Effects of Vagus Nerve Stimulation and Vagotomy on Systemic and Pulmonary Inflammation in a Two-Hit Model in Rats

Matthijs Kox,Michiel Vaneker,Johannes G Van Der Hoeven,Gert-Jan Scheffer,Peter Pickkers,Cornelia W Hoedemaekers,Rory Edward Morty

doi:10.1371/journal.pone.0034431

Abstract

Pulmonary inflammation contributes to ventilator-induced lung injury. Sepsis-induced pulmonary inflammation (first hit) may be potentiated by mechanical ventilation (MV, second hit). Electrical stimulation of the vagus nerve has been shown to attenuate inflammation in various animal models through the cholinergic anti-inflammatory pathway. We determined the effects of vagotomy (VGX) and vagus nerve stimulation (VNS) on systemic and pulmonary inflammation in a two-hit model. Male Sprague-Dawley rats were i.v. administered lipopolysaccharide (LPS) and subsequently underwent VGX, VNS or a sham operation. 1 hour following LPS, MV with low (8 mL/kg) or moderate (15 mL/kg) tidal volumes was initiated, or animals were left breathing spontaneously (SP). After 4 hours of MV or SP, rats were sacrificed. Cytokine and blood gas analysis was performed. MV with 15, but not 8 mL/kg, potentiated the LPS-induced pulmonary pro-inflammatory cytokine response (TNF-α, IL-6, KC: p<0.05 compared to LPS-SP), but did not affect systemic inflammation or impair oxygenation. VGX enhanced the LPS-induced pulmonary, but not systemic pro-inflammatory cytokine response in spontaneously breathing, but not in MV animals (TNF-α, IL-6, KC: p<0.05 compared to SHAM), and resulted in decreased pO2 (p<0.05 compared to sham-operated animals). VNS did not affect any of the studied parameters in both SP and MV animals. In conclusion, MV with moderate tidal volumes potentiates the pulmonary inflammatory response elicited by systemic LPS administration. No beneficial effects of vagus nerve stimulation performed following LPS administration were found. These results questions the clinical applicability of stimulation of the cholinergic anti-inflammatory pathway in systemically inflamed patients admitted to the ICU where MV is initiated.

Highlights

Patients with severe sepsis and septic shock often suffer from respiratory failure, placing them in need of mechanical ventilation (MV)
In the present study we investigated the effects of vagus nerve stimulation and vagotomy on systemic and pulmonary inflammation using a two-hit model in rats
Compared to spontaneously breathing animals, MV with a tidal volume of 8 mL/kg did not result in an increase in pulmonary levels of the pro-inflammatory cytokine TNF-a or the antiinflammatory cytokine IL-10 (Figure 2)

Summary

Introduction

Patients with severe sepsis and septic shock often suffer from respiratory failure, placing them in need of mechanical ventilation (MV) While this intervention is lifesaving, MV can lead to, or worsen lung injury; a condition called ventilator-induced lung injury (VILI) [1]. It is thought that the additional inflammatory insult, or second ‘hit’ induced by MV, synergizes with the underlying systemic inflammatory process, resulting in detrimental effects on the lungs and other organs (multiple-hit theory) [5,6]. This cascade of events can lead to multiple organ dysfunction syndrome (MODS), associated with high mortality [7]. Limiting the second inflammatory hit caused by MV may represent a viable therapy to reduce lung injury and subsequent multi-organ failure in systemically inflamed patients

Methods

Results

Conclusion