Interaction between endoplasmic/sarcoplasmic reticulum stress (ER/SR stress), mitochondrial signaling and Ca²⁺ 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 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 TNFα and IL-13, the transient increase in [Ca2+]mito is blunted despite enhanced [Ca2+]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 Ca2+ buffering, mitochondrial fragmentation, and increased cell proliferation.

1α,25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells

“…To assess the extent of filamentous versus fragmented morphometry, the form factor (an index of mitochondrial branching) and aspect ratio (an index of mitochondrial branch length) were calculated for each cell using a custom-written MATLAB (The MathWorks)-based program (36,37). A decrease in aspect ratio and/or form factor indicates mitochondrial fragmentation (33)(34)(35)(36)(37).…”

Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease

“…269026, containing 35 endotoxin units/mg, normalized to protein content; GREER, Lenoir, NC) extract suspended in PBS through intranasal administration on day 1 and boosted again on day 8. Mice were then administered 25 g of HDM consecutively on days [15][16][17][18][19] 1A, 5A, and 9A). Another set of mice received two additional doses of HDM on days 25 and 27 (see Fig.…”

“…In turn, ER stress activates the unfolded protein response, resulting in the activation of downstream signaling pathways to restore ER homeostasis (10,11). Furthermore, ER stress plays a critical role in several inflammatory disease conditions, including airway inflammation, chronic airway disorders, and remodeling (9,15,25,33,34,51).…”

Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma

“…Its signaling promotes the differentiation of goblet cells. IL-13 severely impairs mucus transport by airway epithelial cells (Tyner et al, 2006, Yan et al, 2014, Bonser et al, 2016)and induces ROS formation and ER stress in airway smooth muscle (Delmotte and Sieck, 2015). Consistent with previous results showing an increase in IL-13 in the lungs of mice exposed to OVA, we found that Lyn and 4-PBA suppressed IL-13 in mice exposed to OVA (Fig.…”