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