title: Interaction between endoplasmic/sarcoplasmic reticulum stress (ER/SR stress), mitochondrial signaling and Ca(2+) regulation in airway smooth muscle (ASM).
abstract: Airway inflammation is a key aspect of diseases such as asthma. Several inflammatory cytokines (e.g., TNFα and IL-13) increase cytosolic Ca(2+) ([Ca(2+)]cyt) responses to agonist stimulation and Ca(2+) sensitivity of force generation, thereby enhancing airway smooth muscle (ASM) contractility (hyper-reactive state). Inflammation also induces ASM proliferation and remodeling (synthetic state). In normal ASM, the transient elevation of [Ca(2+)]cyt induced by agonists leads to a transient increase in mitochondrial Ca(2+) ([Ca(2+)]mito) that may be important in matching ATP production with ATP consumption. In human ASM (hASM) exposed to TNFα and IL-13, the transient increase in [Ca(2+)]mito is blunted despite enhanced [Ca(2+)]cyt responses. We also found that TNFα and IL-13 induce reactive oxidant species (ROS) formation and endoplasmic/sarcoplasmic reticulum (ER/SR) stress (unfolded protein response) in hASM. ER/SR stress in hASM is associated with disruption of mitochondrial coupling with the ER/SR membrane, which relates to reduced mitofusin 2 (Mfn2) expression. Thus, in hASM it appears that TNFα and IL-13 result in ROS formation leading to ER/SR stress, reduced Mfn2 expression, disruption of mitochondrion-ER/SR coupling, decreased mitochondrial Ca(2+) buffering, mitochondrial fragmentation, and increased cell proliferation.
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, 4-184 West Joseph SMH, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delmotte
authors.forename: Gary C
authors.initials: GC
authors.lastname: Sieck
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response
chemical_list: D016207:Cytokines; D017382:Reactive Oxygen Species; D002118:Calcium
keywords: ER/SR stress; airway; asthma; asthme; inflammation; réponse aux protéines dépliées; stress du RE/RS; unfolded protein response; voies respiratoires