title: IL-1β expression in the distal lung epithelium disrupts lung morphogenesis and epithelial cell differentiation in fetal mice.
abstract: Perinatal inflammation and the inflammatory cytokine IL-1 can modify lung morphogenesis. To examine the effects of antenatal expression of IL-1β in the distal airway epithelium on fetal lung morphogenesis, we studied lung development and surfactant expression in fetal mice expressing human IL-1β under the control of the surfactant protein (SP)-C promoter. IL-1β-expressing pups suffered respiratory failure and died shortly after birth. IL-1β caused fetal lung inflammation and enhanced the expression of keratinocyte-derived chemokine (KC/CXCL1) and monocyte chemoattractant protein 3 (MCP-3/CCL7), the calgranulins S100A8 and S100A9, the acute-phase protein serum amyloid A3, the chitinase-like proteins Ym1 and Ym2, and pendrin. IL-1β decreased the percentage of the total distal lung area made up of air saccules and the number of air saccules in the lungs of fetal mice. IL-1β inhibited the expression of VEGF-A and its receptors VEGFR-1 and VEGFR-2. The percentage of the cellular area of the distal lung made up of capillaries was decreased in IL-1β-expressing fetal mice. IL-1β suppressed the production of SP-B and pro-SP-C and decreased the amount of phosphatidylcholine and the percentage of palmitic acid in the phosphatidylcholine fraction of lung phospholipids, indicating that IL-1β prevented the differentiation of type II epithelial cells. The production of Clara cell secretory protein in the nonciliated bronchiolar (Clara) cells was likewise suppressed by IL-1β. In conclusion, expression of IL-1β in the epithelium of the distal airways disrupted the development of the airspaces and capillaries in the fetal lung and caused fatal respiratory failure at birth.
authors.affiliation: Univ. of Gothenburg, Dept. of Pediatrics, The Queen Silvia Children's Hospital, SWE-416 85 Gothenburg, Sweden. kristina.bry@pediat.gu.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Hogmalm
authors.forename: Maija
authors.initials: M
authors.lastname: Bry
authors.forename: Birgitta
authors.initials: B
authors.lastname: Strandvik
authors.forename: Kristina
authors.initials: K
authors.lastname: Bry
mesh_terms: D056809:Alveolar Epithelial Cells / Q000502:physiology*; D000818:Animals; D027321:Anion Transport Proteins / Q000378:metabolism; D040501:Calgranulin A / Q000378:metabolism; D040502:Calgranulin B / Q000378:metabolism; D002454:Cell Differentiation; D054410:Chemokine CCL7 / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000378:metabolism; D002688:Chitinases / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism; D008168:Lung / Q000196:embryology* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D010455:Peptides / Q000378:metabolism; D011014:Pneumonia; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000378:metabolism; D037701:Pulmonary Surfactant-Associated Protein B / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D012131:Respiratory Insufficiency / Q000378:metabolism* / Q000473:pathology; D000685:Serum Amyloid A Protein / Q000378:metabolism; D000076988:Sulfate Transporters; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D040501:Calgranulin A; D040502:Calgranulin B; C515451:Ccl7 protein, mouse; D054410:Chemokine CCL7; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; D037102:Lectins; D010455:Peptides; D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; C076498:Saa3 protein, mouse; D000685:Serum Amyloid A Protein; C489680:Sftpc protein, mouse; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040262:Receptors, Vascular Endothelial Growth Factor; D002688:Chitinases; C525260:Ym2 protein, mouse; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases
keywords: alveolarization; bronchopulmonary dysplasia; inflammation; microvascular development; surfactant