Host response to mechanical ventilation for viral respiratory tract infection

Abstract

Respiratory syncytial virus (RSV) bronchiolitis causes severe respiratory tract infection in infants, frequently necessitating mechanical ventilatory support. However, life-saving, mechanical ventilation aggravates lung inflammation. We set up a model to dissect the host molecular response to mechanical ventilation in RSV infection. Furthermore, the response to induced hypercapnic acidosis, reported to dampen the inflammatory response to mechanical ventilation in non-infectious models, was assessed.BALB/c mice were inoculated with RSV or mock-suspension and ventilated for 5 h on day 5 post inoculation.Mechanical ventilation of infected mice resulted in enhanced cellular influx and increased concentrations of pro-inflammatory cytokines in the bronchoalveolar space. Microarray analysis showed that enhanced inflammation was associated with a molecular signature of a stress response to mechanical ventilation with little effect on the virus-induced innate immune response. Hypercapnic acidosis during mechanical ventilation of infected mice did not change host transcript profiles.We conclude that mechanical ventilation during RSV infection adds a robust but distinct molecular stress response to virus-induced innate immunity activation, emphasising the importance of lung-protective mechanical ventilation strategies. Induced hypercapnic acidosis has no major effect on host transcription profiles during mechanical ventilation for RSV infection, suggesting that this is a safe approach to minimise ventilator-induced lung injury.KEYWORDS: Gene expression profiles, hypercapnic acidosis, mice, respiratory syncytial virus, ventilator-induced lung injury R espiratory syncytial virus (RSV) is the most common cause of seasonal acute respiratory tract illness of all ages [1,2]. More than 50% of all infants are infected with RSV during the first yr of life and by the age of 2 yrs almost all children have been infected [3]. Of these children ,1-2% will need hospitalisation and ,10% of these hospitalised children (,0.1% of all children) will require mechanical ventilation for a severe RSV infection during their first yr of life [4]. Hence, RSV infection is the most frequent cause of non-elective paediatric intensive care unit (PICU) admission for mechanical ventilatory support in infants during the winter season [5]. RSV pathogenesis is not completely understood. In humans, severe RSV infection results in a predominantly neutrophil infiltrate in bronchoalveolar lavage fluid (BALF) [6] and a strong innate pro-inflammatory response, reflected by exhaustion of the peripheral blood neutrophil pool after peak values of viral load and disease severity [7]. In mice, the innate immune response is characterised by induction of type I interferon (IFN)-regulated genes and chemokine genes, and genes involved in inflammation and antigen processing [8].Although life-saving, mechanical ventilation may induce or aggravate pulmonary inflammation and lung injury. Ventilator-induced lung injury (VILI) results from relatively high tidal volumes...

Mortality due to Respiratory Syncytial Virus. Burden and Risk Factors

“…Spontaneous pneumothoraxes have been rarely reported with RSV, and were low in our population at 0.6%. But mechanical ventilation in RSV-infected patients can induce or aggravate pulmonary inflammation 18 . In addition, segmental atelectasis and lung hyperinflation during RSV disease may result in ventilation using high volumes to overcome hypercapnia, increasing risk of air leaks 19 .…”

Nasopharyngeal gene expression, a novel approach to study the course of respiratory syncytial virus infection

“…Finally, significant upregulation of CCL7 has been observed in mice infected with rhinovirus [20] and in children during infection by different respiratory viruses, including RSV [30]. In addition, CCL7 was shown to be specifically upregulated when no mechanical ventilation was applied during RSV infection in mice and not differentially expressed when uninfected mice received mechanical ventilation [31], strongly suggesting that CCL7 upregulation is caused by RSV infection and is not a consequence of mechanical ventilation.…”

Tidal Volume Drives Inflammation During Mechanical Ventilation for Viral Respiratory Infection

“…This study builds on a recently published model (5). For the current study, new experiments were performed with male BALB/c mice (n = 72) (Harlan, the Netherlands), 6-8 weeks old and weighing 20-28 g. On day 0, mice were randomly assigned to intranasal inoculation with 50 μL of either RSV (containing 2 × 10e6 pfu/50 μL) or mock suspension.…”

“…Spontaneously breathing mice were kept in an enclosed environment in which ambient Fio 2 was maintained at 0.5 for 5 hours. Mice assigned to mechanical ventilation (Vt 12 mL/kg, frequency 40/min, positive end-expiratory pressure [PEEP] 6 cm H 2 O, and Fio 2 0.5 or Vt 6 mL/kg, frequency 110/min, PEEP 6 cm H 2 O, and Fio 2 0.5) were anesthetized, ventilated, and monitored for 5 hours as described previously (5). Systolic blood pressure and heart rate of ventilated mice were monitored noninvasively using a murine tail-cuff system (ADInstruments, Spechbach, Baden-Württemberg, Germany).…”

“…Because the affected lung is no longer homogeneous, ventilatory volume and therefore tissue overstretch are not equally distributed over the lung. When pulmonary inflammation is already present and mechanical ventilation is applied, inflammation may be enhanced (4,5).…”