A sthma is a chronic inflammatory disease which is accompanied by extensive changes in normal airway tissue architecture, termed remodeling (1, 2). Airway remodeling in asthma comprises epithelial dysfunction, hypertrophy of the mucus glands, subepithelial vascularization, and changes in extracellular matrix composition (2). In addition, airway smooth muscle (ASM) from people suffering with asthma exhibits enhanced proliferative (3) and migratory responses (4, 5), as well as increased secretion of a myriad of pro-inflammatory cytokines/ chemokines and growth factors (6). The mechanisms that underly the exaggerated function of ASM in asthma are unknown.Smooth muscle responses to diverse stimuli are controlled by changes in the concentration of free cytosolic Ca 2ϩ ([Ca 2ϩ ] i ). Elevation of [Ca 2ϩ ] i results from increased Ca 2ϩ influx across the plasma membrane following activation of Ca 2ϩ -permeable ion channels and the Na ϩ -Ca 2ϩ -exchanger (NCX, 3Na ϩ :1Ca 2ϩ ), and by release of stored Ca 2ϩ from the sarcoplasmic reticulum (SR), in turn triggered by inositol 1,4,5-triphosphate (IP 3 ) or ryanodine receptor (RyR) channels (7). Termination of the cytosolic Ca 2ϩ signal occurs by extracellular removal of cytosolic Ca 2ϩ by the NCX and by its rapid sequestration into SR stores by the sarco/endoplasmic reticulum Ca 2ϩ (SERCA) pump (7). Impaired replenishment of SR stores arising from reduced activity of the SERCA pump could impact on a wide range of Ca 2ϩ -dependent smooth muscle functions (8) and abnormal Ca 2ϩ handling by ASM has previously been proposed to be an important determinant of the airway hyperresponsiveness that is characteristically present in asthma (9, 10).There are 3 tissue-specific members of the mammalian SERCA family, SERCA1, SERCA2 and SERCA3, each encoded by a separate gene (ATP2A1, ATP2A2, and ATP2A3) (11), with SERCA2 being the most highly expressed in smooth muscle (12, 13). The function of the different isoforms of SERCA2 is similar (14). We have investigated if the secretory and hyperproliferative phenotype of ASM in asthma is associated with impaired SERCA isoform expression. Results SERCA2Expression. SERCA2 mRNA expression was reduced in ASM cells cultured from patients with moderate, but not mild asthma compared with cells derived from healthy subjects (P ϭ 0.04, Fig. 1A). Western immunoblot showed a single band for SERCA2 at the expected size (Ϸ110 kDa) in ASM lysates (Fig. 1). SERCA2 protein expression was correspondingly reduced in ASM cells from patients with moderate asthma (P ϭ 0.015, Fig. 1B). In contrast, IP 3 R1 mRNA and protein expression did not differ between asthmatics and controls ( Fig. 1 A and B), suggesting the change in SERCA2 was not the result of a reduction in total SR. Transcripts for SERCA1, and SERCA3 were not detected in ASM. Further experiments using SERCA2A, SERCA2B, and SERCA2C specific primers demonstrated that predominant isoform in ASM is SERCA2B with the other isoforms expressed at very low levels around the limit of detection. The pattern of ...
This review is published as a Cochrane Review in the Cochrane Database of Systematic Reviews 2014, Issue 7. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Review.
Single inhaler therapy has now been demonstrated to reduce exacerbations requiring oral corticosteroids against current best practice strategies and against a fixed higher dose of inhaled steroids. The strength of evidence that SiT reduces hospitalisation against these same treatments is weak. There were more discontinuations due to adverse events on SiT compared to current best practice, but no significant differences in serious adverse events. Our confidence in these conclusions is limited by the open-label design of the trials, and by the unknown adherence to treatment in the current best practice arms of the trials.Single inhaler therapy can reduce the risk of asthma exacerbations needing oral corticosteroids in comparison with fixed dose maintenance ICS and separate relief medication. The reduced odds of exacerbations with SiT compared with higher dose ICS should be viewed in the context of the possible impact of LABA withdrawal during study run-in. This may have made the study populations more likely to respond to SiT.Single inhaler therapy is not currently licensed for children under 18 years of age in the United Kingdom and there is currently very little research evidence for this approach in children or adolescents.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.