TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

https://doi.org/10.1016/j.pupt.2009.10.007Get rights and content

Abstract

Tumor necrosis factor (TNF)-α, a pleiotropic cytokine that exerts a variety of effects, such as growth promotion, growth inhibition, angiogenesis, cytotoxicity, inflammation, and immunomodulation, has been implicated in several inflammatory conditions. It plays a significant role in many inflammatory diseases of lungs. Given that there is significant literature supporting the pathobiologic role of TNF-α in asthma, mainly in severe refractory asthma, and COPD, TNF-α inhibitors (infliximab, golimumab and etanercept) are now regarded as the potential new medications in asthma and COPD management. The studies reported in literature indicate that TNF-α inhibitors are effective in a relatively small subgroup of patients with severe asthma, possibly defined by an increased TNF axis, but they seem to be ineffective in COPD, although an observational study demonstrated that TNF-α inhibitors were associated with a reduction in the rate of COPD hospitalisation among patients with COPD receiving these agents to treat their rheumatoid arthritis. These findings require a smart approach because there is still good reason to target TNF-α, perhaps in a more carefully selected patient group. TNF-α treatment should, therefore, not be thrown out, or abandoned. Indeed, since severe asthma and COPD are heterogeneous diseases that have characteristics that occur with different phenotypes that remained poorly characterized and little known about the underlying pathobiology contributing to them, it is likely that definition of these phenotypes and choice of the right outcome measure will allow us to understand which kind of patients can benefit from TNF-α inhibitors.

Introduction

Tumor necrosis factor (TNF)-α, a pleiotropic cytokine that exerts a variety of effects, such as growth promotion, growth inhibition, angiogenesis, cytotoxicity, inflammation, and immunomodulation [1], has been implicated in several inflammatory conditions [2], [3], [4], [5], [6].

This cytokine is not only produced predominantly by activated macrophages but also by other immune (lymphocytes, natural killer cells, mast cells) as well as stromal (endothelial cells, fibroblasts, microglial cells) cells. TNF is synthesized as a monomeric type-2 transmembrane protein (tmTNF) that is inserted into the membrane as a homotrimer and cleaved by the matrix metalloprotease TNF-α converting enzyme (TACE; ADAM17) to a soluble circulating trimer (solTNF); both tmTNF and solTNF are biologically active [7], [8]. The balance between tmTNF and solTNF signaling is influenced by cell type, activation status of the cell, the stimulus eliciting TNF production, TACE activity, and expression of endogenous TACE inhibitors leading to divergent TNF-mediated effects on cellular viability [9], [10].

Section snippets

TNF-α receptors and signaling

The actions of TNF-α are mediated as well as regulated by its ubiquitously expressed TNF receptors 1 (TNF-R1, Tnfrsf1a) and 2 (TNF-R2, Tnfrsf1b), which are membrane glycoprotein receptors that specifically bind TNF and homotrimers of lymphotoxin A, but the two receptors differ in their expression profiles, ligand affinity, cytoplasmic tail structure, and downstream signaling pathway activation [11]. TNF-R1 is expressed in most cell types, and can be activated by binding of either solTNF or

Role of TNF-α in asthma and COPD

TNF-α plays a significant role in many inflammatory diseases of lung. Of the various pulmonary diseases, it is implicated in asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), acute lung injury and acute respiratory distress syndrome [30]. Fig. 1 illustrates the putative role of TNF-α in the pathogenesis of asthma and COPD.

TNF-α is expressed in asthmatic airways and may play a key role in amplifying asthmatic inflammation through the activation of NF-κB, AP-1 and other

TNF-α inhibitors

The therapeutic goal when administering TNF-α inhibitors is to eliminate the surplus of TNF-α in the blood and from sites of inflammation. Reduction should be made such that TNF-α levels do not fall below levels that may comprise an individual's immuno-competency. Once a TNF-α inhibitor is administrated and absorbed from the site of administration, a number of interactions occur between tissue/fluids and blood. Upon reaching the target site the TNF inhibitors bind to soluble TNFs and TNF

Safety of TNF-α inhibitors

Given their mechanisms of action, it is possible that use of TNF-α inhibitors may predispose patients to an increased risk of serious and life-threatening infection, recrudescence of tuberculosis (TB), and reactivation of hepatitis B.

