title: Antiapoptotic effect of found in inflammatory zone (FIZZ)1 on mouse lung fibroblasts.
abstract: Myofibroblasts play an essential role in the abnormal deposition of extracellular matrix in pulmonary fibrosis. The presence or prolonged survival of these cells may be a key factor in the pathogenesis of progressive pulmonary fibrosis. Found in inflammatory zone (FIZZ)1 can induce myofibroblast differentiation and has an antiapoptotic effect on embryonic lung explant cultures. In this study, we investigated whether FIZZ1 also has an antiapoptotic effect on mouse lung fibroblasts (MLFs). Cells were treated with FIZZ1 for 24 h and then apoptosis was induced by TNFalpha in the presence of cycloheximide (CHX). FIZZ1 exhibited an antiapoptotic effect in MLFs, as assessed by flow cytometric analysis and TUNEL staining. Moreover, the cell number was higher in the FIZZ1-treated group relative to the non-treated control group after treatment with TNFalpha and CHX. FIZZ1 treatment also inhibited the apoptotic agent-induced activities of caspase-3 and caspase-8. Examination of potential signalling pathways revealed that FIZZ1 induced rapid phosphorylation of ERK-1/2, while PD98059, a MEK/ERK inhibitor, markedly induced activation of caspase-3. This anti-apoptotic effect of FIZZ1 was associated with induction of myofibroblast differentiation in response to FIZZ1 stimulation. Taken together, these findings suggest that FIZZ1 is involved in pulmonary fibrosis through both induction of myofibroblast differentiation and increased or prolonged survival of myofibroblasts. This effect of FIZZ1 was mediated by inhibition of caspase-3 and -8, with involvement of the ERK pathway.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Chung
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.forename: M
authors.initials: M
authors.lastname: Ullenbruch
authors.forename: S H
authors.initials: SH
authors.lastname: Phan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008808:Mice, Inbred CBA; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D011500:Protein Synthesis Inhibitors; D011506:Proteins; C413576:Retnla protein, mouse; D014409:Tumor Necrosis Factor-alpha; D020932:Nerve Growth Factor; D003513:Cycloheximide; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3; D053181:Caspase 8