Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma
| Autor: | Michael J. Sanderson, David H. Broide, Peter Rosenthal, Hirotoshi Unno, Jun Chen, Marina Miller |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Contraction (grammar) Allergy Transgenic sarcoplasmic reticulum Ca(2+) transport ATPase 2b chemistry.chemical_compound Mice 0302 clinical medicine Smooth Muscle Immunology and Allergy 2.1 Biological and endogenous factors Aetiology Lung sarcoplasmic reticulum Ca2+ transport ATPase 2b ORMDL3 respiratory system musculoskeletal system airway smooth muscle Up-Regulation 030220 oncology & carcinogenesis Respiratory Muscle Smooth medicine.drug Muscle Contraction medicine.medical_specialty Myosin light-chain kinase SERCA Immunology chemistry.chemical_element Biology Calcium Contractility 03 medical and health sciences Internal medicine Calcium flux medicine Respiratory Hypersensitivity Animals Humans Sphingosine-1-phosphate Calcium Signaling Cell Proliferation Myocytes airway hyperresponsiveness Membrane Proteins asthma respiratory tract diseases 030104 developmental biology Endocrinology Good Health and Well Being chemistry Methacholine |
| Zdroj: | The Journal of allergy and clinical immunology, vol 142, iss 1 |
| Popis: | Background Airway hyperresponsiveness is a major feature of asthma attributed predominantly to an extrinsic immune/inflammatory response increasing airway smooth muscle (ASM) contractility. Objective We investigated whether increased ASM expression of orosomucoid-like 3 (ORMDL3), a gene on chromosome 17q21 highly linked to asthma, induced increased ASM proliferation and contractility in vitro and influenced airway contractility and calcium flux in ASM in precision-cut lung slices (PCLSs) from wild-type and hORMDL3 Zp3-Cre mice (which express increased levels of human ORMDL3 [hORMDL3]). Methods Levels of ASM proliferation and contraction were assessed in ASM cells transfected with ORMDL3 in vitro . In addition, airway contractility and calcium oscillations were quantitated in ASM cells in PCLSs derived from naive wild-type and naive hORMDL3 Zp3-Cre mice, which do not have a blood supply. Results Increased ASM expression of ORMDL3 in vitro resulted in increased ASM proliferation and contractility. PCLSs derived from naive hORMDL3 Zp3-Cre mice, which do not have airway inflammation, exhibit increased airway contractility with increased calcium oscillations in ASM cells. Increased ASM ORMDL3 expression increases levels of ASM sarcoplasmic reticulum Ca 2+ ATPase 2b (SERCA2b), which increases ASM proliferation and contractility. Conclusion Overall, these studies provide evidence that an intrinsic increase in ORMDL3 expression in ASM can induce increased ASM proliferation and contractility, which might contribute to increased airway hyperresponsiveness in the absence of airway inflammation in asthmatic patients. |
| Databáze: | OpenAIRE |
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