Effects of inhaled tumour necrosis factor alpha in subjects with mild asthma

Background: Inhaled tumour necrosis factor alpha (TNFalpha) has previously been shown to induce airway neutrophilic and increased airway reactivity in normal subjects. It was hypothesised that a similar challenge would increase airway reactivity in those with mild asthma, but that the inflammatory profile may differ. Methods: Ten mild asthmatic subjects were recruited on the basis of clinical asthma and either a sensitivity to methacholine within the range defined for asthma or a 20% improvement in forced expiratory volume (FEV1) after 200 mug salbutamol. Subjects inhaled either vehicle control or 60 ng recombinant human (rh)TNFalpha and were studied at baseline, 6, 24, and 48 hours later. Variables included spirometric parameters, methacholine provocative concentration causing a 20% fall in FEV1 (PC20), induced sputum differential cell count, relative sputum level of mRNA of interleukins (IL)-4, IL-5, IL-9, IL-1 4, IL-15 and TNFalpha, and the exhaled gaseous markers of inflammation, nitric oxide and carbon monoxide. Results: PC20 showed an increase in sensitivity after TNFalpha compared with control (p<0.01). The mean percentage of neutrophils increased at 24-48 hours (24 hour control: 1.1 (95% CI 0.4 to 2.7) v 9.2 (95% Cl 3.5 to 14.9), p<0.05), and there was also a rise in eosinophils (p=0.05). Relative levels of sputum mRNA suggested a rise in expression of TNFalpha, IL-1 4, and IL-1 5, but no change in IL-4 and IL-5. Spirometric parameters and exhaled gases showed no significant change. Conclusion: The increase in airway responsiveness and sputum inflammatory cell influx in response to rhTNFalpha indicates that TNFalpha may contribute to the airway inflammation that characterises asthma.