Telomerase deficiency does not alter bleomycin-induced fibrosis in mice

Exp Lung Res. 2012 Apr;38(3):124-34. doi: 10.3109/01902148.2012.658148.

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by interstitial lung infiltrates, dyspnea, and progressive respiratory failure. Reports linking telomerase mutations to familial interstitial pneumonia (FIP) suggest that telomerase activity and telomere length maintenance are important in disease pathogenesis. To investigate the role of telomerase in lung fibrotic remodeling, intratracheal bleomycin was administered to mice deficient in telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) and to wild-type controls. TERT-deficient and TERC-deficient mice were interbred to the F6 and F4 generation, respectively, when they developed skin manifestations and infertility. Fibrosis was scored using a semiquantitative scale and total lung collagen was measured using a hydroxyprolinemicroplate assay. Telomere lengths were measured in peripheral blood leukocytes and isolated type II alveolar epithelial cells (AECs). Telomerase activity in type II AECs was measured using a real-time polymerase chain reaction (PCR)-based system. Following bleomycin, TERT-deficient and TERC-deficient mice developed an equivalent inflammatory response and similar lung fibrosis (by scoring of lung sections and total lung collagen content) compared to controls, a pattern seen in both early (F1) and later (F6 TERT and F4 TERC) generations. Telomere lengths were reduced in peripheral blood leukocytes and isolated type II AECs from F6 TERT-deficient and F4 TERC-deficient mice compared to controls. Telomerase deficiency in a murine model leads to telomere shortening, but does not predispose to enhanced bleomycin-induced lung fibrosis. Additional genetic or environmental factors may be necessary for development of fibrosis in the presence of telomerase deficiency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Airway Remodeling / drug effects
  • Airway Remodeling / genetics
  • Animals
  • Antibiotics, Antineoplastic / toxicity
  • Bleomycin / toxicity*
  • Collagen / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Female
  • Idiopathic Pulmonary Fibrosis / chemically induced*
  • Idiopathic Pulmonary Fibrosis / enzymology*
  • Idiopathic Pulmonary Fibrosis / genetics
  • Leukocytes / drug effects
  • Leukocytes / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Pneumonia / chemically induced
  • Pneumonia / genetics
  • Pneumonia / metabolism
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / metabolism
  • RNA / genetics
  • Telomerase / deficiency*
  • Telomerase / genetics
  • Telomerase / metabolism
  • Telomere Homeostasis / drug effects*
  • Telomere Homeostasis / genetics
  • Telomere Shortening / drug effects
  • Telomere Shortening / genetics

Substances

  • Antibiotics, Antineoplastic
  • telomerase RNA
  • Bleomycin
  • RNA
  • Collagen
  • Telomerase