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Anne Chetty, Heber C Nielsen Tufts Medical Center, Tufts University, Boston, MA, USACorrespondence: Heber C NielsenDepartment of Pediatrics, Tufts Medical Center, Boston, MA, USAEmail heber.nielsen@tufts.eduAbstract: Airway smooth muscle (ASM) cell dysfunction is an important component of several obstructive pulmonary diseases, particularly asthma. External stimuli such as allergens, dust, air pollutants, and change in environmental temperatures provoke ASM cell hypertrophy, proliferation, and migration without adequate mechanistic controls. ASM cells can switch between quiescent, migratory, and proliferative phenotypes in response to extracellular matrix proteins, growth factors, and other soluble mediators. While some aspects of airway hypertrophy and remodeling could have beneficial effects, in many cases these contribute to a clinical phenotype of difficult to control asthma. In this review, we discuss the factors responsible for ASM hypertrophy and proliferation in asthma, focusing on cytokines, growth factors, and ion transporters, and discuss existing and potential approaches that specifically target ASM hypertrophy to reduce the ASM mass and improve asthma symptoms. The goal of this review is to highlight strategies that appear ready for translational investigations to improve asthma therapy.Keywords: airway smooth muscle cells, hypertrophy, proliferation, airway remodeling

Anne Chetty,1 Azeem Sharda,1 Rod Warburton,2 Ellen O Weinberg,3 Jinghui Dong,4 Min Fang,5 G Gary Sahagian,5 Tiangmeng Chen,3 Chang Xue,3 John J Castellot,3,6 Philip G Haydon,4 Heber C Nielsen1,6 1Department of Pediatrics, Tufts Medical Center, Boston, MA, USA; 2Department of Medicine, Tufts Medical Center, Boston, MA, USA; 3Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA; 4Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA; 5Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA; 6Graduate Program in Cell, Molecular and Developmental Biology, Tufts University School of Medicine, Boston, MA, USABackground: Purinergic receptors control cell proliferation, apoptosis, migration, inflammation, and cytokine secretion. Increased expression of specific purinergic receptors is reported in asthma. The role of purinergic P2Y6 receptors (P2Y6R) in asthma is controversial. Hypothesis: P2Y6R activation in asthma improves pulmonary function and reduces inflammation and smooth muscle amount. Methods: Female mice (C57/BL6, age 30 days) were randomly assigned to receive intranasal house dust mite (HDM) antigen (40 or 80 µg) or saline, 5 days/week, for 6 weeks. Randomly selected subgroups received intraperitoneal P2Y6R agonist prodrug (GC021109; 10 or 100 μg/kg weight/dose) simultaneously with HDM. After 6 weeks, lung function was measured. Lung lavage fluid (LLF) was used to measure total cell count, total protein, and cytokines. Immunohistochemistry for alpha smooth muscle actin (α-SMA) was done. Airway wall thickness was measured on micro-computed tomography (micro-CT) images. Results: Pulmonary function testing revealed a HDM dose-dependent airway hyperresponsiveness. Airway resistance was increased 2-fold while compliance was decreased by 50% at the higher HDM dose (P