Asthma is characterized by airway inflammation and airflow obstruction from human airway smooth muscle (HASM) constriction due to increased local bronchoconstrictive substances. We have recently found bitter taste receptors (TAS2Rs) on HASM, which increase [Ca2+]i and relax the muscle. We report here that some, but not all, TAS2R agonists decrease [Ca2+]i and relax HASM contracted by G-protein coupled receptors (GPCRs) that stimulate [Ca2+]i. This suggests both a second pathway by which TAS2Rs relax, and, a heterogeneity of the response phenotype. We utilized eight TAS2R agonists and five procontractile GPCR agonists in cultured HASM cells. We find that heterogeneity in the inhibitory response hinges on which procontractile GPCR is activated. For example, chloroquine inhibits [Ca2+]i increases from histamine, but failed to inhibit [Ca2+]i increases from endothelin-1. Conversely, aristolochic acid inhibited [Ca2+]i increases from endothelin-1 but not histamine. Other dichotomous responses were found when [Ca2+]i was stimulated by bradykinin, angiotensin, and acetylcholine. There was no association between [Ca2+]i inhibition and TAS2R subtype, nor whether [Ca2+]i was increased by Gq- or Gi-coupled GPCRs. Selected studies revealed a correlation between [Ca2+]i inhibition and HASM cell-membrane hyperpolarization. To demonstrate physiologic correlates, ferromagnetic beads were attached to HASM cells and cell stiffness measured by magnetic twisting cytometry. Consistent with the [Ca2+]i inhibition results, chloroquine abolished the cell stiffening response (contraction) evoked by histamine but not by endothelin-1, while aristolochic acid inhibited cell stiffening from endothelin-1, but not from histamine. In studies using intact human bronchi, these same differential responses were found. Those TAS2R agonists that decreased [Ca2+]i, promoted hyperpolarization, and decreased HASM stiffness, caused relaxation of human airways. Thus TAS2Rs relax HASM in two ways: a low-efficiency de novo [Ca2+]i stimulation, and, a high-efficiency inhibition of GPCR-stimulated [Ca2+]i. Furthermore, there is an interaction between TAS2Rs and some GPCRs that facilitates this [Ca2+]i inhibition limb.
The mechanisms responsible for the development of airway hyperresponsiveness in asthma are poorly understood. Adenosine levels are high in the lungs of patients with asthma, but a role for adenosine in the development of this cardinal feature of asthma has not been previously reported.
To determine the capacity of adenosine to induce airway hyperresponsiveness, and to investigate the mechanisms behind these effects of adenosine on airway physiology.
Wild-type C57BL/6 mice were exposed to aerosolized adenosine analog adenosine-5′ N-ethylcarboxamide (NECA), and subsequent hyperresponsiveness to methacholine was investigated by measuring airway mechanics after anesthesia and tracheostomy. Similar experiments were conducted with A1-deficient, A3-deficient, and mast cell–deficient mice, as well as with mast cell–deficient mice engrafted with wild-type (wt) or A3−/− mast cells. The effect of NECA on methacholine-induced tension development in ex vivo tracheal rings was also examined.
Exposure of wt mice to NECA resulted in the robust induction of airway hyperresponsiveness. NECA failed to induce hyperresponsiveness to methacholine in tracheal ring preps ex vivo, and NECA-induced airway hyperresponsiveness in vivo was not affected by the genetic inactivation of the A1 adenosine receptor. In contrast, NECA-induced airway hyperresponsiveness was abolished in A3 adenosine receptor-deficient mice and in mice deficient in mast cells. Reconstitution of mast cell–deficient mice with wt mast cells restored hyperresponsiveness, whereas reconstitution with A3 receptor–deficient mast cells did not.
Adenosine induces airway hyperresponsiveness indirectly by activating A3 receptors on mast cells.
Airway hyperresponsiveness; adenosine; mast cell; asthma
Occluded ligand-binding pockets (LBP)
such as those found in nuclear
receptors (NR) and G-protein coupled receptors (GPCR) represent a
significant opportunity and challenge for computer-aided drug design.
