title: Cigarette smoke enhances proliferation and extracellular matrix deposition by human fetal airway smooth muscle.
abstract: Cigarette smoke is a common environmental insult associated with increased risk of developing airway diseases such as wheezing and asthma in neonates and children. In adults, asthma involves airway remodeling characterized by increased airway smooth muscle (ASM) cell proliferation and increased extracellular matrix (ECM) deposition, as well as airway hyperreactivity. The effects of cigarette smoke on remodeling and contractility in the developing airway are not well-elucidated. In this study, we used canalicular-stage (18-20 wk gestational age) human fetal airway smooth muscle (fASM) cells as an in vitro model of the immature airway. fASM cells were exposed to cigarette smoke extract (CSE; 0.5-1.5% for 24-72 h), and cell proliferation, ECM deposition, and intracellular calcium ([Ca(2+)]i) responses to agonist (histamine 10 μM) were used to evaluate effects on remodeling and hyperreactivity. CSE significantly increased cell proliferation and deposition of ECM molecules collagen I, collagen III, and fibronectin. In contrast, [Ca(2+)]i responses were not significantly affected by CSE. Analysis of key signaling pathways demonstrated significant increase in extracellular signal-related kinase (ERK) and p38 activation with CSE. Inhibition of ERK or p38 signaling prevented CSE-mediated changes in proliferation, whereas only ERK inhibition attenuated the CSE-mediated increase in ECM deposition. Overall, these results demonstrate that cigarette smoke may enhance remodeling in developing human ASM through hyperplasia and ECM production, thus contributing to development of neonatal and pediatric airway disease.
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota;
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Vogel
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Sarah K
authors.initials: SK
authors.lastname: VanOosten
authors.affiliation: Mayo Medical School, Rochester, Minnesota;
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Holman
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Danielle D
authors.initials: DD
authors.lastname: Hohbein
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Vassallo
authors.affiliation: Department of Pediatrics, University of Leicester, Leicester, United Kingdom.
authors.forename: Hitesh C
authors.initials: HC
authors.lastname: Pandya
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota;
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Pabelick.christina@mayo.edu.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pabelick
mesh_terms: D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D049109:Cell Proliferation; D024042:Collagen Type I / Q000096:biosynthesis; D024061:Collagen Type III / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005333:Fetus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D012137:Respiratory System / Q000378:metabolism* / Q000473:pathology; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium
keywords: asthma; collagen; lung development; prematurity