Interaction between endoplasmic/sarcoplasmic reticulum stress (ER/SR stress), mitochondrial signaling and Ca(2+) regulation in airway smooth muscle (ASM)

Can J Physiol Pharmacol. 2015 Feb;93(2):97-110. doi: 10.1139/cjpp-2014-0361. Epub 2014 Nov 25.


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.

Keywords: ER/SR stress; airway; asthma; asthme; inflammation; réponse aux protéines dépliées; stress du RE/RS; unfolded protein response; voies respiratoires.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Asthma / metabolism
  • Asthma / pathology
  • Calcium / metabolism*
  • Cytokines / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Inflammation / metabolism
  • Lung / metabolism*
  • Lung / pathology
  • Mitochondria / metabolism*
  • Muscle, Smooth / metabolism*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction*
  • Unfolded Protein Response


  • Cytokines
  • Reactive Oxygen Species
  • Calcium