The anti-TNF-α therapies have subtly different side-effect profiles. Patients taking infliximab appear to have a higher risk of infection from histoplasmosis, coccidiomycosis or reactivation TB [84], [85]. Cases of TB were also reported in the studies of

TNF-α inhibitors and asthma

Considering the critical role of TNF-α in the pathogenesis of asthma and the need for alternative treatments for those asthmatic patients with severe disease who are particularly resistant to conventional therapy, molecules targeted at blocking the effects of TNF-α are likely to constitute a considerable advance in the management of these difficult patients. Indeed, some trials have explored the possibility of using TNF-α inhibitors in asthmatic patients (Table 1).

An uncontrolled study of

TNF-α inhibitors and COPD

In view of the similarities between chronic severe asthma and COPD, it has been suggested that blocking the biological effects of TNF-α may be beneficial in the treatment of COPD. Although randomized controlled trials to evaluate the effectiveness of TNF-α inhibitors in patients with COPD have been few, the results of the first studies seem to indicate that they are not real effective in this disease (Table 2).

An exploratory study of infliximab treatment in patients with COPD did not show a

What can we learn from trials

The studies reported in literature indicate that TNF-α inhibitors are effective in a relatively small subgroup of patients with severe asthma, possibly defined by an increased TNF axis [102], but they seem to be ineffective in COPD, although in the study of Rennard et al. [99], the 6-MWT post hoc analyses suggested that cachectic individuals, as well as younger individuals, derived relatively greater benefit from treatment with infliximab. The discrepancy in the results obtained in two

Conflict of interest statement

We declare that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. We gratefully acknowledge the support of the Pneumolabs UK Ltd of NPIMR, Y Block, Watford Road, Harrow, HA1 3UJ, UK, that is sponsoring LC’s research.

References (119)

  • R. Mueller et al.

    Different cytokine patterns in bronchial biopsies in asthma and chronic bronchitis

    Respir Med

    (1996)
  • S.S. Hacievliyagil et al.

    Association between cytokines in induced sputum and severity of chronic obstructive pulmonary disease

    Respir Med

    (2006)
  • S. Sakao et al.

    Association of tumor necrosis factor-α gene promoter polymorphism with low attenuation areas on high-resolution CT in patients with COPD

    Chest

    (2002)
  • V. Keatings et al.

    A polymorphism in the tumor necrosis factor-α gene promoter region may predispose to a poor prognosis in COPD

    Chest

    (2000)
  • D. Tracey et al.

    Tumor necrosis factor antagonist mechanisms of action: a comprehensive review

    Pharmacol Ther

    (2008)
  • M. Nakelchik et al.

    Reactivation of histoplasmosis after treatment with infliximab

    Am J Med

    (2002)
  • F.N. Rouhani et al.

    Effect of tumor necrosis factor antagonism on allergen-mediated asthmatic airway inflammation

    Respir Med

    (2005)
  • D.A. Meyers et al.

    Pharmacogenetic identification of increased responsiveness in severe asthma with anti-TNF (golimumab) therapy

    J Allergy Clin Immunol

    (2008)
  • B.B. Aggarwal et al.

    Tumor necrosis factors: developments during the last decade

    Eur Cytokine Netw

    (1996)
  • M. Sack

    Tumor necrosis factor-α in cardiovascular biology and the potential role for anti-tumor necrosis factor-α therapy in heart disease

    Pharmacol Ther

    (2002)
  • C.E. Kleyn et al.

    Infliximab for the treatment of psoriasis

    Expert Opin Biol Ther

    (2006)
  • S. Danese et al.

    Biological therapies for inflammatory bowel disease: research drives clinics

    Mini Rev Med Chem

    (2006)
  • M. Cacquevel et al.

    Cytokines in neuroinflammation and Alzheimer's disease

    Curr Drug Targets

    (2004)
  • B.B. Aggarwal et al.

    TNFα

  • A.J. Gearing et al.

