IL-1beta disrupts postnatal lung morphogenesis in the mouse.
Pulmonary inflammation and increased production of the inflammatory cytokine IL-1beta are associated with the development of bronchopulmonary dysplasia (BPD) in premature infants. To study the actions of IL-1beta in the fetal and newborn lung in vivo, we developed a bitransgenic mouse in which IL-1beta is expressed under conditional control in airway epithelial cells. Perinatal pulmonary expression of IL-1beta caused respiratory insufficiency that was associated with increased postnatal mortality. While intrauterine growth of IL-1beta-expressing mice was normal, their postnatal growth was impaired. IL-1beta disrupted alveolar septation and caused abnormalities in alpha-smooth muscle actin and elastin deposition in the septa of distal airspaces. IL-1beta disturbed capillary development and inhibited the production of vascular endothelial growth factor in the lungs of infant mice. IL-1beta induced the expression of CXC chemokines KC (CXCL1) and macrophage inflammatory protein-2 (CXCL2) and of CC chemokines monocyte chemotactic protein (MCP)-1 (CCL2) and MCP-3 (CCL7), consistent with neutrophilic and monocytic infiltration of the lungs. IL-1beta caused goblet cell metaplasia and bronchial smooth muscle hyperplasia. Perinatal expression of IL-1beta in epithelial cells of the lung caused a lung disease that was clinically and histologically similar to BPD.
Bry
Kristina
K
Goteborg University, Department of Pediatrics, The Queen Silvia Children's Hospital, 41685 Goteborg, Sweden. kristina.bry@pediat.gu.se
Whitsett
Jeffrey A
JA
Lappalainen
Urpo
U
D000199:Actins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism / Q000473:pathology*; D018932:Chemokine CCL2 / Q000378:metabolism; D054410:Chemokine CCL7; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000378:metabolism; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007231:Infant, Newborn; D053583:Interleukin-1beta / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000002:abnormalities / Q000098:blood supply / Q000254:growth & development*; D051379:Mice; D008822:Mice, Transgenic; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000199:Actins; C515450:CCL7 protein, human; C491768:Ccl2 protein, mouse; C515451:Ccl7 protein, mouse; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D053583:Interleukin-1beta; D018945:Monocyte Chemoattractant Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D004549:Elastin