The selective α7 nicotinic acetylcholine receptor agonist GTS-21 attenuates ventilator-induced inflammation and lung injury

Introduction

Mechanical ventilation (MV) induces an inflammatory response that contributes to lung injury such as in acute lung injury or acute respiratory distress syndrome. The efferent vagus nerve can limit the inflammatory response via the α7 nicotinic acetylcholine receptor (α7nAChR), the so-called cholinergic anti-inflammatory pathway. The aim of this study was to evaluate the effect of the selective α7nAChR agonist GTS-21 on pulmonary and systemic inflammation and lung injury induced by MV using clinically relevant ventilator settings.

Methods

C57BL6 mice (n = 40) were intraperitoneally injected with 8 mg/kg GTS-21 or placebo, after which they were mechanically ventilated for 4 hours (tidal volume 8 ml/kg; positive end-expiratory pressure 1.5 cm H₂O; FiO₂ 0.45). Untreated, not mechanically ventilated mice were used as controls. Arterial blood gases were obtained at the end of the experiment and TNFα, IL-6, IL-1α, IL-1β, keratinocyte-derived cytokine (IL-8 homologue) and IL-10 were determined in plasma and lung homogenates. Lung TNFα and IL-10 mRNA expression was measured using quantitative PCR.

Results

In GTS-21-treated mice, the alveolar–arterial gradient after MV was significantly reduced compared with placebo (14.0 ± 0.76 vs. 16.2 ± 0.59 kPa; P = 0.03). MV resulted in an increase of all cytokines in plasma and lung compared with control mice. TNFα was significantly lower in plasma of GTS-21-treated animals compared with placebo (196.2 ± 50.8 vs. 331.9 ± 31.9 pg/ml; P = 0.04). Similarly, in lung homogenates a distinct trend was observed towards lower TNFα levels in GTS-21-treated mice (53.9 ± 12.5 vs. 79.1 ± 5.6 pg/mg protein; P = 0.06). IL-10 levels were unaffected by GTS-21. MV strongly increased TNFα mRNA expression in lungs of placebo animals (21-fold compared with controls); this was significantly lower in GTS-21-treated mice (11-fold compared with controls; P = 0.02). IL-10 mRNA expression was similar in GTS-21-treated and placebo animals.

Conclusion

MV with clinically relevant ventilator settings results in activation of the immune system. GTS-21 inhibits proinflammatory cytokine production while not affecting the anti-inflammatory cytokine IL-10. The reduced alveolar–arterial gradient in GTS-21-treated animals indicates attenuation of lung injury. In conclusion, limiting the inflammatory response appears to reduce lung injury, and therefore the cholinergic anti-inflammatory pathway may represent new treatment options for MV-induced lung injury.