The identification of short telomeres as a prevalent defect in IPF has opened new possibilities for studying the biology of age-related lung disease in genetically relevant models, such as the telomerase knockout mouse. When lung phenotypes were examined in mice with short telomeres, no obvious gross phenotypes were found[54
]. However, when mice with short telomeres were chronically challenged with cigarette smoke exposure, they developed air space destruction that is characteristic of emphysema[54
]. The emphysema defect was intrinsic to the lung parenchyma and was associated with cumulative DNA damage in alveolar epithelial cells[54
]. Emphysema is characterized by alveolar destruction and, like IPF, age and cigarette smoke are the primary risk factors[55
]. Interestingly, observations in families with telomerase mutations indicate that emphysema may be a first manifestation of telomere-related lung disease in some telomerase mutation carriers[54
]. The emphysema in this setting can manifest alone, or concurrently with pulmonary fibrosis as a mixed pulmonary defect[54
]. In one study examining radiographs of telomerase mutation carriers with IPF, there was evidence of superimposed emphysema in 20% of cases[43
]. Therefore, short telomeres manifest as a heterogeneous group of age-related lung disorders, among them IPF is most common, but the spectrum may encompass some forms of emphysema which may manifest alone or as a combined interstitial lung disease-emphysema syndrome ().
Emphysema is the fourth most common cause of death in the United States. The observation that short telomere length is a susceptibility factor in emphysema is significant as its genetics are not completely understood. Although traditionally considered distinct entities, emphysematous changes are known to co-occur with pulmonary fibrosis in 10% of individuals who smoke cigarettes[56
]. In these individuals, emphysematous changes appear in the lung apex, while IPF in the basilar portions. The recent studies in animals with telomere dysfunction, along with clinical observations in telomerase mutation carriers, indicate that IPF and emphysema, in at least a subset, may represent regional responses to cumulative injury superimposed on a short telomere genetic background[54
]. The study of regional effectors that determine whether emphysema or fibrosis is the predominant lung phenotype have the potential to yield a better understanding of the biology of these age-related disorders. There is therefore an intimate connection between telomere dysfunction and the genetics of several common, age-related lung disorders.
The studies in mice with short telomeres suggest that the short telomere defect alone is not sufficient to cause lung disease. Instead, short telomeres lower the threshold to cumulative damage that occurs with age[54
]. Similar to the multi-step progression for carcinogenesis, age-related lung disease may be the end result of multiple “hits” that occur with aging. In such a model, short telomeres, as genetically determined, would represent a first hit. With age, additional injuries accumulate and ultimately provoke what appears to be irreversible lung damage. The requirement for additional hits may explain why mutant telomerase genes in IPF patients manifest late in life where the average age of onset is in the sixth decade[26
]. Indeed, symptomatic pulmonary disease in the setting of telomerase mutations is rare prior to the third decade, except when precipitated by toxic drugs in the setting of bone marrow transplant. Cigarette smoke exposure is a highly relevant example of an environmental second hit[54
]. Based on the fact that telomere dysfunction causes progressive irreversible stem cell failure in the hematopoietic system, we have previously proposed that telomere dysfunction may cause an irreversible stem cell failure in alveolar epithelial cells[37
], a putative site of injury in IPF and emphysema. A better understanding of the regenerative mechanisms of alveolar epithelial cells can advance current paradigms for understanding the biology of telomere-mediated lung disease.