TNFα enhances force generation in airway smooth muscle

Doğan, Murat; Han, Young‐Soo; Delmotte, Philippe; Sieck, Gary C.

doi:10.1152/ajplung.00550.2016

Cited by 29 publications

(54 citation statements)

References 65 publications

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“…However, hASM sensitivity to muscarinic stimulation is also increased after TNFα, which largely accounts for the enhanced [Ca 2+ ] cyt response, but not the force response (Sieck et al, 2019). In recent studies, we found that the increase in ASM force induced by 24-h TNFα exposure is due to an increase in contractile protein expression (Dogan et al, 2017;Sieck et al, 2019). Importantly, the increase in hASM force generation induced by TNFα exposure is associated with an increase in ATP consumption and tension cost (Dogan et al, 2017).…”

Section: Cytokine Exposure Increases Hasm Force Atp Consumption and mentioning

confidence: 81%

“…In previous studies, we showed that 24-h exposure of hASM cells to TNFα increases both [Ca 2+ ] cyt and force responses to 1 µM muscarinic (ACh) stimulation (White et al, 2006;Sathish et al, 2009Sathish et al, , 2011Delmotte et al, 2012;Jia et al, 2013;Delmotte and Sieck, 2015;Dogan et al, 2017;Sieck et al, 2019). However, hASM sensitivity to muscarinic stimulation is also increased after TNFα, which largely accounts for the enhanced [Ca 2+ ] cyt response, but not the force response (Sieck et al, 2019).…”

Section: Cytokine Exposure Increases Hasm Force Atp Consumption and mentioning

confidence: 94%

“…Mitochondrial Ca 2+ influx via the MCU (Baughman et al, 2011;De Stefani et al, 2011) is only activated by microdomains of higher [Ca 2+ ] cyt ("hotspots" > 2 µM) (Gunter et al, 2000;Gunter and Gunter, 2001;Rizzuto and Pozzan, 2006;Gunter and Sheu, 2009;Rizzuto et al, 2009;Giacomello et al, 2010), which exceed the normal global transient [Ca 2+ ] cyt response to agonist stimulation in hASM (∼500-600 nM) (Pabelick et al, 1999;Sieck et al, 2008;Sathish et al, 2009Sathish et al, , 2011Delmotte et al, 2012). Higher levels of [Ca 2+ ] cyt do occur after 24-h TNFα exposure in response to muscarinic stimulation (Delmotte et al, 2012;Delmotte and Sieck, 2015;Dogan et al, 2017;Sieck et al, 2019), but are still well below levels required to activate the MCU (Gunter et al, 2000;Gunter and Gunter, 2001;Rizzuto and Pozzan, 2006;Gunter and Sheu, 2009;Rizzuto et al, 2009;Giacomello et al, 2010). However, much higher levels of [Ca 2+ ] cyt ("hotspots") are observed in regions in close proximity to the ER Ca 2+ efflux channels (IP 3 and RyR).…”

Section: Role Of Mfn2 In Tethering Mitochondria To Ermentioning

confidence: 99%

“…function, there's a considerable need for new tools allowing to studies these mechanisms within single mitochondrion in live cells and tissues. A few imaging and/or molecular tools to measure mitochondrial membrane potential m , succinate dehydrogenase (SDH) activity (Sieck et al, 1986(Sieck et al, , 1989(Sieck et al, , 1995(Sieck et al, , 1996, ATP consumption (Jones et al, 1999a,b;Dogan et al, 2017), ATP/ADP (Berg et al, 2009), and NAD/NADH ratio (Hung et al, 2011;Cohen et al, 2018) have been developed for use in live cells or tissue but have never been used in hASM.…”

Section: Excitation-energy Coupling Via Mitochondrial Ca 2+ Influxmentioning

confidence: 99%

“…An emergent theme in this context is the role of inflammation-induced endoplasmic reticulum (ER) stress and mitochondria. Previously, we showed that cytokine exposure increases agonist-induced hASM force and ATP consumption due to an increase in contractile protein expression (Dogan et al, 2017). Initially, the increase in hASM ATP demand is met by increased mitochondrial O 2 consumption and ATP production, but at the expense of reactive oxygen species (ROS) formation and oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic Reticulum Stress and Mitochondrial Function in Airway Smooth Muscle

Delmotte

Sieck

2020

Front. Cell Dev. Biol.

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Inflammatory airway diseases such as asthma affect more than 300 million people worldwide. Inflammation triggers pathophysiology via such as tumor necrosis factor α (TNFα) and interleukins (e.g., IL-13). Hypercontraction of airway smooth muscle (ASM) and ASM cell proliferation are major contributors to the exaggerated airway narrowing that occurs during agonist stimulation. An emergent theme in this context is the role of inflammationinduced endoplasmic reticulum (ER) stress and altered mitochondrial function including an increase in the formation of reactive oxygen species (ROS). This may establish a vicious cycle as excess ROS generation leads to further ER stress. Yet, it is unclear whether inflammation-induced ROS is the major mechanism leading to ER stress or the consequence of ER stress. In various diseases, inflammation leads to an increase in mitochondrial fission (fragmentation), associated with reduced levels of mitochondrial fusion proteins, such as mitofusin 2 (Mfn2). Mitochondrial fragmentation may be a homeostatic response since it is generally coupled with mitochondrial biogenesis and mitochondrial volume density thereby reducing demand on individual mitochondrion. ER stress is triggered by the accumulation of unfolded proteins, which induces a homeostatic response to alter protein balance via effects on protein synthesis and degradation. In addition, the ER stress response promotes protein folding via increased expression of molecular chaperone proteins. Reduced Mfn2 and altered mitochondrial dynamics may not only be downstream to ER stress but also upstream such that a reduction in Mfn2 triggers further ER stress. In this review, we summarize the current understanding of the link between inflammation-induced ER stress and mitochondrial function and the role played in the pathophysiology of inflammatory airway diseases.

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