The pro-inflammatory cytokine tumour necrosis factor-α (TNF) is produced by astrocytes and microglial macrophages during inflammation and stress (Turnbull & Rivier, 1999). Its role in CNS respiratory control is unknown, although its role in mediating sleep is notable in this context (Krueger, 2001). Recent data suggest that stress attenuates the ventilatory response to hypercapnia (Kinkead et al. 2001). Here, the hypothesis that TNF directly inhibits respiratory output has been explored.

Adult Sprague-Dawley rats (270-320 g) were anaesthetized (induction: pentobarbitone 60 mg kg^-1 I.P.; maintenance: 30 mg kg^-1 h^-1 propofol or 100 µg kg h^-1 pentobarbitone, I.V. infusion), and mechanically ventilated with neuromuscular blockade (gallamine triethiodide 10 mg kg^-1 I.V., then 2-4 mg kg^-1 h^-1 I.V.). All studies were undertaken in accordance with the UK Animals (Scientific Procedures) Act, 1986. At the end of experiments rats were humanely killed by anaesthetic overdose. Adequate depth of anaesthesia was ensured by maintaining stable levels of blood pressure, heart rate and respiratory output (RO), as recorded from phrenic nerve activity. Homeothermic warming maintained core temperature at 37 °C. Artificial cerebrospinal fluid (ACSF) or recombinant rat TNF-α (R&D Systems, USA) were administered either by intracerebroventicular (I.C.V.) injections via a guide cannula placed stereotaxically into the left lateral ventricle (n = 6 rats) or by brainstem superfusion (n = 4 rats). Intracerebroventricular ACSF had no effect on RO or cardiovascular parameters. 2-15 µl I.C.V. injections of 0.5-100 pg TNF-α produced an 18 ± 7 % fall in RO (mean ± S.E.M.; P < 0.05; Student’s paired t test). A 10 % fall in peak phrenic activity was seen 32 ± 10 min (mean ± S.E.M.) after I.C.V. injection. Mean arterial blood pressure declined by 10 ± 2 mmHg from pre-injection levels (mean ± S.E.M.; P < 0.05; Student’s paired t test). Bathing the dorsal surface of the brainstem with 10 ng ml^-1 TNF-α also inhibited RO in 3/4 rats, with peak phrenic activity reduced by 25 % 621 ± 141 s after application. This effect could be reversed by further application of ACSF vehicle.

These data suggest that TNF-α can modulate central respiratory output. During periods of acute major inflammation or stress, CNS expression of TNF may contribute to a reduction in respiratory drive. This may explain the observation that stress results in attenuation of hypercapnic respiratory drive (Kinkead, 2001).

This work was supported in part by a grant from The Institute of Child Health.