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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 1263-1268, (2002)
© 2002 American Thoracic Society

Original Article

Transient Lung-Specific Expression of the Chemokine KC Improves Outcome in Invasive Aspergillosis

Borna Mehrad, Maria Wiekowski, Brad E. Morrison, Shu-Cheng Chen, Elizabeth C. Coronel, Denise J. Manfra and Sergio A. Lira

Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey

Correspondence and requests for reprints should be addressed to Dr. Borna Mehrad, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390–9034. E-mail: borna.mehrad{at}utsouthwestern.edu

Invasive aspergillosis is a common and devastating pneumonia in immunocompromised hosts. Neutrophils are critical for defense against this infection, and ELR+ CXC chemokines are potent neutrophil chemoattractants. We hypothesized that transient lung-specific overexpression of one such ligand, KC, in mice with invasive aspergillosis improves the outcome of disease. We generated mice in which transgenic expression of KC was limited to the lungs and occurred only upon exposure to tetracycline analogues, and we exposed them to doxycycline after the onset of invasive aspergillosis. Transgenic mice had a threefold greater survival, a 74% lower lung fungal burden, a greater magnitude of lung KC induction, and an earlier and higher peak of lung neutrophil influx compared with wild-type mice. In addition to a higher number of neutrophils, we found a 1.8-fold higher number of monocytes–macrophages in the lungs of transgenic mice as compared with wild-type mice. Furthermore, transgenic mice had greater lung expression of interferon-{gamma} and interleukin-12 in response to infection, suggesting that transgenic expression of KC indirectly regulated the expression of other cytokines associated with improved host defense against this pathogen. Taken together, these data suggest that overexpression of KC in the lung in the setting of established invasive aspergillosis results in improved host defense and outcome of disease.

Key Words: fungi • neutrophils • pneumonia • transgenic mice




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