    Processing of tumour necrosis factor-α precursor by metalloproteinases

    Nature

    (1994)
  • D.S. Smookler et al.

    Tissue inhibitor of metalloproteinase 3 regulates TNF-dependent systemic inflammation

    J Immunol

    (2006)
  • B.B. Aggarwal et al.

    TNF receptors

  • M. Grell et al.

    The type 1 receptor (CD120a) is the high-affinity receptor for soluble tumor necrosis factor

    Proc Natl Acad Sci U S A

    (1998)
  • Z.G. Liu

    Molecular mechanism of TNF signaling and beyond

    Cell Res

    (2005)
  • G. Dranoff

    Cytokines in cancer pathogenesis and cancer therapy

    Nat Rev Cancer

    (2004)
  • E.Y. Kim et al.

    Critical role of TNF receptor type-2 (p75) as a costimulator for IL-2 induction and T cell survival: a functional link to CD28

    J Immunol

    (2004)
  • S.J. Turner et al.

    Differential tumor necrosis factor receptor 2-mediated editing of virus-specific CD8+ effector T cells

    Proc Natl Acad Sci U S A

    (2004)
  • E.Y. Kim et al.

    TNF receptor type 2 (p75) functions as a costimulator for antigen-driven T cell responses in vivo

    J Immunol

    (2006)
  • X. Zhao et al.

    Tumor necrosis factor receptor 2-mediated tumor suppression is nitric oxide dependent and involves angiostasis

    Cancer Res

    (2007)
  • D. Aderka et al.

    Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors

    J Exp Med

    (1992)
  • B.A. Beutler

    The role of tumor necrosis factor in health and disease

    J Rheumatol

    (1999)
  • J.R. Bradley

    TNF-mediated inflammatory disease

    J Pathol

    (2008)
  • H.M. Shen et al.

    TNF receptor superfamily-induced cell death: redox-dependent execution

    FASEB J

    (2006)
  • G. Chen et al.

    TNF-R1 signaling: a beautiful pathway

    Science

    (2002)
  • N. Mukaida et al.

    Cooperative interaction of NF-κB and cis-regulatory enhancer binding protein-like factor binding elements in activating the IL-8 gene by pro-inflammatory cytokines

    J Biol Chem

    (1990)
  • M.P. Russo et al.

    Differential requirement for NF-κB-inducing kinase in the induction of NF-κB by IL-1β, TNF-α, and Fas

    Am J Physiol Cell Physiol

    (2002)
  • R. Witkamp et al.

    Signal transduction in inflammatory processes, current and future therapeutic targets: a mini review

    Vet Q

    (2000)
  • S. Mukhopadhyay et al.

    Role of TNFα in pulmonary pathophysiology

    Respir Res

    (2006)
  • J.C. Kips et al.

    The potential role of tumour necrosis factor α in asthma

    Clin Exp Allergy

    (1993)
  • P. Gosset et al.

    Tumor necrosis factor α and interleukin-6 production by human mononuclear phagocytes from allergic asthmatics after IgE-dependent stimulation

    Am Rev Respir Dis

    (1992)
  • M. Cembrzynska-Nowak et al.

    Elevated release of tumor necrosis factor-α and interferon-γ by bronchoalveolar leukocytes from patients with bronchial asthma

    Am Rev Respir Dis

    (1993)
  • S. Ying et al.

    TNF α mRNA expression in allergic inflammation

    Clin Exp Allergy

    (1991)
  • P. Bradding et al.

    Interleukin-4, -5, and -6 and tumor necrosis factor-α in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines

    Am J Respir Cell Mol Biol

    (1994)
  • V.M. Keatings et al.

    Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD

    Am J Respir Crit Care Med

    (1997)
  • C. Lilly et al.

    Expression of eotaxin by human lung epithelial cells: induction by cytokines and inhibition by glucocorticoids

    J Clin Invest

    (1997)
  • Cited by (116)

    • Use of biologics in the treatment of asthma, COPD, ACOS, and idiopathic pulmonary fibrosis

      2020, Targeting Chronic Inflammatory Lung Diseases Using Advanced Drug Delivery Systems
    View all citing articles on Scopus
    View full text