Exacerbation of Ventilation-Induced Lung Injury and Inflammation in Preterm Lambs by High-Dose Nanoparticles

Ishmael M Inocencio,Tammy Lim,Magdalena Plebanski,Sue D Xiang,Domenic Larosa,Mary Tolcos,Timothy J Moss,Valerie A Zahra,Vy Nguyen,Robert J Bischof,Jade Barbuto,Graeme R Polglase

doi:10.1038/s41598-017-13113-9

Ishmael M Inocencio, Tammy Lim + Show 10 more

Open Access

https://doi.org/10.1038/s41598-017-13113-9

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Abstract

Mechanical ventilation of preterm neonates causes lung inflammation and injury, with potential life-long consequences. Inert 50-nm polystyrene nanoparticles (PS50G) reduce allergic inflammation in the lungs of adult mice. We aimed to confirm the anti-inflammatory effects of PS50G in a sheep asthma model, and investigate the effects of prophylactic administration of PS50G on ventilation-induced lung injury (VILI) in preterm lambs. We assessed lung inflammatory cell infiltration, with and without PS50G, after airway allergen challenge in ewes sensitised to house dust mite. Preterm lambs (0.83 gestation) were delivered by caesarean section for immediate tissue collection (n = 5) or ventilation either with (n = 6) or without (n = 5) prophylactic intra-tracheal administration of PS50G nanoparticles (3% in 2 ml). Ventilation was continued for a total of 2 h before tissue collection for histological and biomolecular assessment of lung injury and inflammation. In ewes with experimental asthma, PS50G decreased eosinophilic infiltration of the lungs. Ventilated preterm lambs showed molecular and histological signs of lung injury and inflammation, which were exacerbated in lambs that received PSG50G. PS50G treatment decreased established inflammation in the lungs of asthmatic sheep. However, prophylactic administration of PSG50 exacerbated ventilation-induced lung injury and lung inflammation in preterm lambs.

Highlights

Mechanical ventilation of preterm neonates causes lung inflammation and injury, with potential lifelong consequences
The inflammatory cascade initiated by ventilation-induced lung injury represents a potentially modifiable pathway to bronchopulmonary dysplasia (BPD)
Our study demonstrates that nanoparticles, which can reduce inflammation in one context, can exacerbate lung injury and inflammation induced by ventilation in preterm lambs

Summary

Introduction

Mechanical ventilation of preterm neonates causes lung inflammation and injury, with potential lifelong consequences. Prophylactic administration of PSG50 exacerbated ventilation-induced lung injury and lung inflammation in preterm lambs. BPD is a severe lung disease that develops in 20% of infants who receive mechanical ventilation[9] It is characterised by the continued requirement for respiratory support for at least 28 days after birth. Proinflammatory cytokines (Interleukin (IL) -1β, -6 and -8) and the injury response genes, Early Growth Response Gene 1 (EGR1), Cysteine-Rich 61 (CYR-61), and Connective Tissue Growth Factor (CTGF) are up-regulated in response to ventilation-induced lung injury (VILI)[11,12]. These mediators likely play integral roles in propagating abnormal lung development. This technology offers a plethora of potential therapeutic uses of nanoparticles, including their use as vaccine vectors and drug carriers, and for targeted gene therapy[14]

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