Hyperoxia-induced cellular senescence in fetal airway smooth muscle cells

Pavan Parikh, Rodney Jr. Britt, Logan J. Manlove, Sarah A. Wicher, Anne Roesler, Jovanka Ravix, Jacob Teske, Michael A. Thompson, Gary C Sieck, James L Kirkland, Nathan K LeBrasseur, Daniel J Tschumperlin, Christina M Pabelick, Y.s. Prakash

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Supplemental O2 (hyperoxia; 30-90% O2) is a necessary intervention for premature infants, but it contributes to development of neonatal and pediatric asthma, necessitating better understanding of contributory mechanisms in hyperoxia-induced changes to airway structure and function. In adults, environmental stressors promote formation of senescent cells that secrete factors (senescence-associated secretory phenotype), which can be inflammatory and have paracrine effects that enhance chronic lung diseases. Hyperoxia-induced changes in airway structure and function are mediated in part by effects on airway smooth muscle (ASM). In the present study, using human fetal ASM cells as a model of prematurity, we ascertained the effects of clinically relevant moderate hyperoxia (40% O2) on cellular senescence. Fetal ASM exposed to 40% O2 for 7 days exhibited elevated concentrations of senescence-associated markers, including β-galactosidase; cell cycle checkpoint proteins p16, p21, and p-p53; and the DNA damage marker p-γH2A.X (phosphorylated γ-histone family member X). The combination of dasatinib and quercetin, compounds known to eliminate senescent cells (senolytics), reduced the number of hyperoxia-exposed β-galactosidase-, p21-, p16-, and p-γH2A.X-positive ASM cells. The senescenceassociated secretory phenotype profile of hyperoxia-exposed cells included both profibrotic and proinflammatory mediators. Naive ASM exposed to media from hyperoxia-exposed senescent cells exhibited increased collagen and fibronectin and higher contractility. Our data show that induction of cellular senescence by hyperoxia leads to secretion of inflammatory factors and has a functional effect on naive ASM. Cellular senescence in the airway may thus contribute to pediatric airway disease in the context of sequelae of preterm birth.

Original languageEnglish (US)
Pages (from-to)51-60
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume61
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Hyperoxia
Cell Aging
Smooth Muscle Myocytes
Muscle
Cells
Smooth Muscle
Galactosidases
Pediatrics
Phenotype
Cell Cycle Proteins
Quercetin
Premature Birth
Cell Cycle Checkpoints
Pulmonary diseases
Genetic Markers
Fibronectins
Premature Infants
Histones
Lung Diseases
DNA Damage

Keywords

  • Asthma
  • Neonatal
  • Reactive airway disease
  • Senescence

ASJC Scopus subject areas

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

Cite this

Hyperoxia-induced cellular senescence in fetal airway smooth muscle cells. / Parikh, Pavan; Britt, Rodney Jr.; Manlove, Logan J.; Wicher, Sarah A.; Roesler, Anne; Ravix, Jovanka; Teske, Jacob; Thompson, Michael A.; Sieck, Gary C; Kirkland, James L; LeBrasseur, Nathan K; Tschumperlin, Daniel J; Pabelick, Christina M; Prakash, Y.s.

In: American journal of respiratory cell and molecular biology, Vol. 61, No. 1, 01.01.2019, p. 51-60.

Research output: Contribution to journalArticle

Parikh, Pavan ; Britt, Rodney Jr. ; Manlove, Logan J. ; Wicher, Sarah A. ; Roesler, Anne ; Ravix, Jovanka ; Teske, Jacob ; Thompson, Michael A. ; Sieck, Gary C ; Kirkland, James L ; LeBrasseur, Nathan K ; Tschumperlin, Daniel J ; Pabelick, Christina M ; Prakash, Y.s. / Hyperoxia-induced cellular senescence in fetal airway smooth muscle cells. In: American journal of respiratory cell and molecular biology. 2019 ; Vol. 61, No. 1. pp. 51-60.
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