Moderate hyperoxia induces senescence in developing human lung fibroblasts.

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Neonatology

Background:

• Premature infant hyperoxia exposure elevates risks for lung diseases like asthma and bronchopulmonary dysplasia.
• Fibroblasts are crucial for maintaining lung integrity, making their response to hyperoxia critical.
• Cellular senescence is a significant factor in various disease pathologies.

Purpose of the Study:

• To investigate if clinically relevant moderate hyperoxia induces senescence in developing human fetal lung fibroblasts.
• To examine the effects of hyperoxia on senescence, endoplasmic reticulum (ER) stress, and autophagy pathways.
• To characterize the senescence-associated secretory phenotype (SASP) and its profibrotic potential.

Main Methods:

• Primary human fetal lung fibroblasts were exposed to 40% oxygen (hyperoxia) or 21% oxygen for 7 days.
• Senescence was assessed via morphology, β-galactosidase activity, DNA damage markers, and cell cycle analysis.
• Autophagy, ER stress, and SASP markers (including inflammatory and profibrotic factors) were evaluated.

Main Results:

• Hyperoxia reduced fibroblast proliferation but increased cell size, alongside elevated senescence markers (SA-β-gal, DNA damage, G2/M arrest, p53/p21 activation).
• Autophagy was reduced under hyperoxia, while ER stress was not significantly enhanced.
• Hyperoxia upregulated key SASP factors, creating a profibrotic secretome that stimulated extracellular matrix formation.

Conclusions:

• Moderate hyperoxia induces senescence in human fetal lung fibroblasts, characterized by reduced autophagy.
• The hyperoxia-induced SASP is profibrotic and may drive aberrant lung repair mechanisms.
• Understanding these fibroblast responses is vital for mitigating hyperoxia-related lung disease in premature infants.