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Mechanisms underlying TNF?-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 (TNF?). Our goal was to systematically examine the potential mechanisms underlying the effect of TNF? on airway smooth muscle (ASM) contractility. Porcine ASM strips were incubated for 24 h with and without TNF?. Exposure to TNF? 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 TNF? and control ASM, while force increased; thus, Ca2+ sensitivity appeared to increase. Exposure to TNF? increased the basal level of regulatory myosin light chain (rMLC) phosphorylation in ASM; however, the ACh-dependent increase in rMLC phosphorylation was blunted by TNF? with no difference in the extent of rMLC phosphorylation at the EC50 ACh concentration. In TNF?-treated ASM, total actin and myosin heavy chain concentrations increased. TNF? exposure also enhanced the ACh-dependent polymerization of G- to F-actin. The results of this study confirm TNF?-induced hyperreactivity to ACh in porcine ASM. We conclude that the TNF?-induced increase in ASM force, cannot be attributed to an enhanced [Ca2+ ]cyt response or to an increase in rMLC phosphorylation. Instead, TNF? 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.

SUBMITTER: Sieck GC

PROVIDER: S-EPMC6739507 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Mechanisms underlying TNFα-induced enhancement of force generation in airway smooth muscle.

Sieck Gary C GC Dogan Murat M Young-Soo Han H Osorio Valencia Sara S Delmotte Philippe P

Physiological reports 20190901 17

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 ...[more]

PMID: 31512410

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Project description:BACKGROUND AND PURPOSE: ??-Adrenoceptor agonists are important therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease. The regular use of these drugs has been associated with proasthmatic-like changes that limit their efficacy and increase the risk of severe adverse reactions. We investigated whether the peroxisome-proliferator-activated receptor (PPAR)? agonist rosiglitazone modulated salbutamol-induced ??-adrenoceptor desensitization in vivo and in vitro. EXPERIMENTAL APPROACH: An in vivo model of homologous ??-adrenoceptor desensitization, established in guinea-pigs by administering salbutamol continuously, was used to study the ability of rosiglitazone to prevent ??-adrenoceptor tolerance. In vitro experiments on human bronchial smooth muscle cells were performed to increase the clinical relevance of the study. KEY RESULTS: In tracheal smooth muscle tissues from desensitized animals, we observed a decrease in the protective effect of salbutamol on carbachol-induced contraction, a hyperresponsiveness to cholinergic stimuli, a modest underexpression of ??-adrenoceptor gene and a marked decrease in ?-adrenoceptor number, relative to control values. Treatment with rosiglitazone preserved salbutamol relaxant activity, mitigated carbachol hyperresponsiveness and partially restored ??-adrenoceptor binding sites in tracheal tissues from homologously desensitized animals. The highly selective PPAR? agonist, GW1929, reproduced the effect of rosiglitazone, in vivo. In vitro ??-adrenoceptor desensitization decreased salbutamol-mediated cAMP production, without affecting forskolin responses and ??-adrenoceptor expression. Rosiglitazone and 15-deoxy-?¹²(,)¹?-prostaglandin J? restored salbutamol sensitivity in homologously desensitized cells. CONCLUSIONS AND IMPLICATIONS: These data suggest a potential pharmacodynamic interaction between PPAR? agonists and salbutamol on airway smooth muscle responsiveness, supporting the therapeutic potential of this combination in chronic airway disease.

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Mechanisms underlying TNF?-induced enhancement of force generation in airway smooth muscle.

Publications

Mechanisms underlying TNFα-induced enhancement of force generation in airway smooth muscle.

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