Understanding the Effect Of 1,3-Butadiene on Human Lung Fibroblasts: Does Exposure to 1,3-Butadiene Induce Senescence?

Cellular senescence is a state of irreversible growth arrest induced by either telomere shortening (replicative senescence) or telomere-independent signals (stress-induced premature senescence or SIPS). Recent studies have shown that cigarette smoke extract induces senescence in lung fibroblasts and alveolar epithelial cells. 1,2,3,4-diexpoxybutane, or diepoxybutane (DEB), is the most reactive metabolite of 1,3-butadiene, an important hazardous air pollutant and potent genotoxic agent found in cigarette smoke. In this study we examined the effect of DEB on the proliferative capacity of human lung cells. We hypothesized that exposure of human lung fibroblasts (HLF) to DEB induces stress-induced premature senescence (SIPS). Cell culture experiments demonstrated that exposure of HLF to DEB induced persistent DNA damage and senescence. This senescence was characterized by a dose-dependent increase in senescence-associated β-galactosidase activity, senescence-associated alterations in morphology, formation of DNA damage foci, activation of the ATM-p53-p21 pathway, and irreversible growth arrest. These observations suggest that DEB induces senescence and provide the first evidence for senescence induced by an environmental toxicant. As a component of cigarette smoke and as a hazardous air pollutant, DEB-induced senescence could contribute to the pathogenesis of lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and cancer, by inhibiting normal lung fibroblast function and repair.

Name thesis:degree_name

Molecular Biophysics Educational Track (Doctoral)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Microbiology and Immunology

Grantor

The University of Texas Medical Branch at Galveston

Author dc:creator

• Thomasson, Erica 1977-

Advisor dc:contributor.advisor

• Boldogh, Istvan

Committee members dc:contributor.committeemember

• Treinen Moslen, Mary
• Nichols, Joan E
• Ameredes, Bill T
• Kruzel, Marian L

• 1,3-butadiene
• senescence
• diepoxybutane
• stress-induced premature senescence

Handle dc:identifier.uri

http://hdl.handle.net/2152.3/784

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/784