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Interleukin-1ß Causes Pulmonary Inflammation, Emphysema, and Airway Remodeling in the Adult Murine Lung

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

The production of the inflammatory cytokine interleukin (IL)-1 is increased in lungs of patients with chronic obstructive pulmonary disease (COPD) or asthma. To characterize the in vivo actions of IL-1 in the lung, transgenic mice were generated in which human IL-1ß was expressed in the lung epithelium with a doxycycline-inducible system controlled by the rat Clara cell secretory protein (CCSP) promoter. Induction of IL-1ß expression in the lungs of adult mice caused pulmonary inflammation characterized by neutrophil and macrophage infiltrates. IL-1ß caused distal airspace enlargement, consistent with emphysema. IL-1ß caused disruption of elastin fibers in alveolar septa and fibrosis in airway walls and in the pleura. IL-1ß increased the thickness of conducting airways, enhanced mucin production, and caused lymphocytic aggregates in the airways. Decreased immunostaining for the winged helix transcription factor FOXA2 was associated with goblet cell hyperplasia in IL-1ß–expressing mice. The production of the neutrophil attractant CXC chemokines KC (CXCL1) and MIP-2 (CXCL2), and of matrix metalloproteases MMP-9 and MMP-12, was increased by IL-1ß. Chronic production of IL-1ß in respiratory epithelial cells of adult mice causes lung inflammation, enlargement of distal airspaces, mucus metaplasia, and airway fibrosis in the adult mouse.

Key Words: cytokine • asthma • chronic obstructive pulmonary disease • metalloprotease • neutrophil

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