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Adenosine metabolism and murine strain–specific IL-4–induced inflammation, emphysema, and fibrosis
Bing Ma, … , Hays W. Young, Jack A. Elias
Bing Ma, … , Hays W. Young, Jack A. Elias
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1274-1283. https://doi.org/10.1172/JCI26372.
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Research Article Pulmonology

Adenosine metabolism and murine strain–specific IL-4–induced inflammation, emphysema, and fibrosis

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Abstract

To define the factors that control the tissue effects of IL-4, we compared the effects of Tg IL-4 in Balb/c and C57BL/6 mice. In the former, IL-4 caused modest eosinophilic inflammation and mild airway fibrosis and did not shorten survival. In C57BL/6 mice, IL-4 caused profound eosinophilic inflammation, airway fibrosis, emphysematous alveolar destruction, and premature death. These differences could not be accounted for by changes in Th2 or Th1 cytokines, receptor components, STAT6 activation, MMPs, or cathepsins. In contrast, in C57BL/6 mice, alveolar remodeling was associated with decreased levels of tissue inhibitors of metalloproteinase 2, -3, and -4 and α1-antitrypsin, and fibrosis was associated with increased levels of total and bioactive TGF-β1. Impressive differences in adenosine metabolism were also appreciated, with increased tissue adenosine levels and A1, A2B, and A3 adenosine receptor expression and decreased adenosine deaminase (ADA) activity in C57BL/6 animals. Treatment with ADA also reduced the inflammation, fibrosis, and emphysematous destruction and improved the survival of C57BL/6 Tg animals. These studies demonstrate that genetic influences control IL-4 effector pathways in the murine lung. They also demonstrate that IL-4 has different effects on adenosine metabolism in Balb/c and C57BL/6 mice and that these differences contribute to the different responses that IL-4 induces in these inbred animals.

Authors

Bing Ma, Michael R. Blackburn, Chun Geun Lee, Robert J. Homer, Wei Liu, Richard A. Flavell, Lynn Boyden, Richard P. Lifton, Chun-Xiao Sun, Hays W. Young, Jack A. Elias

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Figure 1

Different phenotypes induced by IL-4 in C57BL/6 and Balb/c mice.

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Different phenotypes induced by IL-4 in C57BL/6 and Balb/c mice.
IL-4 Tg...
IL-4 Tg mice were generated on C57BL/6 (B6) and Balb/c (BC) backgrounds. At 3 months of age, total and differential BAL fluid cell recovery (A), histology (B), lung volume (C), alveolar chord length (D), collagen content (E), and trichrome staining (F) were assessed. The survival of Tg-positive C57BL/6 and Tg-positive Balb/c mice and F1 and F2 backcrosses of Tg-positive Balb/c mice with wild-type C57BL/6 animals is illustrated in G. B and F are representative of at least 5 similar experiments. The values in the rest of the figures represent the mean ± SEM of experiments with a minimum of 5 animals. Neu, neutrophil; lym, lymphocyte; eos, eosinophil; mac, macrophage. *P < 0.01. Original magnification, ×10 (B); ×20 (F).
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