Interaction between endoplasmic/sarcoplasmic reticulum stress (ER/SR stress), mitochondrial signaling and Ca2+ regulation in airway smooth muscle (ASM)

Airway inflammation is a key aspect of diseases such as asthma. Several inflammatory cytokines (e.g., TNF alpha and IL-13) increase cytosolic Ca2+ ([Ca2+](cyt)) responses to agonist stimulation and Ca2+ 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 [Ca2+](cyt) induced by agonists leads to a transient increase in mitochondrial Ca2+ ([Ca2+](mito)) that may be important in matching ATP production with ATP consumption. In human ASM (hASM) exposed to TNF alpha and IL-13, the transient increase in [Ca2+](mito) is blunted despite enhanced [Ca2+](cyt) responses. We also found that TNF alpha 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 TNF alpha and IL-13 result in ROS formation leading to ER/SR stress, reduced Mfn2 expression, disruption of mitochondrion-ER/SR coupling, decreased mitochondrial Ca2+ buffering, mitochondrial fragmentation, and increased cell proliferation.