Tumour necrosis factor (TNF ) as a novel therapeutic target in symptomatic corticosteroid dependent asthma

Howarth, Peter H.; Babu, K. Suresh; Arshad, Hasan; Lau, L.; Buckley, Michael; McConnell, W.T.; Beckett, Paul; Ali, Maria; Chauhan, Anoop; Wilson, Susan J.; Reynolds, Ann; Davies, Donna E.; Holgate, Stephen T.

doi:10.1136/thx.2005.045260

Cited by 460 publications

(359 citation statements)

References 33 publications

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“…Treatment of severe asthmatics with soluble TNF␣ receptor IgG1 Fc fusion proteins appears to be effective (23). However, the specific targets in the lung affected by TNF␣ and the mechanisms of altered airway hyperreactivity are still under investigation.…”

Section: Discussionmentioning

confidence: 99%

Regulation of store-operated Ca²⁺entry by CD38 in human airway smooth muscle

Sieck¹,

White²,

Thompson³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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(11,15,20,26,38,39,46) or by plasma membrane Ca 2ϩ influx.TNF␣, a potent proinflammatory cytokine found in bronchoalveolar lavage fluid (12) and sputum (50) from asthmatics, has been implicated as a mediator in the pathophysiology of asthma (45, 51, 52) and chronic obstructive pulmonary disease (8, 16). Indeed, TNF␣ has been shown to enhance ASM contractility (13,43,47 (11,20,46) as well as via ryanodine receptor (RyR) channels (15, 26), the latter resulting from increased levels of the novel second messenger cyclic ADP ribose (cADPR) (27,39). cADPR, in turn, is synthesized and degraded by the bifunctional ectoenzyme CD38 via ADP ribosyl cyclase and cADPR hydrolase activities, respectively (22). Indeed, the CD38/cADPR pathway has been implicated in [Ca 2ϩ ] i regulation in ASM (39, 57) and intestinal (30, 31), uterine (7, 53), and vascular (17, 25) smooth muscles. Recent studies suggest that the CD38/cADPR signaling pathway contributes to TNF␣-induced augmentation of [Ca 2ϩ ] i responses in ASM (14). Such an effect is thought to result from an increase in cADPRinduced Ca 2ϩ mobilization from the SR. However, this does not explain the effect of TNF␣ on both peak and plateau responses. While it is likely that SR Ca 2ϩ release is augmented by TNF␣, whether Ca 2ϩ influx is also increased remains to be determined.Ca 2ϩ influx in ASM can occur through voltage-gated (59), receptor-operated (33), and/or store-operated channels (6). In the last case, store-operated Ca 2ϩ entry (SOCE) is triggered by depletion of SR Ca 2ϩ stores (6,41,42,49,55,56). We and others have shown that different transient receptor potential channel (TRPC) isoforms are expressed in ASM (6,58). In a recent study using human ASM, we further demonstrated that TNF␣ treatment increases SOCE (58). TNF␣ treatment also increases CD38 expression. Studies in other cell types suggest that CD38 itself can also regulate SOCE (10, 21). Whether altered CD38 expression contributes to TNF␣-induced changes in Ca 2ϩ influx is not known. In the present study, we hypothesized that the effects of TNF␣ treatment on CD38 expression and SOCE in human ASM cells are linked. Accordingly, we examined the effects of CD38 overexpression vs. knockdown of CD38 expression [via specific small interfering RNA (siRNA)] on TNF␣-induced enhancement of SOCE. METHODSHuman ASM cells. Human bronchi were obtained from discarded surgical specimens in accordance with procedures reviewed and approved (as well as deemed exempt from Human Subjects classification under 45CFR 46) by the Mayo Clinic Institutional Review Board. The techniques for isolation of ASM cells from bronchi have

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Section: Discussionmentioning

confidence: 99%

Regulation of store-operated Ca²⁺entry by CD38 in human airway smooth muscle

Sieck¹,

White²,

Thompson³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In an open-label trial of 15 patients maximally treated for chronic severe asthma [64], 25 mg ETA administered SC twice a week for 12 weeks clearly improved lung function, attenuated airway hyperresponsiveness, and reduced overall asthma symptoms scores with all but 1 patient discontinuing regular bronchodilators by study end. In a 10-week, randomized placebo-controlled crossover trial of ETA (25 mg SC twice weekly) in 10 patients with chronic severe asthma refractory to treatment with inhaled corticosteroids, ETA-treated patients had attenuation in airway hyperresponsiveness and significant improvement in FEV1 and in overall asthma symptoms scores compared with placebo [65].…”

Section: Lung Inflammation-mentioning

confidence: 98%

TNFα blockade in human diseases: An overview of efficacy and safety

Lin

Ziring

Desai

et al. 2008

Clinical Immunology

231

187

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“…TNF-α together with IL-1β has been identified as key cytokine that is able to initiate inflammatory cascades during exacerbations of severe asthma [79] and COPD [80]. In particular, it has been reported that TNF-α is the initial and predictive cytokine released in the cascade following lipopolysaccharide (LPS) exposure [80].…”

Section: Role Of Tnf-α In Asthma and Copdmentioning

confidence: 99%

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

Matera

Calzetta

Cazzola

2010

Pulmonary Pharmacology & Therapeutics

113

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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 lung. 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 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 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.

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Tumour necrosis factor (TNF ) as a novel therapeutic target in symptomatic corticosteroid dependent asthma

Cited by 460 publications

References 33 publications

Regulation of store-operated Ca²⁺entry by CD38 in human airway smooth muscle

Regulation of store-operated Ca²⁺entry by CD38 in human airway smooth muscle

TNFα blockade in human diseases: An overview of efficacy and safety

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

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Tumour necrosis factor (TNF ) as a novel therapeutic target in symptomatic corticosteroid dependent asthma

Cited by 460 publications

References 33 publications

Regulation of store-operated Ca2+entry by CD38 in human airway smooth muscle

Regulation of store-operated Ca2+entry by CD38 in human airway smooth muscle

TNFα blockade in human diseases: An overview of efficacy and safety

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

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Regulation of store-operated Ca²⁺entry by CD38 in human airway smooth muscle

Regulation of store-operated Ca²⁺entry by CD38 in human airway smooth muscle