title: Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts.
abstract: Cell-cell signaling roles for reactive oxygen species (ROS) generated in response to growth factors/cytokines in nonphagocytic cells are not well defined. In this study, we show that fibroblasts isolated from lungs of patients with idiopathic pulmonary fibrosis (IPF) generate extracellular hydrogen peroxide (H2O2) in response to the multifunctional cytokine, transforming growth factor-beta1 (TGF-beta1). In contrast, TGF-beta1 stimulation of small airway epithelial cells (SAECs) does not result in detectable levels of extracellular H2O2. IPF fibroblasts independently stimulated with TGF-beta1 induce loss of viability and death of overlying SAECs when cocultured in a compartmentalized Transwell system. These effects on SAECs are inhibited by the addition of catalase to the coculture system or by the selective enzymatic blockade of H2O2 production by IPF fibroblasts. IPF fibroblasts heterogeneously express alpha-smooth muscle actin stress fibers, a marker of myofibroblast differentiation. Cellular localization of H2O2 by a fluorescent-labeling strategy demonstrated that extracellular secretion of H2O2 is specific to the myofibroblast phenotype. Thus, myofibroblast secretion of H2O2 functions as a diffusible death signal for lung epithelial cells. This novel mechanism for intercellular ROS signaling may be important in physiological/pathophysiological processes characterized by regenerating epithelial cells and activated myofibroblasts.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
authors.forename: Meghna
authors.initials: M
authors.lastname: Waghray
authors.forename: Zongbin
authors.initials: Z
authors.lastname: Cui
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Horowitz
authors.forename: Indhu M
authors.initials: IM
authors.lastname: Subramanian
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
mesh_terms: D002374:Catalase / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division; D002478:Cells, Cultured; D018920:Coculture Techniques; D004058:Diffusion; D004847:Epithelial Cells / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology*; D032342:Muscle Cells / Q000502:physiology; D018384:Oxidative Stress; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D006861:Hydrogen Peroxide; D002374:Catalase