Caspase-1 Inhibition Attenuates Hyperoxia-induced Lung and Brain Injury in Neonatal Mice

Fredrick Dapaah-Siakwan, Ronald Zambrano, Shihua Luo, Matthew R. Duncan, Nadine Kerr, Keyur Donda, Juan Pablo De Rivero Vaccari, Robert W. Keane, W. Dalton Dietrich, Merline Benny, Karen Young, Shu Wu

Research output: Contribution to journalArticle

Abstract

Hyperoxia plays a key role in the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of preterm infants. Infants with BPD often have brain injury that leads to long-term neurodevelopmental impairment, but the underlying mechanisms that control BPD-induced neurodevelopmental impairment remain unclear. Our previous studies have shown that hyperoxia-induced BPD in rodents is associated with lung inflammasome activation. Here, we tested the hypothesis that hyperoxia-induced lung and brain injury is mediated by inflammasome activation, and that inhibition of caspase-1, a key component of the inflammasome, attenuates hyperoxia-induced lung and brain injury in neonatal mice. C57/BL6 mouse pups were randomized to receive daily intraperitoneal injections of Ac-YVAD-CMK, an irreversible caspase-1 inhibitor, or placebo during exposure to room air or hyperoxia (85% O2) for 10 days. We found that hyperoxia activated the NLRP1 inflammasome, increased production of mature IL-1b, and upregulated expression of p30 gasdermin-D (GSDMD), the active form of GSDMD that is responsible for the programmed cell death mechanism of pyroptosis in both lung and brain tissue. Importantly, we show that inhibition of caspase-1 decreased IL-1b activation and p30 GSDMD expression, and improved alveolar and vascular development in hyperoxia-exposed lungs. Moreover, caspase-1 inhibition also promoted cell proliferation in the subgranular zone and subventricular zone of hyperoxia-exposed brains, resulting in lessened atrophy of these zones. Thus, the inflammasome plays a critical role in hyperoxia-induced neonatal lung and brain injury, and targeting this pathway may be beneficial for the prevention of lung and brain injury in preterm infants.

Original languageEnglish (US)
Pages (from-to)341-354
Number of pages14
JournalAmerican journal of respiratory cell and molecular biology
Volume61
Issue number3
DOIs
StatePublished - Jan 1 2019

Fingerprint

Caspase 1
Hyperoxia
Lung Injury
Inflammasomes
Brain Injuries
Brain
Bronchopulmonary Dysplasia
Chemical activation
Premature Infants
Lung
Pulmonary diseases
Cell proliferation
Cell death
Lateral Ventricles
Intraperitoneal Injections
Lung Diseases
Atrophy
Tissue
Blood Vessels
Rodentia

Keywords

  • Brain
  • Caspase-1
  • Hyperoxia
  • Inflammasome
  • Neonatal lung

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Caspase-1 Inhibition Attenuates Hyperoxia-induced Lung and Brain Injury in Neonatal Mice. / Dapaah-Siakwan, Fredrick; Zambrano, Ronald; Luo, Shihua; Duncan, Matthew R.; Kerr, Nadine; Donda, Keyur; De Rivero Vaccari, Juan Pablo; Keane, Robert W.; Dalton Dietrich, W.; Benny, Merline; Young, Karen; Wu, Shu.

In: American journal of respiratory cell and molecular biology, Vol. 61, No. 3, 01.01.2019, p. 341-354.

Research output: Contribution to journalArticle

Dapaah-Siakwan, Fredrick ; Zambrano, Ronald ; Luo, Shihua ; Duncan, Matthew R. ; Kerr, Nadine ; Donda, Keyur ; De Rivero Vaccari, Juan Pablo ; Keane, Robert W. ; Dalton Dietrich, W. ; Benny, Merline ; Young, Karen ; Wu, Shu. / Caspase-1 Inhibition Attenuates Hyperoxia-induced Lung and Brain Injury in Neonatal Mice. In: American journal of respiratory cell and molecular biology. 2019 ; Vol. 61, No. 3. pp. 341-354.
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