p38 MAPK inhibitors, IKK2 inhibitors, and TNFα inhibitors in COPD

https://doi.org/10.1016/j.coph.2012.01.016Get rights and content

COPD represents a major respiratory disorder, causing significant morbidity and mortality throughout the world. While therapies exist for COPD, they are not always effective, and many patients experience exacerbations and morbidity despite current therapies. Study of the molecular mechanisms involved in the underlying physiological manifestations of COPD has yielded multiple new targets for therapeutic intervention. In this review, we discuss signaling pathways involved in COPD pathogenesis and review clinical studies of p38 MAPK inhibitors, TNFα inhibitors, and IKK2 inhibitors as potential COPD therapies.

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)

  • P. Caposio et al.

    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

    (2007)
  • T. Hideshima et al.

    NF-kappa B as a therapeutic target in multiple myeloma

    J Biol Chem

    (2002)
  • S. Rajendrasozhan et al.

    Anti-inflammatory effect of a selective IkappaB kinase-beta inhibitor in rat lung in response to LPS and cigarette smoke

    Pulm Pharmacol Ther

    (2011)
  • H. Nakamura et al.

    Molecular therapy via transcriptional regulation with double-stranded oligodeoxynucleotides as decoys

    In Vivo

    (2002)
  • C. Karner et al.

    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

    (2011)
  • S. Spencer et al.

    Inhaled corticosteroids versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease

    Cochrane Database Syst Rev

    (2011)
  • T. Renda et al.

    Increased activation of p38 MAPK in COPD

    Eur Respir J

    (2008)
  • I. Rahman et al.

    Oxidative stress and redox regulation of lung inflammation in COPD

    Eur Respir J

    (2006)
  • G. Volpi et al.

    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

    (2011)
  • X. Wang et al.

    Interleukin 1alpha (IL-1alpha) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function

    Mol Psychiatry

    (2004)
  • T. Fujisawa et al.

    Involvement of the p38 MAPK pathway in IL-13-induced mucous cell metaplasia in mouse tracheal epithelial cells

    Respirology

    (2008)
  • J.D. Spahn et al.

    A novel action of IL-13: induction of diminished monocyte glucocorticoid receptor-binding affinity

    J Immunol

    (1996)
  • L.M. Kent et al.

    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

    (2009)
  • S. Medicherla et al.

    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

    (2008)
  • Cited by (50)

    • A systematic exploration of ginsenoside Rg5 reveals anti-inflammatory functions in airway mucosa cells

      2023, Journal of Ginseng Research
      Citation Excerpt :

      In addition, p38 MAPK activation is initiated via a kinase cascade triggered by extracellular inflammatory stimulation and induces apoptosis in human airway epithelial cells [45]. Therefore, inflammatory drugs capable of targeting molecules involved in lung pathways may prove to be useful in the treatment of respiratory diseases [4,46]. Additionally, targeting lipid metabolism pathways and molecules could contribute to superior treatment approaches by regulating lipid homeostasis and mucus production [47].

    • The role of lung macrophages in chronic obstructive pulmonary disease

      2022, Respiratory Medicine
      Citation Excerpt :

      Chinese Herbal Medicines: The effects of AMPK/Nrf2 and NF-κB signaling pathways in LMs inflammation response have already been identified [50]. Studies have shown that IL-17 can activate the MAPK and NF-κB pathways, further regulated the expression of pro-inflammatory cytokines in COPD [139]. Li et al. proposed that five Chinese Herbal Medicines compound (ECC) played an important role in inhibiting the IL-17-related inflammatory response by regulating the activation of MAPK/Nrf2 and NF-kB signaling [140].

    • Drug screening and high throughput in three-dimensional lung models

      2022, 3D Lung Models for Regenerating Lung Tissue
    • A chinese herbal formula ameliorates COPD by inhibiting the inflammatory response via downregulation of p65, JNK, and p38

      2021, Phytomedicine
      Citation Excerpt :

      Moreover, mitogen-activated protein kinases (MAPKs) and the nuclear factor-kappaB (NF-κB) signaling pathway are activated to upregulate inflammatory genes in airway epithelial cells (Gaffey et al., 2013). Inhibition of MAPKs and NF-κB signals is an effective approach to suppressing airway inflammation in COPD (Banerjee et al., 2012). Therefore, we investigated the therapeutic effect of the KAM-BYF on COPD rats, and the anti-inflammatory mechanisms in airway epithelial cells induced by TNF-α.

    • TNF-α and Pulmonary Diseases

      2021, Encyclopedia of Respiratory Medicine, Second Edition
    View all citing articles on Scopus
    View full text