Hyperoxia-induced Cellular Senescence in Fetal Airway Smooth Muscle Cells

Abstract

Supplemental O 2 (hyperoxia; 30-90% O 2 ) 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% O 2 ) on cellular senescence. Fetal ASM exposed to 40% O 2 for 7 days exhibited elevated concentrations of senescence-associated markers, including b-galactosidase; cell cycle checkpoint proteins p16, p21, and p-p53; and the DNA damage marker p-gH2A.X (phosphorylated g-histone family member X). The combination of dasatinib and quercetin, compounds known to eliminate senescent cells (senolytics), reduced the number of hyperoxia-exposed b-galactosidase-, p21-, p16-, and p-gH2A.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.

Cellular senescence: friend or foe to respiratory viral infections?

“…In addition to replicative senescence induced by aging, several other factors contribute to the development of stress-induced senescence in the lung, including radiation therapy, smoking, mechanical ventilation, and chronic use of supplemental oxygen (Figure 1). [24,[67][68][69][70], which supports the concept that other processes besides natural aging lead to senescence. Similarly, aged mice, which likely exhibit increased lung senescence, also exhibit enhanced lung permeability and increased levels of reactive oxygen species in response to an LPS challenge, which is linked to deficient Nox4 (a ROS-generating mitochondrial protein) ubiquination [86].…”

Senolytic drugs: from discovery to translation

“…Diabetes/ Obesity [109,110,112,[116][117][118] Cardiac dysfunction [13,18,114] Vascular hyporeactivity/ calcification [114] AV fistulae [115] Frailty [21,51,52,87] Age-related muscle loss (Sarcopenia) [119] Chemotherapy complications [21,51,93,120,121] Radiation complications [122] Cancers [51] Bone marrow transplant complications [120] Organ transplantation complications [123,124] Myeloma/ MGUS [125] Age-related cognitive dysfunction [126] Alzheimer's disease [23,127] Parkinson's disease [76] Amyotrophic lateral sclerosis [128] Ataxia [87] Obesity-related neuropsychiatric dysfunction [24] Renal dysfunction [111,129] Urinary incontinence [87] Osteoporosis [14,71,130] Osteoarthritis [131] Age-related intervertebral disc disease [87,132] Idiopathic pulmonary fibrosis [21,133]…”

Potential Role of Cellular Senescence in Asthma

“…Some asthmarelated factors have shown to induce senescence in smooth muscle cells. In vitro study showed that hypoxia induced cellular senescence in fetal ASMCs, leading to the upregulation of proinflammatory and profibrotic mediators, as well as increased contractility, which conduces to inflammation, tissue remodeling and airway obstruction (Parikh et al, 2019a). IgE and its receptor play an important role in the pathogenesis of allergic diseases like asthma.…”

“…This indicates that there is premature senescence triggered at young age in asthma. In this regard, studies have demonstrated that hypoxia in infants, air pollutants exposure, and allergen challenge in childhood/adolescence could induce underlying senescence process (Deng et al, 2013;Chan et al, 2016Chan et al, , 2017Lee et al, 2017Lee et al, , 2019Parikh et al, 2019a). Such stressors might induce cellular senescence in airway epithelial cells, mesenchymal cells or immune cells, leading to their dysfunction and facilitating the initiation of asthma.…”