American Journal of Respiratory and Critical Care Medicine

Exciting new findings reported in this issue of the Journal (pp. 729–737) by Cronkhite and colleagues (1) add new insights to a tragic lung disease. A report in 1838 on “cirrhosis of the lung” described the condition as follows: “as contracting fibres … tend to draw in the tissue of the lung, obliterating its small air tubes and its blood vessels, the large bronchial tubes dilate … until at last the tissue of the lung, diminished to a very small size, presents but a dense fibro-cellular tissue” (2). It seems quite plausible that Dr. Corrigan was indeed describing the condition that we know today as idiopathic pulmonary fibrosis (IPF). Because effective therapy has remained elusive, one might contend that little progress in elucidating the pathogenesis of IPF has been made since that time, at least as it has impacted treatment.

Cronkhite and colleagues describe the unexpected and fascinating finding that telomeres are severely shortened in peripheral leukocytes in approximately one-quarter of sporadic and familial cases of pulmonary fibrosis (1). Interestingly, this research direction was originated by a junior investigator, studying a very rare disease, just a few years ago. Dr. Mary Armanios, then an oncology fellow, with her associates, meticulously described a family with dyskeratosis congenita (3) that was manifested by many clinical syndromes, all resulting from a mutation in telomerase reverse transcriptase (TERT). Death of the grandmother from IPF at age 65 suggested the possibility that similar mutations might be a cause of IPF in families. Armanios and colleagues' verified their hypothesis by demonstrating mutations in TERT, and in the RNA component of telomerase, in six families with IPF (4), and soon thereafter nearly identical findings were described by the authors of the current report in another seven families (5). In families with IPF with a genomic telomerase mutation as the basis, the parenchymal lung cells have a mutant telomerase, suggesting the possibility that cell demise or limited regenerative capacity, or both, may be a central feature that may initiate the disease process.

The histopathologic pattern associated with clinical IPF is termed “usual interstitial pneumonia” (UIP). Although this histopathologic pattern is seen in a number of clinical contexts of chronic lung injury (e.g., inhaled inorganic/organic dust particles, drug toxicities, connective tissue diseases), in the absence of an associated systemic disease process or specific etiologic agent the term “idiopathic UIP,” or IPF, is used. The striking loss of cellular homeostasis in IPF is notable for the increase in the number of mesenchymal cells, including clusters of myofibroblasts within the architecturally remodeled alveoli of the UIP lung.

What is the genesis of altered cellular homeostasis in IPF? Might this represent an age-related disorder of impaired regeneration in the genetically or epigenetically susceptible host? The report by Cronkhite and colleagues, together with existing clinico-epidemiologic data, lends support to this general notion. IPF is primarily a disease of the elderly, with a remarkable increase in incidence and prevalence beyond the fifth decade of life (6). Tissue regenerative mechanisms that maintain cellular homeostasis in multicellular metazoans, and humans in particular, classically involve the activation of tissue-resident stem/progenitor cells that proliferate and differentiate to replace damaged/apoptotic cells in adult tissues. In the lung, the alveolar epithelial lining composed primarily of flattened, differentiated alveolar type 1 (AT1) cells comprise more than 95% of the alveolar surface area and are replenished by its tissue- and lineage-specific progenitors, the alveolar type 2 (AT2) cells. Lung-resident mesenchymal stem/progenitor cells (MSCs) have only recently been identified, both in adult lung of humans (7) and mice (8, 9). As is true for adult tissue-resident stem/progenitor cells (but not differentiated somatic cells), both AT2 cells (10) and MSCs (9) express telomerase, an enzyme critical for maintenance of telomere length in adult stem cells.

Telomere shortening is associated with reduced capacity for stem cell renewal, cellular senescence, and organism aging (11). One might predict that telomere shortening in AT2 cells would diminish regenerative capacity of the alveolar epithelium. The study by Cronkhite and colleagues did not directly examine AT2 cells of patients with IPF; however, a correlation of telomere lengths between peripheral leukocytes and oral buccal epithelial cells in individual patients with IPF with a specific TERT mutation suggested a germline defect. It is quite possible that the “short telomere phenotype” would have been found in an even greater proportion of patients with IPF if AT2 cells had been sampled directly. Local profibrotic factors that are known to directly contribute to telomere shortening include transforming growth factor-β1, which suppresses telomerase expression (12), and chronic oxidative stress, which mediates telomere attrition (13). Another possibility is that the short telomere–expressing leukocytes themselves participate in disease pathogenesis by as yet undefined mechanisms. Interestingly, telomerase-expressing bone marrow cells promote, rather than protect against, fibrogenesis in an animal model (14).

Another intriguing question that the study raises is why the same host and environmental factors that presumably suppress the regenerative capacity of epithelial stem cells do not affect the mesenchymal response. This may be explained by the observation that telomere length and telomerase activity in stem/progenitor cells may be cell specific and autonomous (15). In fact, it is likely that cells within even the same stem cell compartment may be influenced to varying degrees by the cumulative, stochastic events that influence telomere length and resultant regenerative capacity (Figure 1). This may also provide a plausible explanation for the observed spatial–temporal heterogeneity in UIP. Further studies are required to define telomerase-expressing cells in the lungs of patients with IPF as well as telomere (dys)function in different stem cell compartments and their resultant cellular phenotypes. Such studies will aid in defining whether IPF represents a disorder of stem cell senescence and impaired lung regeneration.

1. Cronkhite JT, Xing C, Raghu G, Chin KM, Torres F, Rosenblatt RL, Garcia CK. Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med 2008;178:729–737.
2. Corrigan DJ. On cirrhosis of the lung. Dublin J Med Sci 1838;13:266–286.
3. Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci USA 2005;102:15960–15964.
4. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA III, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 2007;356:1317–1326.
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12. Li H, Xu D, Li J, Berndt MC, Liu JP. Transforming growth factor beta suppresses human telomerase reverse transcriptase (hTRET) by Smad3 interactions with c-Myc and the hTERT gene. J Biol Chem 2006;281:25588–25600.
13. Proctor CJ, Kirkwood TB. Modelling telomere shortening and the role of oxidative stress. Mech Ageing Dev 2002;123:351–363.
14. Liu T, Chung MJ, Ullenbruch M, Yu H, Jin H, Hu B, Choi YY, Ishikawa F, Phan SH. Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice. J Clin Invest 2007;117:3800–3809.
15. Samper E, Fernandez P, Eguia R, Martin-Rivera L, Bernad A, Blasco MA, Aracil M. Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells. Blood 2002;99:2767–2775.


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