Journal
ANNALS OF THE AMERICAN THORACIC SOCIETY
Volume 13, Issue -, Pages S447-S451Publisher
AMER THORACIC SOC
DOI: 10.1513/AnnalsATS.201609-718AW
Keywords
aging; alpha-1 antitrypsin deficiency; senescence; idiopathic pulmonary fibrosis; hepatopulmonary syndrome
Categories
Funding
- National Institutes of Health [RO1 CA160433, RO1 HL119476, T32 HL007534]
- Commonwealth Foundation
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In the past five decades, alpha-1 antitrypsin deficiency has been the only known genetic cause of emphysema, yet it explains the genetics in only 1-2% of severe cases. Recently, mutations in telomerase genes were found to induce susceptibility to young-onset, severe, and familial emphysema at a frequency comparable to that of alpha-1 antitrypsin deficiency. Telomerase mutation carriers with emphysema report a family history of idiopathic pulmonary fibrosis, and both lung phenotypes show autosomal dominant inheritance within families. The data so far point to a strong gene-environment interaction that determines the lung disease type. In never-smokers, pulmonary fibrosis predominates, while smokers, especially females, are at risk for developing emphysema alone or in combination with pulmonary fibrosis. The telomere-mediated emphysema phenotype appears to have clinically recognizable features that are distinct from alpha-1 antitrypsin deficiency, and patients are prone to developing short telomere syndrome comorbidities that influence clinical outcomes. In animal models, telomere dysfunction causes alveolar epithelial stem cell senescence, which is sufficient to drive lung remodeling and recruit inflammation. Here, we review the implications of these discoveries for understanding emphysema biology as well as for patient care.
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