To determine free energies maps of functional groups of these LBPs,
a Grand-Canonical Monte Carlo/Molecular Dynamics (GCMC/MD) strategy
is combined with the Site Identification by Ligand Competitive Saturation
(SILCS) methodology. SILCS-GCMC/MD is shown to map functional group
affinity patterns that recapitulate locations of functional groups
across diverse classes of ligands in the LBPs of the androgen (AR)
and peroxisome proliferator-activated-γ (PPARγ) NRs and
the metabotropic glutamate (mGluR) and β2-adreneric
(β2AR) GPCRs. Inclusion of protein flexibility identifies
regions of the binding pockets not accessible in crystal conformations
and allows for better quantitative estimates of relative ligand binding
affinities in all the proteins tested. Differences in functional group
requirements of the active and inactive states of the β2AR LBP were used in virtual screening to identify high efficacy
agonists targeting β2AR in Airway Smooth Muscle (ASM)
cells. Seven of the 15 selected ligands were found to effect ASM relaxation
representing a 46% hit rate. Hence, the method will be of use for
the rational design of ligands in the context of chemical biology
and the development of therapeutic agents.
Background and Aims:
With the expanding use of diagnostic and therapeutic radiological modalities in critically ill patients, doctors working in Intensive Care Units (ICUs) are increasingly exposed to ionizing radiation. This risk of radiation exposure occurs not only during bedside radiologic procedures, but also when ICU physicians accompany patients to radiology suites. The aim of this study was to quantify levels of radiation exposure among medical professionals working in the ICU.
Materials and Methods:
The study was carried out prospectively over 6 months in the ICU of a tertiary-referral cancer hospital. Two teams consisting of 4 ICU resident doctors each were instructed to wear thermoluminescent dosimeters (TLDs) during their duty shifts. Standard radiation protection precautions were used throughout the study period. TLDs were also placed in selected areas of the ICU to measure the amount of scattered radiation. TLDs were analyzed at the end of every 3 months.
The readings recorded on TLDs placed in the ICU were almost immeasurable. The mean value of residents' radiation exposure was 0.059 mSv, though the highest individual reading approached 0.1 mSv. The projected maximum yearly radiation exposure was 0.4 mSv.
If standard radiation safety precautions are followed, the cumulative radiation exposure to ICU resident doctors is well within permissible limits and is not a cause of concern. However, with the increasing use of radiological procedures in the management of critically ill patients, there is a need to repeat such audits periodically to monitor radiation exposure.
Dosimetry; Intensive Care Unit; occupational exposure
The objective of this study was to investigate the dose enhancement to soft tissue due to backscatter radiation near metal interfaces during head and neck radiotherapy. The influence of titanium-mandibular plate with the screws on radiation dose was tested on four real bones from mandible with the metal and screws fixed. Radiochromic films were used for dosimetry. The bone and metal were inserted through the film at the center symmetrically. This was then placed in a small jig (7 cm × 7 cm × 10 cm) to hold the film vertically straight. The polymer granules (tissue-equivalent) were placed around the film for homogeneous scatter medium. The film was irradiated with 6 MV X-rays for 200 monitor units in Trilogy linear accelerator for 10 cm × 10 cm field size with source to axis distance of 100 cm at 5 cm. A single film was also irradiated without any bone and metal interface for reference data. The absolute dose and the vertical dose profile were measured from the film. There was 10% dose enhancement due to the backscatter radiation just adjacent to the metal-bone interface for all the materials. The extent of the backscatter effect was up to 4 mm. There is significant higher dose enhancement in the soft tissue/skin due to the backscatter radiation from the metallic components in the treatment region.
Backscatter; head and neck radiotherapy; linear accelerator; metallic interface; radiochromic films
The objective of this paper was to measure the peripheral dose (PD) with diode and thermoluminescence dosimeter (TLD) for intensity modulated radiotherapy (IMRT) with linear accelerator (conventional LINAC), and tomotherapy (novel LINAC). Ten patients each were selected from Trilogy dual-energy and from Hi-Art II tomotherapy. Two diodes were kept at 20 and 25 cm from treatment field edge. TLDs (LiF:MgTi) were also kept at same distance. TLDs were also kept at 5, 10, and 15 cm from field edge. The TLDs were read with REXON reader. The readings at the respective distance were recorded for both diode and TLD. The PD was estimated by taking the ratio of measured dose at the particular distance to the prescription dose. PD was then compared with diode and TLD for LINAC and tomotherapy. Mean PD for LINAC with TLD and diode was 2.52 cGy (SD 0.69), 2.07 cGy (SD 0.88) at 20 cm, respectively, while at 25 cm, it was 1.94 cGy (SD 0.58) and 1.5 cGy (SD 0.75), respectively. Mean PD for tomotherapy with TLD and diode was 1.681 cGy SD 0.53) and 1.58 (SD 0.44) at 20 cm, respectively. The PD was 1.24 cGy (SD 0.42) and 1.088 cGy (SD 0.35) at 25 cm, respectively, for tomotherapy. Overall, PD from tomotherapy was found lower than LINAC by the factor of 1.2-1.5. PD measurement is essential to find out the potential of secondary cancer. PD for both (conventional LINAC) and novel LINACs (tomotherapy) were measured and compared with each other. The comparison of the values for PD presented in this work and those published in the literature is difficult because of the different experimental conditions. The diode and TLD readings were reproducible and both the detector readings were comparable.
