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Macrophage Elastase Prevents Gemella morbillorum Infection and Improves Outcome Following Murine Bone Marrow Transplantation^*

^* From the Departments of Medicine and Cell Biology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO.

Correspondence to: William Hartzell, MD, Pulmonary and Critical Care, Washington University, 216 S Kingshighway Blvd, St. Louis, MO 63110

Lung injury after bone marrow transplant (BMT) is a major cause of morbidity and mortality limiting the benefits of this procedure. One type of lung injury, idiopathic pneumonia syndrome, has been found to contain abundant expression of a macrophage-derived metalloproteinase, macrophage elastase (ME), in human lung biopsy specimens. To determine the role of ME in post-BMT lung injury, we developed a murine BMT model using wild-type (MME+/+) and mice deficient in ME (MME-/-), generated by gene targeting. Allogeneic single major histocompatibility complex mismatched BMTs were performed to replicate conditions that lead to lung injury.

Groups of wild-type (MME+/+) and MME-/- mice in a pure 129/Sv (H2K^b) background underwent total body irradiation (10 Gy in a single fraction), followed by BMT extracted from (H2K^d) NOD mice injected via tail vein. Initially groups of six MME+/+ and MME-/- mice were monitored for survival. Presently, all MME+/+ have lived for > 2 months while five of six MME-/- mice developed apparent respiratory distress and died by 2 weeks. Similar results were found using the bone marrow from B6.C-H2bm12 mice that have mutation at the IA^b site of the H-2 complex. Mice were subjected to BMT as above and killed at day 7 to 14 for assessment of pathologic changes and bone marrow engraftment. Hematologic indexes were comparable in both MME+/+ and MME-/- mice for that stage of bone marrow engraftment, demonstrating that marrow engraftment was not a significant factor in early mortality. Lung histology of MME-/- mice revealed alveolar hemorrhage in four of six mice along with areas of mononuclear cell infiltrates and necrosis, while wild-type mice had no significant lung pathologic findings. Necrosis was also observed in the gut, liver, and kidneys in several MME-/- mice. Bacterial stains of these organs from MME-/- mice revealed the presence of Gram-positive cocci in areas of tissue necrosis. Tissue cultures have subsequently grown Gemella morbillorum, an -hemolytic streptococcus. No bacterial infections in the lungs from wild-type mice have been observed by culture or by bacterial staining.

In summary, in the absence of ME, mice subjected to radiation therapy followed by allogeneic mismatched BMT are prone to pulmonary hemorrhage, tissue necrosis, and bacterial infection. We surprisingly conclude that ME appears to play a role in host defense crucial during times of neutropenia. We are currently investigating the novel bactericidal properties of ME.

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