title: The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia.
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.
authors.affiliation: Department of Pediatrics, Center for Pulmonary &Vascular Biology, University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas Texas 75390-9063, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Liao
authors.affiliation: Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas Texas 75390-9063, USA.
authors.forename: Vishal S
authors.initials: VS
authors.lastname: Kapadia
authors.affiliation: Health Systems Research, Parkland Health and Hospital System, 5200 Harry Hines Boulevard, Dallas Texas 75235, USA.
authors.forename: L Steven
authors.initials: LS
authors.lastname: Brown
authors.affiliation: Department of Pediatrics, Center for Pulmonary &Vascular Biology, University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas Texas 75390-9063, USA.
authors.forename: Naeun
authors.initials: N
authors.lastname: Cheong
authors.affiliation: Department of Pediatrics, Center for Pulmonary &Vascular Biology, University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas Texas 75390-9063, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Longoria
authors.affiliation: Department of Pediatrics, Center for Pulmonary &Vascular Biology, University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas Texas 75390-9063, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Mija
authors.affiliation: Department of Pediatrics, Center for Pulmonary &Vascular Biology, University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas Texas 75390-9063, USA.
authors.forename: Mrithyunjay
authors.initials: M
authors.lastname: Ramgopal
authors.affiliation: Department of Pediatrics, Center for Pulmonary &Vascular Biology, University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas Texas 75390-9063, USA.|Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas Texas 75390-9063, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Mirpuri
authors.affiliation: Department of Pediatrics, University of Texas Health Sciences Center at San Antonio and The Southwest Foundation for Biomedical Research, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA.
authors.forename: Donald C
authors.initials: DC
authors.lastname: McCurnin
authors.affiliation: Department of Pediatrics, Center for Pulmonary &Vascular Biology, University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas Texas 75390-9063, USA.|Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas Texas 75390-9063, USA.
authors.forename: Rashmin C
authors.initials: RC
authors.lastname: Savani
mesh_terms: D000118:Acetylglucosaminidase; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D001997:Bronchopulmonary Dysplasia / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D020170:Caspase 1 / Q000276:immunology*; D015331:Cohort Studies; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D018496:Hyperoxia / Q000235:genetics* / Q000276:immunology; D007071:Immunoglobulin A, Secretory / Q000276:immunology; D007231:Infant, Newborn; D007234:Infant, Premature; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000276:immunology / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010215:Papio; D009195:Peroxidase; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D007071:Immunoglobulin A, Secretory; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009195:Peroxidase; D000118:Acetylglucosaminidase; D020170:Caspase 1; D005905:Glyburide