title: Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho-GTPase-dependent actin cytoskeletal signaling in fetal lungs.
abstract: The present study tested the hypothesis that maternal smoke exposure results in fetal lung growth retardation due to dysregulation in various signaling pathways, including the Wnt (wingless-related integration site)/β-catenin pathway. Pregnant female C57BL/6J mice were exposed to cigarette smoke (100-150 mg/m3) or room air, and offspring were humanely killed on 12.5, 14.5, 16.5, and 18.5 dpost coitum(dpc). We assessed lung stereology with Cavalieri estimation; apoptosis with proliferating cell nuclear antigen, TUNEL, and caspase assays; and gene expression with quantitative PCR (qPCR) and RNA sequencing on lung epithelium and mesenchyme retrieved by laser capture microdissection. Results demonstrated a significant decrease in body weight and lung volume of smoke-exposed embryos. At 16.5 dpc, the reduction in lung volume was due to loss of lung mesenchymal tissue correlating with a decrease in cell proliferation (n= 10; air: 61.65%vs.smoke: 44.21%,P< 0.05). RNA sequence analysis demonstrated an alteration in the Wnt pathway, and qPCR confirmed an increased expression of secreted frizzled-related protein 1 (sFRP-1) [n= 12; relative quantification (RQ) 1vs.2.33,P< 0.05] and down-regulation of Cyclin D1 (n= 7; RQ 1vs.0.61,P< 0.05) in mesenchymal tissue. Furthermore, genome expression studies revealed a smoke-induced up-regulation of Rho-GTPase-dependent actin cytoskeletal signaling that can lead to loss of tissue integrity.-Unachukwu, U., Trischler, J., Goldklang, M., Xiao, R., D'Armiento, J. Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho-GTPase-dependent actin cytoskeletal signaling in fetal lungs.
authors.affiliation: Center for Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Uchenna
authors.initials: U
authors.lastname: Unachukwu
authors.affiliation: Center for Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Jordis
authors.initials: J
authors.lastname: Trischler
authors.affiliation: Center for Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Goldklang
authors.affiliation: Center for Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Center for Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA jmd12@cumc.columbia.edu.
authors.forename: Jeanine
authors.initials: J
authors.lastname: D'Armiento
mesh_terms: D000199:Actins / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton; D005260:Female; D005333:Fetus / Q000187:drug effects; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D008168:Lung / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012906:Smoke / Q000009:adverse effects*; D062789:Tobacco Products; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D020690:GTPase-Activating Proteins; D012906:Smoke; D051153:Wnt Proteins
keywords: Wnt/β-catenin; apoptosis; cigarette smoke; in utero; proliferation