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Mitochondrial Uncoupling Protein‐2 and Fibroblast Senescence in Age‐Related Lung Fibrosis
Author(s) -
Rangarajan Sunad,
Locy Morgan L,
Zmijewski Jaroslaw W,
Tuder Rubin M,
Eickelberg Oliver,
Thannickal Victor J
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.543.6
Subject(s) - idiopathic pulmonary fibrosis , senescence , fibroblast , pulmonary fibrosis , bleomycin , fibrosis , biology , myofibroblast , pathology , lung , cancer research , medicine , microbiology and biotechnology , in vitro , biochemistry , genetics , chemotherapy
Objective Our objective was to examine the role of mitochondrial uncoupling protein‐2 (UCP2), highly expressed in lung fibroblasts of patients with idiopathic pulmonary fibrosis (IPF), in mediating mitochondrial dysfunction, fibroblast senescence and myofibroblast differentiation in age‐related pathologic fibrosis. Methods We studied tissues and fibroblasts obtained from lung explants of IPF patients and utilized the murine model of lung fibrosis and resolution following bleomycin‐induced injury. We silenced UCP2 expression using siRNA in vitro and in vivo . Specific endpoints were analyzed by RT‐PCR, SDS‐PAGE western blotting, immunofluorescence, flow cytometry, mass spectrometry and extracellular flux analysis. Results UCP2 gene expression was increased in lungs (whole lung lysates as well as fibroblasts) of IPF patients compared to those without IPF; in particular, mesenchymal stromal cells derived from bronchoalveolar lavage of patients with rapidly progressive clinical course had higher UCP2 expression compared to those with a slower course. Human lung fibroblasts undergoing replicative senescence expressed high levels of UCP2. Lung fibroblasts from aged mice expressed higher UCP2 than younger counterparts, more pronounced after bleomycin‐induced lung injury. UCP2 silencing in IPF fibroblasts decreased pro‐fibrotic markers such as α‐SMA and collagen; this was associated with enhanced mitochondrial biogenesis, decreased mitochondrial ROS (superoxide and hydrogen peroxide), increased ATP‐linked oxygen consumption and decreased aerobic glycolysis. In addition, UCP2 silencing induced a decrease in senescence markers and decreased expression of senescence‐associated secretory phenotype (SASP) genes. In aged mice after bleomycin injury, therapeutic oro‐tracheal administration of UCP2 siRNA resulted in decreased lung collagen and fibrotic remodeling, indicating enhanced resolution capacity. Conclusion Our results suggest that expression of mitochondrial UCP2 in lung fibroblasts increases with age. UCP2 is highly expressed in lung fibroblasts of patients with IPF, more so in those with rapidly progressive clinical course; UCP2 promotes myofibroblast senescence and impairs resolution of bleomycin injury‐induced fibrosis in aged mice. Further studies are warranted to study the link between cellular aging and UCP2, and the therapeutic potential of targeting UCP2 in age‐related fibrotic disorders such as IPF. Support or Funding Information NIH grants K08 HL135399 (SR); P01 HL114470 and R01 AG046210 (VJT), VA Merit Award I01BX003056 (VJT)Schematic showing the role of UCP2 in fibroblast (patho)biologyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .