Mechanism of cytokine-induced modulation of beta-adrenoceptor responsiveness in airway smooth muscle.

Hákonarson, Hákon; Herrick, David; Serrano, P G; Grunstein, Michael

doi:10.1172/jci118708

Cited by 128 publications

(134 citation statements)

References 45 publications

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“…Previously, we have shown that TNFR1 is expressed on ASM cells (1,4,9) and mediates the potentiating effect of TNF-␣ on GPCR-coupled calcium signaling in human cultured ASM cells (8,40). Interestingly, we also show that PTX, a G i ␣ inhibitor (but not CTX, an activator of G s ) prevented the modulatory effects of TNF-␣ on both cholinergic and ␤-adrenergic responsiveness in agreement with previous observations showing the involvement of a PTX-sensitive pathway in the modulation of ASM responsiveness induced either by cytokines (23,60) or by asthmatic serum (21). The mechanisms by which PTX abrogates cytokine effects on GPCR responsiveness remain unknown.…”

supporting

confidence: 92%

Selected Contribution: TNF-α modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl

Chen

Tliba

Besien

et al. 2003

Journal of Applied Physiology

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Although the mechanisms that underlie airway hyperresponsiveness in asthma are complex and involve a variety of factors, evidence now suggests that intrinsic abnormalities in airway smooth muscle (ASM) may play an important role. We previously reported that TNF-α, a cytokine involved in asthma, augments G-protein-coupled receptor (GPCR) agonist-evoked calcium responses in cultured ASM cells. Here we have extended our previous studies by investigating whether TNF-α also modulates the contractile and relaxant responses to GPCR activation using cultured murine tracheal rings. We found that in tracheal rings treated with 50 ng/ml TNF-α, carbachol-induced isometric force was significantly increased by 30% compared with those treated with diluent alone ( P < 0.05). TNF-α also augmented KCl-induced force generation by 70% compared with rings treated with diluent alone ( P < 0.01). The enhancing effect of TNF-α on carbachol-induced isometric force generation was completely abrogated in the tracheal rings obtained from TNF-α receptor (TNFR)1-deficient mice and in control rings treated with a TNF-α mutant that solely activates TNFR2. TNF-α also attenuated relaxation responsiveness to isoproterenol but not to PGE2 or forskolin. TNF-α modulatory effects on GPCR-induced ASM responsiveness were completely abrogated by pertussis toxin, an inhibitor of Giα proteins. Taken together, these data suggest that TNF-α may participate in the development of airway hyperresponsiveness in asthma via the modulation of ASM responsiveness to both contractile and β-adrenoceptor GPCR agonists.

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supporting

confidence: 92%

Selected Contribution: TNF-α modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl

Chen

Tliba

Besien

et al. 2003

Journal of Applied Physiology

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“…There was also attenuation of relaxation of acetylcholine-induced contraction to isoprenaline [72,73]. G i protein expression was increased in sensitized airway smooth muscle, due to enhanced G i a 3 subunit, and increased muscarinic M 2 receptor [71], ef-fects attributed to an induced release of IL-1b [74,75]. Autocrine pro-inflammatory signalling and altered receptor/G protein-coupled second messenger accumulation and action may contribute to increase airway smooth muscle contractility in asthma and decrease responsiveness to b-adrenergic agonists.…”

Section: Effects Of Inflammatory Factors On Airway Smooth Muscle Contmentioning

confidence: 96%

Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?

