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* From the Departments of Internal Medicine (Drs. Zhu, Zheng, Q. Chen, and Elias and Ms N-Y Chen) and Pathology (Dr. Homer), Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT; and the Department of Obstetrics/Gynecology (Dr. Enhorning), State University of New York at Buffalo, Buffalo, NY.
Correspondence to: Zhou Zhu, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520; e-mail: zhou.zhu{at}yale.edu
Overexpression of interleukin (IL)-13 in the murine lung causes eosinophil-predominant and macrophage-predominant inflammation, increased airway resistance, and airway hyperresponsiveness.1 These mice also manifest increased production and accumulation of surfactant apoproteins and alterations in surfactant phospholipid composition.2 However, the effects of IL-13 on surfactant function have not been defined. We hypothesized that IL-13 alters surfactant function as well as production.
To test this hypothesis, we evaluated surfactant function, phospholipid concentration, the total amount of proteins, and potential inhibitory factors in the BAL fluid from CC10-IL-13 transgene-positive (+) mice and transgene-negative (-) littermate controls. A capillary surfactometer was used to assess the ability of the surfactant to maintain the openness of a capillary glass tube modeling a terminal-conducting airway. IL-13(+) mice had increased phospholipid concentrations but showed significantly lower surfactant activity compared to those of littermate controls (p < 0.05), when calibrated to an equal amount of phospholipids. Purified surfactants from IL-13(+) and IL-13(-) mice were equally active in maintaining patency, indicating that the surfactants were functionally normal. We then determined whether the BAL protein fractions altered the function of a calf lung surfactant extract (CLSE) positive control. The protein fraction in BAL fluid samples from IL-13(-) mice showed no adverse effect on CLSE function. In contrast, the protein fraction from IL-13(+) mice suppressed CLSE function by > 80%. Furthermore, the inhibitory effect of this fraction on the patency test correlated with increased total protein concentrations in BAL fluid samples of IL-13(+) mice (p < 0.001).
Significantly increased levels of fibrinogen and serum albumin, both known inhibitors of surfactant function, were present in the BAL fluid samples from IL-13(+) mice, indicating either a leakage of serum proteins into the airways or an abnormal production of these inhibitors in the lungs of these mice. In conclusion, airway surfactants were increased in IL-13(+) mice, and purified surfactants were functionally normal. However, highly potent factors are present in the lungs of IL-13 transgenic mice that inhibit surfactant function. Surfactant alterations may contribute to the pathogenesis of IL-13-induced pathologic and physiologic abnormalities. Blockade or elimination of the factors that inhibit surfactant function may have therapeutic implications for IL-13-induced diseases.
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