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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Science: general issues --- Physiology --- vascular remodeling --- Smooth Muscle Cell --- endothelial cell --- hypoxia --- Fibrosis --- pulmonary arterial hypertension --- Mitochondria --- Bleomycin --- Inflammation --- Iron --- vascular remodeling --- Smooth Muscle Cell --- endothelial cell --- hypoxia --- Fibrosis --- pulmonary arterial hypertension --- Mitochondria --- Bleomycin --- Inflammation --- Iron

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Asthma is a common complex and heterogeneous respiratory disease with an increasing prevalence in developed countries. Asthma is a disease consisting of different phenotypes that are driven by different mechanistic pathways (endotypes). The recognition of these phenotypes and endotypes is central to asthma management entailing prognostic and therapeutic implications. It is acknowledged that despite optimal treatment, many patients are poorly controlled, highlighting the need for phenotype-guided treatments. In this context, the emergence of novel therapies (monoclonal antibody therapy, bronchial thermoplasty) is paving the way for personalized asthma therapy. A better understanding of disease pathogenesis may enable the identification of biomarkers, mediators, novel therapeutic targets, and treatable traits. Further molecular phenotyping or endotyping of asthma will be necessary to tailor new therapeutic strategies. The present Special Issue on Asthma aims to provide the current knowledge on phenotypes and endotypes in appreciating and managing the heterogeneous condition that is asthma.

Medicine --- asthma --- lactic acidosis --- hyperchloremic acidosis --- hypocapnia --- hypercapnia --- wheezing --- bronchial biopsies --- symptom persistence --- clinical remission --- eosinophil --- adhesion --- viability --- proliferation --- airway smooth muscle cell --- pulmonary fibroblast --- phenotype --- acute severe asthma exacerbation --- near fatal asthma --- severe asthma --- inflammation --- interleukin-5 (IL-5) --- anti-IL-5 --- interleukin-4 --- airway remodeling --- matrix metalloproteinases-9 --- tissue inhibitor of metalloproteinase-1 --- alveolar macrophages --- lung function --- bronchodilation --- resistance --- obstruction --- reproducible --- spirometry --- obstructive sleep apnea --- bronchial asthma --- alternative overlap syndrome --- exacerbation --- reactive oxygen species --- PBMC --- mitochondrial function --- innate immunity --- immune regulation --- NLRP3 --- IL-1β --- allergic airway inflammation --- microbiome --- pathogenesis --- immune responses --- PreDicta --- preschool --- FeNO --- asthma-specific quality of life --- chronic rhinitis --- disease-specific quality of life --- health-related quality of Life (HRQLQ) --- children --- longitudinal study --- asthma --- lactic acidosis --- hyperchloremic acidosis --- hypocapnia --- hypercapnia --- wheezing --- bronchial biopsies --- symptom persistence --- clinical remission --- eosinophil --- adhesion --- viability --- proliferation --- airway smooth muscle cell --- pulmonary fibroblast --- phenotype --- acute severe asthma exacerbation --- near fatal asthma --- severe asthma --- inflammation --- interleukin-5 (IL-5) --- anti-IL-5 --- interleukin-4 --- airway remodeling --- matrix metalloproteinases-9 --- tissue inhibitor of metalloproteinase-1 --- alveolar macrophages --- lung function --- bronchodilation --- resistance --- obstruction --- reproducible --- spirometry --- obstructive sleep apnea --- bronchial asthma --- alternative overlap syndrome --- exacerbation --- reactive oxygen species --- PBMC --- mitochondrial function --- innate immunity --- immune regulation --- NLRP3 --- IL-1β --- allergic airway inflammation --- microbiome --- pathogenesis --- immune responses --- PreDicta --- preschool --- FeNO --- asthma-specific quality of life --- chronic rhinitis --- disease-specific quality of life --- health-related quality of Life (HRQLQ) --- children --- longitudinal study

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Asthma is a common complex and heterogeneous respiratory disease with an increasing prevalence in developed countries. Asthma is a disease consisting of different phenotypes that are driven by different mechanistic pathways (endotypes). The recognition of these phenotypes and endotypes is central to asthma management entailing prognostic and therapeutic implications. It is acknowledged that despite optimal treatment, many patients are poorly controlled, highlighting the need for phenotype-guided treatments. In this context, the emergence of novel therapies (monoclonal antibody therapy, bronchial thermoplasty) is paving the way for personalized asthma therapy. A better understanding of disease pathogenesis may enable the identification of biomarkers, mediators, novel therapeutic targets, and treatable traits. Further molecular phenotyping or endotyping of asthma will be necessary to tailor new therapeutic strategies. The present Special Issue on Asthma aims to provide the current knowledge on phenotypes and endotypes in appreciating and managing the heterogeneous condition that is asthma.

