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Idiopathic Pneumonia Syndrome after Syngeneic Bone Marrow Transplant in Mice

Departments of Medicine and Cell Biology, Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina

Correspondence and requests for reprints should be addressed to Rodney J. Folz, M.D., Ph.D., Duke University Medical Center, Box 2620, Room 331 MSRB, Durham, NC 27710. E-mail: rodney.folz{at}duke.edu

Idiopathic pneumonia syndrome is characterized by noninfectious diffuse lung injury after myeloablative chemotherapy and bone marrow transplant. Because little is known about its pathogenesis after autologous-based regimens, we have developed a murine model that closely mimics the human lung disease process. Using an autologous regimen similar to that used for patients with metastatic breast cancer, mice developed pulmonary injury as early as 1 day posttransplant. This lung injury was most dramatically characterized by decreased lung compliance that was associated with an intense monocytic cellular infiltrate of activated macrophages. This influx was preceded by an acute elevation in monocyte chemotactic protein-1 and macrophage inflammatory protein-1. The conditioning regimen caused substantial oxidative stress as manifest by elevations in lung lipid peroxidation and oxidized glutathione. To test the hypothesis that oxidation is directly responsible for the lung toxicity, we administered the antioxidant, n-acetylcysteine. These mice showed substantially less lung injury, thus providing direct evidence that oxidative stress plays a distinct role in the development of lung injury in the early periautologous bone marrow transplant period. Attenuation of lung oxidative stress and/or inflammation in patients undergoing autologous bone marrow transplant may reduce the subsequent development of idiopathic pneumonia syndrome.

Key Words: acute lung injury • interstitial pneumonitis • oxidative stress • inflammation

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