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.

This article has been cited by other articles:

				A.-M. Pulichino, I-M. Wang, A. Caron, J. Mortimer, A. Auger, Y. Boie, J. A. Elias, A. Kartono, L. Xu, J. Menetski, et al. Identification of Transforming Growth Factor {beta}1-Driven Genetic Programs of Acute Lung Fibrosis Am. J. Respir. Cell Mol. Biol., September 1, 2008; 39(3): 324 - 336. [Abstract] [Full Text] [PDF]

				J. L. Wright, M. Cosio, and A. Churg Animal models of chronic obstructive pulmonary disease Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L1 - L15. [Abstract] [Full Text] [PDF]

				D. D. Sin and S. F. P. Man Interleukin-6: A Red Herring or a Real Catch in COPD? Chest, January 1, 2008; 133(1): 4 - 6. [Full Text] [PDF]

				M. R. Edwards, J. Haas, R. A. Panettieri Jr., M. Johnson, and S. L. Johnston Corticosteroids and beta2 Agonists Differentially Regulate Rhinovirus-induced Interleukin-6 via Distinct Cis-acting Elements J. Biol. Chem., May 25, 2007; 282(21): 15366 - 15375. [Abstract] [Full Text] [PDF]

				Y. Bosse, K. Maghni, and T. J. Hudson 1{alpha},25-Dihydroxy-vitamin D3 stimulation of bronchial smooth muscle cells induces autocrine, contractility, and remodeling processes Physiol Genomics, April 24, 2007; 29(2): 161 - 168. [Abstract] [Full Text] [PDF]

				M. Dahl, J. Vestbo, P. Lange, S. E. Bojesen, A. Tybjaerg-Hansen, and B. G. Nordestgaard C-reactive Protein As a Predictor of Prognosis in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., February 1, 2007; 175(3): 250 - 255. [Abstract] [Full Text] [PDF]

				A. J. Ammit, L. M. Moir, B. G. Oliver, J. M. Hughes, H. Alkhouri, Q. Ge, J. K. Burgess, J. L. Black, and M. Roth Effect of IL-6 trans-signaling on the pro-remodeling phenotype of airway smooth muscle Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L199 - L206. [Abstract] [Full Text] [PDF]

				A. Hirano, A. Kanehiro, K. Ono, W. Ito, A. Yoshida, C. Okada, H. Nakashima, Y. Tanimoto, M. Kataoka, E. W. Gelfand, et al. Pirfenidone Modulates Airway Responsiveness, Inflammation, and Remodeling after Repeated Challenge Am. J. Respir. Cell Mol. Biol., September 1, 2006; 35(3): 366 - 377. [Abstract] [Full Text] [PDF]

				Y. Adachi, H. Oyaizu, S. Taketani, K. Minamino, K. Yamaguchi, L. D. Shultz, M. Iwasaki, M. Tomita, Y. Suzuki, K. Nakano, et al. Treatment and Transfer of Emphysema by a New Bone Marrow Transplantation Method from Normal Mice to Tsk Mice and Vice Versa Stem Cells, September 1, 2006; 24(9): 2071 - 2077. [Abstract] [Full Text] [PDF]

				W. Ito, A. Kanehiro, K. Matsumoto, A. Hirano, K. Ono, H. Maruyama, M. Kataoka, T. Nakamura, E. W. Gelfand, and M. Tanimoto Hepatocyte Growth Factor Attenuates Airway Hyperresponsiveness, Inflammation, and Remodeling Am. J. Respir. Cell Mol. Biol., April 1, 2005; 32(4): 268 - 280. [Abstract] [Full Text] [PDF]

				R. A. Johnston, I. N. Schwartzman, L. Flynt, and S. A. Shore Role of interleukin-6 in murine airway responses to ozone Am J Physiol Lung Cell Mol Physiol, February 1, 2005; 288(2): L390 - L397. [Abstract] [Full Text] [PDF]

				S. D. Reynolds, A. Giangreco, K. U. Hong, K. E. McGrath, L. A. Ortiz, and B. R. Stripp Airway injury in lung disease pathophysiology: selective depletion of airway stem and progenitor cell pools potentiates lung inflammation and alveolar dysfunction Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1256 - L1265. [Abstract] [Full Text] [PDF]