Diode; TLD-100; intensity modulated radiotherapy; linear accelerator; peripheral dose; tomotherapy
Chronic use of inhaled beta-agonists by asthmatics is associated with a loss of bronchoprotective effect and deterioration of asthma control. Beta-agonist-promoted desensitization of airway smooth muscle beta-2-adrenergic receptors, mediated by G protein-coupled receptor kinases and arrestins, is presumed to underlie these effects, but such a mechanism has never been demonstrated. Using in vitro, ex vivo, and in vivo murine models, we demonstrate that beta-arrestin-2 gene ablation augments beta-agonist-mediated airway smooth muscle relaxation, while augmenting beta-agonist-stimulated cyclic adenosine monophosphate production. In cultures of human airway smooth muscle, small interfering RNA-mediated knockdown of arrestins also augments beta-agonist-stimulated cyclic adenosine monophosphate production. Interestingly, signaling and function mediated by m2/m3 muscarinic acetylcholine receptors or prostaglandin E2 receptors were not affected by either beta-arrestin-2 knockout or arrestin knockdown. Thus, arrestins are selective regulators of beta-2-adrenergic receptor signaling and function in airway smooth muscle. These results and our previous findings, which demonstrate a role for arrestins in the development of allergic inflammation in the lung, identify arrestins as potentially important therapeutic targets for obstructive airway diseases.—Deshpande, D. A., Theriot, B. S., Penn, R. B., Walker, J. K. L. β-Arrestins specifically constrain β2-adrenergic receptor signaling and function in airway smooth muscle.
Bitter taste receptors (TAS2Rs) were shown to be expressed in human airway smooth muscle (ASM). They couple to specialized [Ca2+]i release, leading to membrane hyperpolarization, the relaxation of ASM, and marked bronchodilation. TAS2Rs are G-protein–coupled receptors, known to undergo rapid agonist-promoted desensitization that can limit therapeutic efficacy. Because TAS2Rs represent a new drug target for treating obstructive lung disease, we investigated their capacity for rapid desensitization, and assessed their potential mechanisms. The pretreatment of human ASM cells with the prototypic TAS2R agonist quinine resulted in a 31% ± 5.1% desensitization of the [Ca2+]i response from a subsequent exposure to quinine. No significant change in the endothelin-stimulated [Ca2+]i response was attributed to the short-term use of quinine, indicating a homologous form of desensitization. The TAS2R agonist saccharin also evoked desensitization, and cross-compound desensitization with quinine was evident. Desensitization of the [Ca2+]i response was attenuated by a dynamin inhibitor, suggesting that receptor internalization (a G-protein coupled receptor kinase [GRK]-mediated, β-arrestin–mediated process) plays an integral role in the desensitization of TAS2R. Desensitization was insensitive to antagonists of the second messenger kinases protein kinase A and protein kinase C. Using intact airways, short-term, agonist-promoted TAS2R desensitization of the relaxation response was also observed. Thus these receptors, which represent a potential novel target for direct bronchodilators, undergo a modest degree of agonist-promoted desensitization that may affect clinical efficacy. Collectively, the results of these mechanistic studies, along with the multiple serines and threonines in intracellular loop 3 and the cytoplasmic tail of TAS2Rs, suggest a GRK-mediated mode of desensitization.
airway smooth muscle relaxation; taste receptors; tachyphylaxis; phosphorylation; G-protein–coupled receptor kinases
Bitter taste receptors (TAS2Rs) of the tongue likely evolved to evoke signals for avoiding ingestion of plant toxins. We found expression of TAS2Rs on human airway smooth muscle (ASM) and considered these to be avoidance receptors for inhalants, leading to ASM contraction and bronchospasm. TAS2R agonists such as saccharin, chloroquine and denatonium evoked increased ASM [Ca2+]i in a Gβγ, PLCβ and IP3-receptor dependent manner which would be expected (like acetylcholine) to evoke contraction. Paradoxically, bitter tastants caused relaxation of isolated ASM, and dilation of airways that was 3-fold greater than β-agonists. Relaxation by TAS2Rs is from a localized [Ca2+]i response at the cell membrane which opens BKCa channels leading to ASM membrane hyperpolarization. Inhaled bitter tastants decreased airway obstruction in an asthma mouse model. Given the need for efficacious bronchodilators for treating obstructive lung diseases, this pathway can be exploited for therapy with the thousands of known synthetic and naturally occurring bitter tastants.
