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IL-1 Disrupts Postnatal Lung Morphogenesis in the Mouse

Department of Pediatrics, Goteborg University, Goteborg, Sweden; and Divisions of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Correspondence and requests for reprints should be addressed to Kristina Bry, Goteborg University, Department of Pediatrics, The Queen Silvia Children's Hospital, 41685 Goteborg, Sweden. E-mail: kristina.bry{at}pediat.gu.se

Pulmonary inflammation and increased production of the inflammatory cytokine IL-1 are associated with the development of bronchopulmonary dysplasia (BPD) in premature infants. To study the actions of IL-1 in the fetal and newborn lung in vivo, we developed a bitransgenic mouse in which IL-1 is expressed under conditional control in airway epithelial cells. Perinatal pulmonary expression of IL-1 caused respiratory insufficiency that was associated with increased postnatal mortality. While intrauterine growth of IL-1–expressing mice was normal, their postnatal growth was impaired. IL-1 disrupted alveolar septation and caused abnormalities in -smooth muscle actin and elastin deposition in the septa of distal airspaces. IL-1 disturbed capillary development and inhibited the production of vascular endothelial growth factor in the lungs of infant mice. IL-1 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-1 caused goblet cell metaplasia and bronchial smooth muscle hyperplasia. Perinatal expression of IL-1 in epithelial cells of the lung caused a lung disease that was clinically and histologically similar to BPD.

Key Words: inflammation • bronchopulmonary dysplasia • cytokine

CLINICAL RELEVANCE The research shows for the first time that IL-1 production in the perinatal murine lung causes a disease that is similar to BPD. These results increase our understanding of the mechanisms by which BPD develops in infants with pulmonary inflammation.