TNFα inhibitors
Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine and a member of the TNF superfamily, a group of membrane-bound and soluble proteins implicated in inflammation. TNFα is produced as an integral membrane protein that is translocated to the cell surface, and is released in soluble form by TNFα converting enzyme (TACE); TNFα may also play a central role in COPD pathogenesis (Figure 1). Induced sputum from patients with COPD has higher levels of TNFα than sputum obtained from smokers
IKK2 inhibitors
NFκB is a family of transcription factors that is activated in the inflammatory response of COPD. Both TNFα and cigarette smoke extract increase NFκB activation [38], and NFκB regulates the expression of multiple pro-inflammatory mediators (e.g. TNFα, interleukins, vascular cell adhesion molecules, matrix metalloproteinases and cyclooxyenases) [39], many of which are involved in COPD pathogenesis [40]. Patients with COPD have increased NFκB activation in BAL macrophages and epithelial cells,
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Funded by: NIH’. Grant number(s): K08-HL097032; P30-ES013508; R01-HL097796.
References (48)
Emerging pharmacotherapies for COPD
Chest
(2008)- et al.
Role of p38 mitogen-activated protein kinase in ozone-induced airway hyperresponsiveness and inflammation
Eur J Pharmacol
(2008) - et al.
LPS response and endotoxin tolerance in Flt-3L-induced bone marrow-derived dendritic cells
Cell Immunol
(2011) - et al.
Lipopolysaccharide upregulates the expression of corticotropin-releasing hormone via MAP kinase pathway in rat peritoneal macrophages
Mol Cell Biochem
(2012) - et al.
Inhibition of glucocorticoid receptor-mediated transcriptional activation by p38 mitogen-activated protein (MAP) kinase
J Biol Chem
(2004) - et al.
p38 MAP kinase: molecular target for the inhibition of pro-inflammatory cytokines
Prog Med Chem
(2001) - et al.
Small molecule p38 MAP kinase inhibitors for the treatment of inflammatory diseases: novel structures and developments during 2006–2008
Curr Top Med Chem
(2008) - et al.
Change in inflammation in out-patient COPD patients from stable phase to a subsequent exacerbation
Int J Chron Obstruct Pulmon Dis
(2009) - et al.
Pharmacological profile of PKF242-484 and PKF241-466, novel dual inhibitors of TNF-alpha converting enzyme and matrix metalloproteinases, in models of airway inflammation
Br J Pharmacol
(2002) - et al.
Aminopyridinecarboxamide-based inhaled IKK-2 inhibitors for asthma and COPD: Structure-activity relationship
Bioorg Med Chem
(2011)
Targeting the NF-kappaB pathway through pharmacological inhibition of IKK2 prevents human cytomegalovirus replication and virus-induced inflammatory response in infected endothelial cells
Antiviral Res
NF-kappa B as a therapeutic target in multiple myeloma
J Biol Chem
Anti-inflammatory effect of a selective IkappaB kinase-beta inhibitor in rat lung in response to LPS and cigarette smoke
Pulm Pharmacol Ther
Molecular therapy via transcriptional regulation with double-stranded oligodeoxynucleotides as decoys
In Vivo
Combination inhaled steroid and long-acting beta(2)-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease
Cochrane Database Syst Rev
Inhaled corticosteroids versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease
Cochrane Database Syst Rev
Increased activation of p38 MAPK in COPD
Eur Respir J
Oxidative stress and redox regulation of lung inflammation in COPD
Eur Respir J
Cigarette smoke and alpha,beta-unsaturated aldehydes elicit VEGF release through the p38 MAPK pathway in human airway smooth muscle cells and lung fibroblasts
Br J Pharmacol
Interleukin 1alpha (IL-1alpha) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function
Mol Psychiatry
Involvement of the p38 MAPK pathway in IL-13-induced mucous cell metaplasia in mouse tracheal epithelial cells
Respirology
A novel action of IL-13: induction of diminished monocyte glucocorticoid receptor-binding affinity
J Immunol
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)
J Pharmacol Exp Ther
p38alpha-selective mitogen-activated protein kinase inhibitor SD-282 reduces inflammation in a subchronic model of tobacco smoke-induced airway inflammation
J Pharmacol Exp Ther
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