A study was performed to assess dosimetric characteristics of volumetric modulated arcs (RapidArc, RA) and fixed field intensity modulated therapy (IMRT) for Whole Abdomen Radiotherapy (WAR) after ovarian cancer.
Methods and Materials
Plans for IMRT and RA were optimised for 5 patients prescribing 25 Gy to the whole abdomen (PTV_WAR) and 45 Gy to the pelvis and pelvic nodes (PTV_Pelvis) with Simultaneous Integrated Boost (SIB) technique. Plans were investigated for 6 MV (RA6, IMRT6) and 15 MV (RA15, IMRT15) photons. Objectives were: for both PTVs V90% > 95%, for PTV_Pelvis: Dmax < 105%; for organs at risk, maximal sparing was required. The MU and delivery time measured treatment efficiency. Pre-treatment Quality assurance was scored with Gamma Agreement Index (GAI) with 3% and 3 mm thresholds.
IMRT and RapidArc resulted comparable for target coverage. For PTV_WAR, V90% was 99.8 ± 0.2% and 93.4 ± 7.3% for IMRT6 and IMRT15, and 98.4 ± 1.7 and 98.6 ± 0.9% for RA6 and RA15. Target coverage resulted improved for PTV_Pelvis. Dose homogeneity resulted slightly improved by RA (Uniformity was defined as U5-95% = D5%-D95%/Dmean). U5-95% for PTV_WAR was 0.34 ± 0.05 and 0.32 ± 0.06 (IMRT6 and IMRT15), 0.30 ± 0.03 and 0.26 ± 0.04 (RA6 and RA15); for PTV_Pelvis, it resulted equal to 0.1 for all techniques. For organs at risk, small differences were observed between the techniques. MU resulted 3130 ± 221 (IMRT6), 2841 ± 318 (IMRT15), 538 ± 29 (RA6), 635 ± 139 (RA15); the average measured treatment time was 18.0 ± 0.8 and 17.4 ± 2.2 minutes (IMRT6 and IMRT15) and 4.8 ± 0.2 (RA6 and RA15). GAIIMRT6 = 97.3 ± 2.6%, GAIIMRT15 = 94.4 ± 2.1%, GAIRA6 = 98.7 ± 1.0% and GAIRA15 = 95.7 ± 3.7%.
RapidArc showed to be a solution to WAR treatments offering good dosimetric features with significant logistic improvements compared to IMRT.
Although G protein-coupled receptor (GPCR) kinases (GRKs) have been shown to mediate desensitization of numerous GPCRs in studies using cellular expression systems, their function under physiological conditions is less well understood. In the current study, we employed various strategies to assess the effect of inhibiting endogenous GRK2/3 on signaling and function of endogenously expressed Gs-coupled receptors in human airway smooth muscle (ASM) cells. GRK2/3 inhibition by expression of a Gβγ sequestrant, a GRK2/3 dominant-negative mutant, or siRNA-mediated knockdown increased intracellular cAMP accumulation mediated via β-agonist stimulation of the beta-2-adrenergic receptor (β2AR). Conversely, neither 5′-(N-ethylcarboxamido)-adenosine (NECA; activating the A2b adenosine receptor) nor prostaglandin E2 (PGE2; activating EP2 or EP4 receptors)-stimulated cAMP was significantly increased by GRK2/3 inhibition. Selective knockdown using siRNA suggested the majority of PGE2-stimulated cAMP in ASM was mediated by the EP2 receptor. Although a minor role for EP3 receptors in influencing PGE2-mediated cAMP was determined, the GRK2/3-resistant nature of EP2 receptor signaling in ASM was confirmed using the EP2-selective agonist butaprost. Somewhat surprisingly, GRK2/3 inhibition did not augment the inhibitory effect of the β-agonist on mitogen-stimulated increases in ASM growth. These findings demonstrate that with respect to Gs-coupled receptors in ASM, GRK2/3 selectively attenuates β2AR signaling, yet relief of GRK2/3-dependent β2AR desensitization does not influence at least one important physiological function of the receptor.
