Journal Article

Telomere Length Is a Determinant of Emphysema Susceptibility

Mitzner, Wayne, Anderson, Collin J., Armanios, Mary, Parry, Erin M., Tuder, Rubin M., Biswal, Shyam, Sussan, Thomas, Gorgy, Amany I., Kembou, Frant, Walsh, Michael F., Alder, Jonathan K., Guo, Nini

2011

Overview

Germline mutations in the enzyme telomerase cause telomere shortening, and have their most common clinical manifestation in age-related lung disease that manifests as idiopathic pulmonary fibrosis. Short telomeres are also a unique heritable trait that is acquired with age. We sought to understand the mechanisms by which telomerase deficiency contributes to lung disease. We studied telomerase null mice with short telomeres. Although they have no baseline histologic defects, when mice with short telomeres are exposed to chronic cigarette smoke, in contrast with controls, they develop emphysematous air space enlargement. The emphysema susceptibility did not depend on circulating cell genotype, because mice with short telomeres developed emphysema even when transplanted with wild-type bone marrow. In lung epithelium, cigarette smoke exposure caused additive DNA damage to telomere dysfunction, which limited their proliferative recovery, and coincided with a failure to down-regulate p21, a mediator of cellular senescence, and we show here, a determinant of alveolar epithelial cell cycle progression. We also report early onset of emphysema, in addition to pulmonary fibrosis, in a family with a germline deletion in the Box H domain of the RNA component of telomerase. Our data indicate that short telomeres lower the threshold of cigarette smoke-induced damage, and implicate telomere length as a genetic susceptibility factor in emphysema, potentially contributing to its age-related onset in humans.

• Publisher: American Thoracic Society
• Subject: Age / Age Factors / Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Animals / Biological and medical sciences / Bone marrow / Bone Marrow Transplantation / Cell cycle / Cell division / Cigarettes / Cyclin-dependent kinases / Defects / DNA Damage / Emphysema / Female / Fluorescent Antibody Technique / Genetic Predisposition to Disease / Idiopathic Pulmonary Fibrosis - enzymology / Idiopathic Pulmonary Fibrosis - genetics / Intensive care medicine / Kinases / Lung diseases / Lungs / Male / Medical sciences / Mice / Mice, Inbred C57BL / Miscellaneous / Mutation / Nicotiana - adverse effects / Pulmonary Emphysema - chemically induced / Pulmonary Emphysema - enzymology / Pulmonary Emphysema - genetics / Pulmonary Emphysema - surgery / Pulmonary fibrosis / Real-Time Polymerase Chain Reaction / Respiratory Function Tests / Reverse Transcriptase Polymerase Chain Reaction / Senescence / Smoke - adverse effects / Telomerase / Telomerase - deficiency / Telomerase - genetics / Telomere - chemistry / Yeast