Thy-1 interaction with Fas in lipid rafts regulates fibroblast apoptosis and lung injury resolution.
Thy-1-negative lung fibroblasts are resistant to apoptosis. The mechanisms governing this process and its relevance to fibrotic remodeling remain poorly understood. By using either sorted or transfected lung fibroblasts, we found that Thy-1 expression is associated with downregulation of anti-apoptotic molecules Bcl-2 and Bcl-xL, as well as increased levels of cleaved caspase-9. Addition of rhFasL and staurosporine, well-known apoptosis inducers, caused significantly increased cleaved caspase-3, -8, and PARP in Thy-1-transfected cells. Furthermore, rhFasL induced Fas translocation into lipid rafts and its colocalization with Thy-1. These in vitro results indicate that Thy-1, in a manner dependent upon its glycophosphatidylinositol anchor and lipid raft localization, regulates apoptosis in lung fibroblasts via Fas-, Bcl-, and caspase-dependent pathways. In vivo, Thy-1 deficient (Thy1-/-) mice displayed persistence of myofibroblasts in the resolution phase of bleomycin-induced fibrosis, associated with accumulation of collagen and failure of lung fibrosis resolution. Apoptosis of myofibroblasts is decreased in Thy1-/-mice in the resolution phase. Collectively, these findings provide new evidence regarding the role and mechanisms of Thy-1 in initiating myofibroblast apoptosis that heralds the termination of the reparative response to bleomycin-induced lung injury. Understanding the mechanisms regulating fibroblast survival/apoptosis should lead to novel therapeutic interventions for lung fibrosis.
Respiratory Department, Second Hospital of Jilin University, Changchun, China.
Xiaoqiu
X
Liu
Division of Respiratory Medicine, Department of Pediatrics, University of California San Diego, San Diego, CA, USA.
Simon S
SS
Wong
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Carmen A
CA
Taype
Department of Pediatrics, Stanford University, Palo Alto, CA, USA.
Jeeyeon
J
Kim
Division of Respiratory Medicine, Department of Pediatrics, University of California San Diego, San Diego, CA, USA.
Tzu-Pin
TP
Shentu
Division of Respiratory Medicine, Department of Pediatrics, University of California San Diego, San Diego, CA, USA.
Celia R
CR
Espinoza
Department of Anesthesiology, UCSD, San Diego, CA, USA.
J Cameron
JC
Finley
Department of Microbiology, University of Alabama-Birmingham, Birmingham, AL, USA.
John E
JE
Bradley
Department of Anesthesiology, UCSD, San Diego, CA, USA.|VA San Diego Healthcare System, San Diego, CA, USA.
Brian P
BP
Head
Department of Anesthesiology, UCSD, San Diego, CA, USA.|VA San Diego Healthcare System, San Diego, CA, USA.
Hemal H
HH
Patel
Department of Chemical and Biochemical Engineering, University of California-Irvine, Irvine, CA, USA.
Emma J
EJ
Mah
Division of Respiratory Medicine, Department of Pediatrics, University of California San Diego, San Diego, CA, USA.|Division of Respiratory Medicine, Rady Children's Hospital of San Diego, San Diego, CA, USA.
James S
JS
Hagood
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001761:Bleomycin; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology; D053222:Fas Ligand Protein / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D015151:Immunoblotting; D055370:Lung Injury / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D021962:Membrane Microdomains / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D019311:Staurosporine / Q000494:pharmacology; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D018800:Thy-1 Antigens; D051020:bcl-X Protein; D019014:fas Receptor; D001761:Bleomycin; D053453:Caspase 9; D019311:Staurosporine