Glucocorticoids (GCs) and protein kinase A (PKA)–activating agents (β-adrenergic receptor agonists) are mainstream asthma therapies based on their ability to prevent or reverse excessive airway smooth muscle (ASM) constriction. Their abilities to regulate another important feature of asthma—excessive ASM growth—are poorly understood. Recent studies have suggested that GCs render agents of inflammation such as IL-1β and TNF-α mitogenic to ASM, via suppression of (antimitogenic) induced cyclooxygenase-2–dependent PKA activity. To further explore the mechanistic basis of these observations, we assessed the effects of epidermal growth factor and IL-1β stimulation, and the modulatory effects of GC treatment and PKA inhibition, on the ASM transcriptome by microarray analysis. Results demonstrate that ASM stimulated with IL-1β, in a manner that is often cooperative with stimulation with epidermal growth factor, exhibit a profound capacity to function as immunomodulatory cells. Moreover, results implicate an important role for induced autocrine/paracrine factors (many whose regulation was minimally affected by GCs or PKA inhibition) as regulators of both airway inflammation and ASM growth. Induction of numerous chemokines, in conjunction with regulation of proteases and agents of extracellular matrix remodeling, is suggested as an important mechanism promoting upregulated G protein–coupled receptor signaling capable of stimulating ASM growth. Additional functional assays suggest that intracellular PKA plays a critical role in suppressing the promitogenic effects of induced autocrine factors in ASM. Finally, identification and comparison of GC- and PKA-sensitive genes in ASM provide insight into the complementary effects of β-agonist/GC combination therapies, and suggest specific genes as important targets for guiding the development of new generations of GCs and adjunct asthma therapies.
airway smooth muscle; protein kinase A; glucocorticoid; gene expression; G protein–coupled receptors
A Helical Tomotherapy™ (HT) Hi-Art II (TomoTherapy, Inc., Madison, WI, USA) has been one of the important innovations to help deliver IMRT with image guidance. On-board, mega voltage computed tomography (MVCT) detectors are used for imaging and dosimetric purpose. The two objectives of this study are: (i) To estimate the dosimetric and general capability (TomoImage registration, reconstruction, contrast and spatial resolution, artifacts-free image and dose in TomoImage) of on-board MVCT detectors. (ii) To measure the dosimetric parameters (output and energy) following major repair. The MVCT detectors also estimated the rotational output constancy well. During this study, dosimetric tests were repeated after replacing MVCT detectors and the target. fixed-gantry/fixed-couch measurements were measured daily to investigate; the system stability. Thermoluminescense dosimeter (TLD) was used during both the measurements subsequently. The MVCT image quality with old and new detectors was comparable and hence acceptable clinically. The spatial resolution was optimal and the dose during TomoImage was 2 cGy (well within the manufacturer tolerance of 4 cGy). The results of lateral beam profiles showed an excellent agreement between the two normalized plots. The output from the rotational procedure revealed 99.7% while the energy was consistent over a period of twelve months. The Hi-Art II system has maintained its calibration to within +/− 2% and energy to within +/− 1.5% over the initial twelve-month period. Based on the periodic measurements for rotational output and consistency in the lateral beam profile shape, the on-board detector proved to be a viable dosimetric quality assurance tool for IMRT with Tomotherapy. Tomotherapy was stable from the dosimetric point of view during the twelve-month period.
Tomotherapy; mega voltage computed tomography detector; Dosimetric stability
A Helical Tomotherapy (HT) Hi-Art II machine, Hi ART (TomoTherapy, Inc., Madison, WI, USA) was installed at our center in July 2007, and was the first machine in India. Image-guided HT is a new modality for delivering intensity modulated radiotherapy (IMRT). Dosimetric tests done include (a) primary beam alignment (b) secondary beam alignment (c) water tank measurements (profiles and depth doses) (d) dose rate measurements (e) IMRT verification, and (f) Mega voltage Computed Tomography (MVCT) dose. Primary and secondary beam alignment revealed an acceptable linear accelerator (linac) alignment in both X and Y axes. In addition, it was observed that the beam was aligned in the same plane as gantry and the jaws were not twisted with respect to gantry. The rotational beam stability was acceptable. Multi-leaf collimators (MLC) were found to be stable and properly aligned with the radiation plane. The jaw alignment during gantry rotation was satisfactory. Transverse and longitudinal profiles were in good agreement with the “Gold” standard. During IMRT verification, the variation between the measured and calculated dose for a particular plan at the central and off-axis was found to be within 2% and 1mm in position, respectively. The dose delivered during the TomoImage scan was found to be 2.57 cGy. The Helical Tomotherapy system is mechanically stable and found to be acceptable for clinical treatment. It is recommended that the output of the machine should be measured on a daily basis to monitor the fluctuations in output.