				M. D. Wewers {alpha}1-Antitrypsin Deficiency: More Than a Protease Imbalance? Chest, May 1, 2004; 125(5): 1607 - 1609. [Full Text] [PDF]

				J. Wang, Q. Chen, J. Corne, Z. Zhu, C. G. Lee, V. Bhandari, R. J. Homer, and J. A. Elias Pulmonary Expression of Leukemia Inhibitory Factor Induces B Cell Hyperplasia and Confers Protection in Hyperoxia J. Biol. Chem., August 15, 2003; 278(33): 31226 - 31232. [Abstract] [Full Text] [PDF]

				T. Kobayashi, K. Iijima, and H. Kita Marked Airway Eosinophilia Prevents Development of Airway Hyper-responsiveness During an Allergic Response in IL-5 Transgenic Mice J. Immunol., June 1, 2003; 170(11): 5756 - 5763. [Abstract] [Full Text] [PDF]

				A. M. Vignola, F. Mirabella, G. Costanzo, R. Di Giorgi, M. Gjomarkaj, V. Bellia, and G. Bonsignore Airway Remodeling in Asthma Chest, March 1, 2003; 123(2007): 417S - 422S. [Abstract] [Full Text] [PDF]

				P. R. Eynott, N. Paavolainen, D. A. Groneberg, A. Noble, M. Salmon, P. Nath, S.-Y. Leung, and K. F. Chung Role of Nitric Oxide in Chronic Allergen-Induced Airway Cell Proliferation and Inflammation J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 22 - 29. [Abstract] [Full Text] [PDF]

				R Mahadeva and S D Shapiro Chronic obstructive pulmonary disease * 3: Experimental animal models of pulmonary emphysema Thorax, October 1, 2002; 57(10): 908 - 914. [Abstract] [Full Text] [PDF]

				T. L. CROXTON, G. G. WEINMANN, R. M. SENIOR, and J. R. HOIDAL Future Research Directions in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., March 15, 2002; 165(6): 838 - 844. [Full Text] [PDF]

				B. L. Diaz, H. Fujishima, Y. Kanaoka, Y. Urade, and J. P. Arm Regulation of Prostaglandin Endoperoxide Synthase-2 and IL-6 Expression in Mouse Bone Marrow-Derived Mast Cells by Exogenous But Not Endogenous Prostanoids J. Immunol., February 1, 2002; 168(3): 1397 - 1404. [Abstract] [Full Text] [PDF]

				J. H. J. Vernooy, M. A. Dentener, R. J. van Suylen, W. A. Buurman, and E. F. M. Wouters Long-Term Intratracheal Lipopolysaccharide Exposure in Mice Results in Chronic Lung Inflammation and Persistent Pathology Am. J. Respir. Cell Mol. Biol., January 1, 2002; 26(1): 152 - 159. [Abstract] [Full Text] [PDF]

				A. DUGUET, H. IIJIMA, S.-Y. EUM, Q. HAMID, and D. H. EIDELMAN Eosinophil Peroxidase Mediates Protein Nitration in Allergic Airway Inflammation in Mice Am. J. Respir. Crit. Care Med., October 1, 2001; 164(7): 1119 - 1126. [Abstract] [Full Text] [PDF]

				Z. Wang, T. Zheng, Z. Zhu, R. J. Homer, R. J. Riese, H. A. Chapman , Jr., S. D. Shapiro, and J. A. Elias Interferon {{gamma}} Induction of Pulmonary Emphysema in the Adult Murine Lung J. Exp. Med., December 4, 2000; 192(11): 1587 - 1600. [Abstract] [Full Text] [PDF]

				D. C. Underwood, R. R. Osborn, S. Bochnowicz, E. F. Webb, D. J. Rieman, J. C. Lee, A. M. Romanic, J. L. Adams, D. W. P. Hay, and D. E. Griswold SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung Am J Physiol Lung Cell Mol Physiol, November 1, 2000; 279(5): L895 - L902. [Abstract] [Full Text] [PDF]

				J. Wang, R. J. Homer, Q. Chen, and J. A. Elias Endogenous and Exogenous IL-6 Inhibit Aeroallergen-Induced Th2 Inflammation J. Immunol., October 1, 2000; 165(7): 4051 - 4061. [Abstract] [Full Text] [PDF]