Medicine --- asthma --- lactic acidosis --- hyperchloremic acidosis --- hypocapnia --- hypercapnia --- wheezing --- bronchial biopsies --- symptom persistence --- clinical remission --- eosinophil --- adhesion --- viability --- proliferation --- airway smooth muscle cell --- pulmonary fibroblast --- phenotype --- acute severe asthma exacerbation --- near fatal asthma --- severe asthma --- inflammation --- interleukin-5 (IL-5) --- anti-IL-5 --- interleukin-4 --- airway remodeling --- matrix metalloproteinases-9 --- tissue inhibitor of metalloproteinase-1 --- alveolar macrophages --- lung function --- bronchodilation --- resistance --- obstruction --- reproducible --- spirometry --- obstructive sleep apnea --- bronchial asthma --- alternative overlap syndrome --- exacerbation --- reactive oxygen species --- PBMC --- mitochondrial function --- innate immunity --- immune regulation --- NLRP3 --- IL-1β --- allergic airway inflammation --- microbiome --- pathogenesis --- immune responses --- PreDicta --- preschool --- FeNO --- asthma-specific quality of life --- chronic rhinitis --- disease-specific quality of life --- health-related quality of Life (HRQLQ) --- children --- longitudinal study

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Vascular smooth muscle (VSM) constitutes most of the tunica media in blood vessels and plays an important role in the control of vascular tone. Ca2+ is a major regulator of VSM contraction and is strictly regulated by an intricate system of Ca2+ mobilization and Ca2+ homeostatic mechanisms. The interaction of a physiological agonist with its plasma membrane receptor stimulates the hydrolysis of membrane phospholipids and increases the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 stimulates Ca2+ release from the intracellular stores in the sarcoplasmic reticulum. Agonists also stimulate Ca2+ influx from the extracellular space via voltage-gated, receptor-operated, and store-operated channels. Ca2+ homeostatic mechanisms tend to decrease the intracellular free Ca2+ concentration ([Ca2+]i) by activating Ca2+ extrusion via the plasmalemmal Ca2+ pump and the Na+/Ca2+ exchanger and the uptake of excess Ca2+ by the sarcoplasmic reticulum and possibly the mitochondria. A threshold increase in [Ca2+]i activates Ca2+-dependent myosin light chain (MLC) phosphorylation, stimulates actin-myosin interaction, and initiates VSM contraction. The agonist-induced maintained increase in DAG also activates specific protein kinase C (PKC) isoforms, which in turn cause phosphorylation of cytoplasmic substrates that increase the contractile myofilaments force sensitivity to Ca2+ and thereby enhance VSM contraction. Agonists could also activate Rho kinase (ROCK), leading to inhibition of MLC phosphatase and further enhancement of the myofilaments force sensitivity to Ca2+. The combined increases in [Ca2+]i, PKC and ROCK activity cause significant vasoconstriction and could also stimulate VSM hypertrophy and hyperplasia. The protracted and progressive activation of these processes could lead to pathological vascular remodeling and vascular disease.

Muscle contraction. --- Vascular diseases. --- Vascular smooth muscle. --- Ion Channels --- Muscle Proteins --- Microfilament Proteins --- Hemodynamics --- Muscle, Smooth --- Molecular Motor Proteins --- Cardiovascular Diseases --- Blood Vessels --- Diseases --- Muscles --- Contractile Proteins --- Cardiovascular Physiological Processes --- Cardiovascular System --- Adenosine Triphosphatases --- Membrane Glycoproteins --- Biopolymers --- Membrane Transport Proteins --- Cytoskeletal Proteins --- Polymers --- Tissues --- Carrier Proteins --- Acid Anhydride Hydrolases --- Proteins --- Cardiovascular Physiological Phenomena --- Membrane Proteins --- Anatomy --- Musculoskeletal System --- Amino Acids, Peptides, and Proteins --- Circulatory and Respiratory Physiological Phenomena --- Macromolecular Substances --- Hydrolases --- Chemicals and Drugs --- Phenomena and Processes --- Enzymes --- Enzymes and Coenzymes --- Myosins --- Muscle, Smooth, Vascular --- Vasoconstriction --- Calcium Channels --- Vascular Diseases --- Human Anatomy & Physiology --- Health & Biological Sciences --- Physiology --- Vascular resistance. --- Blood pressure. --- Vascular smooth muscle --- Physiology. --- physiology. --- Signal transduction --- Calcium --- Blood pressure --- AngII, angiotensin II --- ATP, adenosine triphosphate --- CPI-17, PKC-potentiated phosphatase inhibitor protein-17 kDa --- CAM, calmodulin --- DAG, diacylglycerol --- ET-1, endothelin --- IP3, inositol 1,4,5-trisphosphate --- MAPK, mitogen-activated protein kinase --- MARCKs, myristoylated alanine-rich C-kinase substrate --- MEK, MAPK kinase --- MLC, myosin light chain --- NCX, Na+-Ca2+ exchanger --- PDBu, phorbol 12,13-dibutyrate; PIP2, phosphatidylinositol 4,5-bisphosphate --- PKC, protein kinase C --- PMA, phorbol myristate acetate --- RACKs, receptors for activated C-kinase --- ROCK, Rho-kinase --- VSMC, vascular smooth muscle cell