Tomotherapy; commissioning and acceptance; dosimetric validation
Dynamic multileaf collimator (DMLC) and static multileaf collimator (SMLC), along with three-dimensional treatment planning system (3-D TPS), open the possibility of tissue compensation. A method using electronic tissue compensator (ETC) has been implemented in Eclipse 3-D TPS (V 7.3, Varian Medical Systems, Palo Alto, USA) at our center. The ETC was tested for head and neck conformal radiotherapy planning. The purpose of this study was to verify the feasibility of DMLC and SMLC in head and neck field irradiation for delivering homogeneous dose in the midplane at a pre-defined depth. In addition, emphasis was given to the dosimetric aspects in commissioning ETC in Eclipse. A Head and Neck Phantom (The Phantom Laboratory, USA) was used for the dosimetric verification. Planning was carried out for both DMLC and SMLC ETC plans. The dose calculated at central axis by eclipse with DMLC and SMLC was noted. This was compared with the doses measured on machine with ion chamber and thermoluminescence dosimetry (TLD). The calculated isodose curves and profiles were compared with the measured ones. The dose profiles along the two major axes from Eclipse were also compared with the profiles obtained from Amorphous Silicon (AS500) Electronic portal imaging device (EPID) on Clinac 6 EX machine. In uniform dose regions, measured dose values agreed with the calculated doses within 3%. Agreement between calculated and measured isodoses in the dose gradient zone was within 3 mm. The isodose curves and the profiles were found to be in good agreement with the measured curves and profiles. The measured and the calculated dose profiles along the two major axes were flat for both DMLC and SMLC. The dosimetric verification of ETC for both the linacs demonstrated the feasibility and the accuracy of the ETC treatment modality for achieving uniform dose distributions. Therefore, ETC can be used as a tool in head and neck treatment planning optimization for improved dose uniformity.
Dynamic multileaf collimator; electronic tissue compensator; quality assurance; static multileaf collimator
A new generation telecobalt unit, Theratron Equinox-80, (MDS Nordion, Canada) has been evaluated. It is equipped with a single 60-degree motorized wedge (MW), four universal wedges (UW) for 15°, 30°, 45° and 60°. MW was configured in Eclipse (Varian, Palo Alto, USA) 3D treatment planning system (TPS). The profiles and central axis depth doses (CADD) were measured with radiation field analyzer blue water phantom for MW. These profiles and CADD for MW were compared with UW in a homogeneous phantom generated in Eclipse for various field sizes. The absolute dose was measured for a field size of 10 × 10 cm2 only in a MEDTEC water phantom at 10 cm depth with a 0.13 cc thimble ion chamber (Scanditronix Wellhofer, Uppsala, Sweden) and a NE electrometer (Nuclear Enterprises, UK). Measured dose with ion chamber was compared with the TPS predicted dose. MW angle was verified on the Equinox for four angles (15°, 30°, 45° and 60°). The variation in measured and calculated dose at 10 cm depth was within 2%. The measured and the calculated wedge angles were in well agreement within 2°. The motorized wedges were successfully configured in Eclipse for four wedge angles.
Motorized wedge; quality assurance; telecobalt; treatment planning
Growing evidence suggests that interleukin (IL)-13, a Th2-type cytokine, plays a critical role in the development of bronchial hyper-responsiveness (BHR), an essential feature of asthma, although the underlying mechanisms remain unknown. In the present study, we investigated whether IL-13 directly affects airway smooth muscle (ASM) function. In murine tracheal rings, IL-13 (100 ng ml−1, 24 h) significantly increased both the carbachol- and KCl-induced maximal force generation without affecting ASM sensitivity. In cultured human ASM cells, IL-13 (50 ng ml−1, 24 h) also augmented cytosolic calcium levels to bradykinin, histamine and carbachol by 60, 35 and 26%, respectively. The present study demonstrates that IL-13 may promote BHR by directly modulating ASM contractility, an effect that may be due to enhanced G protein-coupled receptor (GPCR)-associated calcium signaling.
Asthma; isometric tension; airway smooth muscle; Th2 cytokine; calcium metabolism