title: Lysophosphatidic Acid Signaling through the Lysophosphatidic Acid-1 Receptor Is Required for Alveolarization.
abstract: Lysophosphatidic acid (LPA) signaling through one of its receptors, LPA1, contributes to both the development and the pathological remodeling after injury of many organs. Because we found previously that LPA-LPA1 signaling contributes to pulmonary fibrosis, here we investigated whether this pathway is also involved in lung development. Quantitative assessment of lung architecture of LPA1-deficient knock-out (KO) and wild-type (WT) mice at 3, 12, and 24 weeks of age using design-based stereology suggested the presence of an alveolarization defect in LPA1 KO mice at 3 weeks, which persisted as alveolar numbers increased in WT mice into adulthood. Across the ages examined, the lungs of LPA1 KO mice exhibited decreased alveolar numbers, septal tissue volumes, and surface areas, and increased volumes of the distal airspaces. Elastic fibers, critical to the development of alveolar septa, appeared less organized and condensed and more discontinuous in KO alveoli starting at P4. Tropoelastin messenger RNA expression was decreased in KO lungs, whereas expression of matrix metalloproteinases degrading elastic fibers was either decreased or unchanged. These results are consistent with the abnormal lung phenotype of LPA1 KO mice, being attributable to reduced alveolar septal formation during development, rather than to increased septal destruction as occurs in the emphysema of chronic obstructive pulmonary disease. Peripheral septal fibroblasts and myofibroblasts, which direct septation in late alveolarization, demonstrated reduced production of tropoelastin and matrix metalloproteinases, and diminished LPA-induced migration, when isolated from LPA1 KO mice. Taken together, our data suggest that LPA-LPA1 signaling is critically required for septation during alveolarization.
authors.affiliation: 1 Departments of Pulmonary Medicine, Inselspital Berne, and.|2 Clinical Research, University of Berne, Berne, Switzerland.|3 Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases, and.
authors.forename: Manuela
authors.initials: M
authors.lastname: Funke
authors.affiliation: 4 Institute of Functional and Applied Anatomy, Hannover Medical School, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, REBIRTH Cluster of Excellence, Hannover, Germany; and.
authors.forename: Lars
authors.initials: L
authors.lastname: Knudsen
authors.affiliation: 3 Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases, and.
authors.forename: David
authors.initials: D
authors.lastname: Lagares
authors.affiliation: 1 Departments of Pulmonary Medicine, Inselspital Berne, and.|2 Clinical Research, University of Berne, Berne, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Ebener
authors.affiliation: 3 Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases, and.
authors.forename: Clemens K
authors.initials: CK
authors.lastname: Probst
authors.affiliation: 3 Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases, and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fontaine
authors.affiliation: 3 Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases, and.
authors.forename: Alicia
authors.initials: A
authors.lastname: Franklin
authors.affiliation: 4 Institute of Functional and Applied Anatomy, Hannover Medical School, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, REBIRTH Cluster of Excellence, Hannover, Germany; and.
authors.forename: Manuela
authors.initials: M
authors.lastname: Kellner
authors.affiliation: 4 Institute of Functional and Applied Anatomy, Hannover Medical School, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, REBIRTH Cluster of Excellence, Hannover, Germany; and.
authors.forename: Mark
authors.initials: M
authors.lastname: Kühnel
authors.affiliation: 4 Institute of Functional and Applied Anatomy, Hannover Medical School, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, REBIRTH Cluster of Excellence, Hannover, Germany; and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Matthieu
authors.affiliation: 4 Institute of Functional and Applied Anatomy, Hannover Medical School, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, REBIRTH Cluster of Excellence, Hannover, Germany; and.
authors.forename: Roman
authors.initials: R
authors.lastname: Grothausmann
authors.affiliation: 5 Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, Scripps Research Institute, La Jolla, California.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.affiliation: 6 Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Roberts
authors.affiliation: 4 Institute of Functional and Applied Anatomy, Hannover Medical School, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, REBIRTH Cluster of Excellence, Hannover, Germany; and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ochs
authors.affiliation: 3 Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases, and.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tager
mesh_terms: D000818:Animals; D002452:Cell Count; D002465:Cell Movement; D048429:Cell Size; D004548:Elasticity; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D011650:Pulmonary Alveoli / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014333:Tropoelastin / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D019714:Tissue Inhibitor of Metalloproteinases; D014333:Tropoelastin; D004549:Elastin; D020782:Matrix Metalloproteinases; C032881:lysophosphatidic acid
keywords: LPA1; alveolarization; elastin; lung development; matrix metalloproteinase