Am. J. Respir. Cell Mol. Biol., Volume 22, Number 3, March, 2000 289-295

Airway Hyperresponsiveness and Airway Obstruction in Transgenic Mice
Morphologic Correlates in Mice Overexpressing Interleukin (IL)-11 and IL-6 in the Lung

Charles Kuhn III, Robert J. Homer, Zhou Zhu, Nicholas Ward, Richard A. Flavell, Gregory P. Geba, and Jack A. Elias

Department of Pathology, Brown University School of Medicine and Memorial Hospital of Rhode Island, Pawtucket, Rhode Island; Department of Pathology, Section of Pulmonary and Critical Care Medicine, and Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven; and Pathology Service, VA-CT Healthcare System, West Haven, Connecticut

Understanding the sources of variation in airway reactivity and airflow is important for unraveling the pathophysiology of asthma, obstructive lung disease, and other pulmonary disorders. Transgenic expression of two closely related cytokines in the mouse lung produced opposite effects on these parameters. Interleukin (IL)-6 did not alter basal airways resistance and decreased methacholine responsiveness, whereas IL-11 caused airways obstruction and increased airway responses to methacholine. To clarify these differences we examined histologic sections and used morphometry to compare bronchiolar and parenchymal dimensions in 1- to 2-mo-old transgenic mice expressing IL-6 or IL-11 and littermate control mice. Both transgenic strains showed similar emphysema-like airspace enlargement, nodular peribronchiolar collections of mononuclear cells, thickening of airway walls, and subepithelial airway fibrosis. When compared with littermate control mice, the IL-6 mice showed an approximately 50% increase in the caliber of their bronchioles and an increase in airway wall thickness that was in proportion to the increase in the size of their airways. In contrast, the remodeling response was more robust in the IL-11 transgenic mice. It was also seen in airways with normal external and luminal diameters and thus was out of proportion to the caliber of their airways. These results support the hypothesis that structural alterations and resulting caliber changes of respiratory airways can have important effects on airway physiology and reactivity.

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