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

10 Scopus citations


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
Issue number1
StatePublished - Jan 1 2019



  • Asthma
  • Neonatal
  • Reactive airway disease
  • Senescence

ASJC Scopus subject areas

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

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