Mechanisms underlying TNFα‐induced enhancement of force generation in airway smooth muscle
Abstract Airway diseases such as asthma are triggered by inflammation and mediated by proinflammatory cytokines such as tumor necrosis factor alpha (TNFα). Our goal was to systematically examine the potential mechanisms underlying the effect of TNFα on airway smooth muscle (ASM) contractility. Porci...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-09-01
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| Series: | Physiological Reports |
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| Online Access: | https://doi.org/10.14814/phy2.14220 |
| _version_ | 1828543318766649344 |
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| author | Gary C. Sieck Murat Dogan Han Young‐Soo Sara Osorio Valencia Philippe Delmotte |
| author_facet | Gary C. Sieck Murat Dogan Han Young‐Soo Sara Osorio Valencia Philippe Delmotte |
| author_sort | Gary C. Sieck |
| collection | DOAJ |
| description | Abstract Airway diseases such as asthma are triggered by inflammation and mediated by proinflammatory cytokines such as tumor necrosis factor alpha (TNFα). Our goal was to systematically examine the potential mechanisms underlying the effect of TNFα on airway smooth muscle (ASM) contractility. Porcine ASM strips were incubated for 24 h with and without TNFα. Exposure to TNFα increased maximum ASM force in response to acetylcholine (Ach), with an increase in ACh sensitivity (hyperreactivity), as reflected by a leftward shift in the dose–response curve (EC50). At the EC50, the [Ca2+]cyt response to ACh was similar between TNFα and control ASM, while force increased; thus, Ca2+ sensitivity appeared to increase. Exposure to TNFα increased the basal level of regulatory myosin light chain (rMLC) phosphorylation in ASM; however, the ACh‐dependent increase in rMLC phosphorylation was blunted by TNFα with no difference in the extent of rMLC phosphorylation at the EC50 ACh concentration. In TNFα‐treated ASM, total actin and myosin heavy chain concentrations increased. TNFα exposure also enhanced the ACh‐dependent polymerization of G‐ to F‐actin. The results of this study confirm TNFα‐induced hyperreactivity to ACh in porcine ASM. We conclude that the TNFα‐induced increase in ASM force, cannot be attributed to an enhanced [Ca2+]cyt response or to an increase in rMLC phosphorylation. Instead, TNFα increases Ca2+ sensitivity of ASM force generation due to increased contractile protein content (greater number of contractile units) and enhanced cytoskeletal remodeling (actin polymerization) resulting in increased tethering of contractile elements to the cortical cytoskeleton and force translation to the extracellular matrix. |
| first_indexed | 2024-12-12T02:10:53Z |
| format | Article |
| id | doaj.art-49ad9e7f20fe45f2989f7e4baa39b147 |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-12-12T02:10:53Z |
| publishDate | 2019-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-49ad9e7f20fe45f2989f7e4baa39b1472022-12-22T00:41:54ZengWileyPhysiological Reports2051-817X2019-09-01717n/an/a10.14814/phy2.14220Mechanisms underlying TNFα‐induced enhancement of force generation in airway smooth muscleGary C. Sieck0Murat Dogan1Han Young‐Soo2Sara Osorio Valencia3Philippe Delmotte4Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MinnesotaDepartment of Physiology and Biomedical Engineering Mayo Clinic Rochester MinnesotaDepartment of Physiology and Biomedical Engineering Mayo Clinic Rochester MinnesotaDepartment of Physiology and Biomedical Engineering Mayo Clinic Rochester MinnesotaDepartment of Physiology and Biomedical Engineering Mayo Clinic Rochester MinnesotaAbstract Airway diseases such as asthma are triggered by inflammation and mediated by proinflammatory cytokines such as tumor necrosis factor alpha (TNFα). Our goal was to systematically examine the potential mechanisms underlying the effect of TNFα on airway smooth muscle (ASM) contractility. Porcine ASM strips were incubated for 24 h with and without TNFα. Exposure to TNFα increased maximum ASM force in response to acetylcholine (Ach), with an increase in ACh sensitivity (hyperreactivity), as reflected by a leftward shift in the dose–response curve (EC50). At the EC50, the [Ca2+]cyt response to ACh was similar between TNFα and control ASM, while force increased; thus, Ca2+ sensitivity appeared to increase. Exposure to TNFα increased the basal level of regulatory myosin light chain (rMLC) phosphorylation in ASM; however, the ACh‐dependent increase in rMLC phosphorylation was blunted by TNFα with no difference in the extent of rMLC phosphorylation at the EC50 ACh concentration. In TNFα‐treated ASM, total actin and myosin heavy chain concentrations increased. TNFα exposure also enhanced the ACh‐dependent polymerization of G‐ to F‐actin. The results of this study confirm TNFα‐induced hyperreactivity to ACh in porcine ASM. We conclude that the TNFα‐induced increase in ASM force, cannot be attributed to an enhanced [Ca2+]cyt response or to an increase in rMLC phosphorylation. Instead, TNFα increases Ca2+ sensitivity of ASM force generation due to increased contractile protein content (greater number of contractile units) and enhanced cytoskeletal remodeling (actin polymerization) resulting in increased tethering of contractile elements to the cortical cytoskeleton and force translation to the extracellular matrix.https://doi.org/10.14814/phy2.14220Actin polymerizationinflammationmyosin heavy chainmyosin light chain phosphorylation |
| spellingShingle | Gary C. Sieck Murat Dogan Han Young‐Soo Sara Osorio Valencia Philippe Delmotte Mechanisms underlying TNFα‐induced enhancement of force generation in airway smooth muscle Physiological Reports Actin polymerization inflammation myosin heavy chain myosin light chain phosphorylation |
| title | Mechanisms underlying TNFα‐induced enhancement of force generation in airway smooth muscle |
| title_full | Mechanisms underlying TNFα‐induced enhancement of force generation in airway smooth muscle |
| title_fullStr | Mechanisms underlying TNFα‐induced enhancement of force generation in airway smooth muscle |
| title_full_unstemmed | Mechanisms underlying TNFα‐induced enhancement of force generation in airway smooth muscle |
| title_short | Mechanisms underlying TNFα‐induced enhancement of force generation in airway smooth muscle |
| title_sort | mechanisms underlying tnfα induced enhancement of force generation in airway smooth muscle |
| topic | Actin polymerization inflammation myosin heavy chain myosin light chain phosphorylation |
| url | https://doi.org/10.14814/phy2.14220 |
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