Chung

2000

Eur Respir J

130

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In addition to its contractile properties, airway smooth muscle may contribute to the pathogenesis of asthma by increased proliferation, and by the expression and secretion of pro‐inflammatory cytokines and mediators. Studies of airway smooth muscle cells in culture have shown that many mitogenic mediators can induce proliferation, and that these may therefore, contribute to the increase in airway smooth muscle mass observed in asthma. Other mechanisms for airway smooth muscle proliferation include the interaction with inflammatory cells such as T‐cells and eosinophils. Airway smooth muscle cells may also be a source of inflammatory mediators and cytokines, in particular chemokines, thus implicating airway smooth muscle cells as contributors to the inflammatory mechanisms of asthma. The pro‐activating signals for converting airway smooth muscle cells into a proliferative and secretory cell in asthma are unknown, but may include viruses and immunoglobulin E. Airway smooth muscle contractility may also be altered in response to inflammation. Airway smooth muscle cells may play an important interactive role with inflammatory and other structural cells, contributing to inflammation, injury and repair of the airways. Such a recognition makes it imperative to consider the airway smooth muscle as a target of therapeutic drugs for suppressing not only the contractile but also the proliferative and secretory effects of asthma.

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“…Cytokines modulate signal transduction in myocardial cells (37)(38)(39)(40). We hypothesize that the alterations in HRC are related to the cellular effects of circulating cytokines.…”

mentioning

confidence: 99%

Abnormal Heart Rate Characteristics Are Associated with Neonatal Mortality

Griffin

OʼShea

Bissonette³

et al. 2004

Pediatr Res

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Estimating the risk of in-hospital mortality in the newborn intensive care unit can provide important information for healthcare providers, and illness severity scores have been devised to provide mortality risk estimates. Calculation of illness severity scores is time-consuming, and the information used to predict mortality is collected only for the first 12 to 24 h of life. A noninvasive continuous measure that uses information collected throughout the hospitalization and that requires no data entry could be less costly and more informative. We have previously shown that the abnormal heart rate characteristics (HRC) of reduced variability and transient decelerations accompany neonatal illness such as late-onset sepsis. We hypothesized that more frequent and severe abnormal HRC are associated with an increased risk of death. We tested this hypothesis in two ways. Using data on infants older than 7 d of age, we first determined the association of the HRC index with death in the next week. Second, we devised a cumulative HRC score and determined its association with in-hospital death. There were 37 deaths in the 685 patients. The major findings were 1) the HRC index showed highly significant association with death in the succeeding 7 d (receiver-operating characteristic area Ͼ 0.7, p Ͻ 0.001), and 2) the cumulative HRC was highly significantly associated with neonatal in-hospital mortality (receiver-operating characteristic area Ͼ 0.80, p Ͻ 0.001). In both analyses, HRC added information to birth weight, gestational age, and postnatal age (p Ͻ 0.01). The HRC index provides independent information about the risk of neonatal death in the upcoming 7 d, and the cumulative HRC is an estimate of the risk of in-hospital neonatal mortality. Abbreviations NICU, newborn intensive care unit HRC, heart rate characteristics ROC, receiver-operating characteristic HR, heart rate SIRS, systemic inflammatory response syndrome UVa, University of Virginia WFU, Wake Forest University BW, birth weight GA, gestational age cHRC, cumulative heart rate characteristics SNAP, Score for Acute Neonatal Physiology RR interval, interval between heartbeats Estimations of the risk of mortality, the illness severity, and the burden of illness are important in planning patient care and providing health-care resources in clinical neonatology. Although standard neonatal illness severity scores correlate with neonatal mortality (1-5), their day-to-day use is limited by the large amount of data collection that is required. In addition, the accuracy of these standard scoring systems diminishes after the first few days (6). A simpler and more informative method for estimating in-hospital mortality in neonates is needed.Early in the course of sepsis and SIRS, newborn infants have abnormal HRC, with reduced HR variability and transient decelerations similar to those of distressed fetuses (7). Predictive mathematical models based on logistic regression that use HRC are significantly associated with neonatal sepsis and SIRS in the subsequent 12 to 24 h (8)....

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Mechanism of cytokine-induced modulation of beta-adrenoceptor responsiveness in airway smooth muscle.

Cited by 128 publications

References 45 publications

Selected Contribution: TNF-α modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl

Selected Contribution: TNF-α modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl

Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?

Abnormal Heart Rate Characteristics Are Associated with Neonatal Mortality

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