The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia.

Jie Liao,Donald C Mccurnin,Vishal S Kapadia,L Steven Brown,Rashmin C Savani,Naeun Cheong,Julie Mirpuri,Dan Mija,Christopher Longoria,Mrithyunjay Ramgopal

doi:10.1038/ncomms9977

Abstract

The pathogenesis of bronchopulmonary dysplasia (BPD), a devastating lung disease in preterm infants, includes inflammation, the mechanisms of which are not fully characterized. Here we report that the activation of the NLRP3 inflammasome is associated with the development of BPD. Hyperoxia-exposed neonatal mice have increased caspase-1 activation, IL1β and inflammation, and decreased alveolarization. Nlrp3(-/-) mice have no caspase-1 activity, no IL1β, no inflammatory response and undergo normal alveolarization. Treatment of hyperoxia-exposed mice with either IL1 receptor antagonist to block IL1β or glyburide to block the Nlrp3 inflammasome results in decreased inflammation and increased alveolarization. Ventilated preterm baboons show activation of the NLRP3 inflammasome with increased IL1β:IL1ra ratio. The IL1β:IL1ra ratio in tracheal aspirates from preterm infants with respiratory failure is predictive of the development of BPD. We conclude that early activation of the NLRP3 inflammasome is a key mechanism in the development of BPD, and represents a novel therapeutic target for BPD.

Highlights

The pathogenesis of bronchopulmonary dysplasia (BPD), a devastating lung disease in preterm infants, includes inflammation, the mechanisms of which are not fully characterized
We found that the Nlrp[3] inflammasome is activated in neonatal mice exposed to 85% oxygen (O2), and that it is a key mediator of the inflammation and decreased alveolarization observed in this model of BPD
The NLRP3 inflammasome is activated in a preterm baboon model of BPD, where ventilated baboons had an increased IL1b:IL1ra ratio when compared with gestational age controls

Summary

Introduction

The pathogenesis of bronchopulmonary dysplasia (BPD), a devastating lung disease in preterm infants, includes inflammation, the mechanisms of which are not fully characterized. Pathogen or endogenous danger signals are recognized by specific pattern recognition receptors that promote a nonspecific, yet robust response to mobilize inflammatory cells[4] These include Toll-like receptors (TLRs), the activation of which results in the transcription of cytokines, especially pro-IL1b, as well as a family of exclusively intracellular proteins called NOD-like receptors (NLRs)[5]. IL1b, IL1ra and the IL1b:ILra ratio in tracheal aspirates obtained in the first 3 days after birth from human preterm infants with respiratory failure were independently predictive of adverse outcome at 36 weeks postmenstrual age (PMA) These cumulative findings reveal that the NLRP3 inflammasome is critically involved in the pathogenesis of BPD, and that it represents a novel therapeutic target for this devastating disorder of infancy. Our data defines a specific population of infants that can be targeted for therapeutic intervention in clinical trials

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