| Autor: |
Puthusseri B; The University of Texas Health Science Center at Tyler, Tyler, Texas, United States., Bhagavath AK; The University of Texas Health Science Center at Tyler, Tyler, Texas, United States., Korir D; The University of Texas Health Science Center at Tyler, Tyler, Texas, United States., Shetty R; The University of Texas Health Science Center at Tyler, Tyler, Texas, United States., Johnson GA; University of North Texas Health Science Center, Fort Worth, Texas, United States., Stankowska DL; University of North Texas Health Science Center, Fort Worth, Texas, United States., Konduru NV; The University of Texas Health Science Center at Tyler, Tyler, Texas, United States., Tang H; The University of Texas Health Science Center at Tyler, Tyler, Texas, United States., Bolla S; Temple University, Thoracic Medicine and Surgery, Philadelphia, Pennsylvania, United States., Criner GJ; Temple University Hospital, Pulm & Crit Care Medicine, Philadelphia, Pennsylvania, United States.; Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, United States., Marchetti N; Temple University School of Medicine, Pulmonary and Critical Care Medicine, Philadelphia, Pennsylvania, United States., Das DN; The University of Texas Health Science Center at Tyler, Tyler, Texas, United States., Shetty S; The University of Texas Health Center at Tyler, Department of Specialty Care Services, Tyler, Texas, United States; sreerama.shetty@uthct.edu. |
| Abstrakt: |
Impaired alveolar epithelial regeneration in patients with idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) is attributed to telomere dysfunction in type II alveolar epithelial cells (A 2 Cs). Genetic susceptibility, aging, and toxicant exposures, including tobacco smoke (TS), contribute to telomere dysfunction in A 2 Cs. Here we investigated whether improvement of telomere function plays a role in CSP7-mediated protection of A 2 Cs against ongoing senescence and apoptosis during bleomycin (BLM)-induced pulmonary fibrosis (PF) as well as alveolar injury caused by chronic TS exposure. We found a significant telomere shortening in A 2 Cs isolated from IPF and COPD lungs in line with other studies. These cells showed increased p53 in addition to its post-translational modification with induction of activated caspase-3 and β-galactosidase , suggesting a p53 -mediated loss of A 2 C renewal. Further, we found increased expression of SIAH-1 , a p53 -inducible E3 ubiquitin ligase known to down-regulate telomere repeats binding factor 2 ( TRF2 ). Consistent with the loss of TRF2 and upregulation of TRF1 , telomerase reverse transcriptase ( TERT ) was downregulated in A 2 Cs. A 2 Cs from fibrotic lungs of mice either repeatedly instilled with BLM or isolated from chronic TS exposure-induced lung injury model showed reduced telomere length along with induction of p53 , PAI-1 , SIAH1 and TRF1 as well as loss of TRF2 and TERT , which were reversed in wild-type mice after treatment with CSP7. Interestingly, PAI-1 -/- mice, or those lacking microRNA-34a expression in A 2 Cs, resisted telomere dysfunction, while uPA -/- mice failed to respond to CSP7 treatment, suggesting p53-microRNA-34a feed-forward induction and p53-uPA pathway contributes to telomere dysfunction. |
