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Am J Respir Cell Mol Biol. 2019 Mar;60(3):308-322. doi: 10.1165/rcmb.2018-0219OC.

TREM-1 Attenuates RIPK3-mediated Necroptosis in Hyperoxia-induced Lung Injury in Neonatal Mice.

Author information

1
1 Drexel University College of Medicine, Philadelphia, Pennsylvania.
2
2 Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; and.
3
3 Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York.

Abstract

Hyperoxia-induced injury to the developing lung, impaired alveolarization, and dysregulated vascularization are critical factors in the pathogenesis of bronchopulmonary dysplasia (BPD); however, mechanisms for hyperoxia-induced development of BPD are not fully known. In this study, we show that TREM-1 (triggering receptor expressed on myeloid cells 1) is upregulated in hyperoxia-exposed neonatal murine lungs as well as in tracheal aspirates and lungs of human neonates with respiratory distress syndrome and BPD as an adaptive response to survival in hyperoxia. Inhibition of TREM-1 function using an siRNA approach or deletion of the Trem1 gene in mice showed enhanced lung inflammation, alveolar damage, and mortality of hyperoxia-exposed neonatal mice. The treatment of hyperoxia-exposed neonatal mice with agonistic TREM-1 antibody decreased lung inflammation, improved alveolarization, and was associated with diminished necroptosis-regulating protein RIPK3 (receptor-interacting protein kinase 3). Mechanistically, we show that TREM-1 activation alleviates lung inflammation and improves alveolarization through downregulating RIPK3-mediated necroptosis and NLRP3 (nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3) inflammasome activation in hyperoxia-exposed neonatal mice. These data show that activating TREM-1, enhancing angiopoietin 1 signaling, or blocking the RIPK3-mediated necroptosis pathway may be used in new therapeutic interventions to control adverse effects of hyperoxia in the development of BPD.

KEYWORDS:

NLRP3 inflammasome; TREM-1; bronchopulmonary dysplasia; hyperoxia-induced lung injury; necroptosis

PMID:
30281332
PMCID:
PMC6397981
[Available on 2020-03-01]
DOI:
10.1165/rcmb.2018-0219OC

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