Interleukin-13 Produces COPD-Like Pathology in Mice
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WESTPORT, CT (Reuters Health) Dec 05 - Overexpression of interleukin-13 (IL-13) in the adult mouse lung leads to a condition mimicking human chronic obstructive pulmonary disease (COPD), researchers report in the November issue of the Journal of Clinical Investigation.
Since IL-13 has been implicated in the pathogenesis of asthma, Dr. Jack A. Elias from Yale University School of Medicine in New Haven, Connecticut, and a multicenter team proposed that the cytokine may also play a role in the pulmonary inflammation observed in chronic obstructive pulmonary disease. To test this idea, they generated transgenic mice that overexpressed IL-13 specifically in the lung when fed doxycycline.
Inducing IL-13 expression in the lungs of adult mice led to inflammatory cell infiltration and pronounced emphysema, with enhanced lung volumes and compliance and airway mucus metaplasia. IL-13 overexpression also induced the expression of matrix metalloproteinases-2, -9, -12, -13, and -14, as well as cathepsins B, S, L, H, and K. IL-13 overexpression did not alter the levels of various lung antiproteases.
To look at the importance of the induced matrix metalloproteinases, the researchers treated the animals with a broad-spectrum metalloproteinase antagonist. Although the treatment significantly decreased the emphysema and inflammation, it did not affect mucus metaplasia in the animals. Similar results were found using two cysteine protease inhibitors. Treating the mice with antagonists of both classes of proteases in combination had an additive effect, but did not restore alveolar volume or lung size to normal.
"These studies demonstrate that the targeted expression of IL-13 in the adult lung causes emphysema, mucus metaplasia, and inflammation that mirror, in many ways, the lesions seen in human chronic obstructive pulmonary disease," Dr. Elias and colleagues conclude. "They also demonstrate that this emphysematous response is mediated via matrix metalloproteinase and cathepsin-dependent pathways. IL-13 may play an important role in the pathogenesis of chronic obstructive pulmonary disease, particularly in patients with asthma-like features including airway hyperresponsiveness and eosinophilia."
J Clin Invest 2000;106:1081-1093. |
