The authors compared efficiency of alveolar macrophage (AM) reconstitution from donor bone marrow post transplant following 4 chemotherapy conditioning regimens and 2 total body irradiation (TBI) regimens. TBI regimens are more effective in inducing AM reconstitution from donor marrow. However, mice conditioned with 13 Gy split-dose TBI or a dual-chemotherapy regimen (25 mg/kg busulfan × 4 days plus cyclophosphamide 100 mg/kg × 2 days) both demonstrate significant AM repopulation from donor marrow. Additionally, both protocols resulted in impaired pulmonary host defense associated with overproduction of prostaglandin E 2 and I 2 by AMs and impaired AM phagocytosis post bone marrow transplant.
Keywords
phagocytosis; prostaglandin; P. aeruginosaThe lung has the largest interface with the outside environment of any internal organ in the body. As such, the lung is constantly bombarded with foreign particles and pathogens. Active host defense requires the orchestration of innate immune cells and immune mediators such as cytokines, chemokines, and eicosanoids to aid in the recognition, containment, and clearance of microorganisms [1]. Unfortunately, patients who have undergone stem cell transplantation are at risk for pulmonary infections [2][3][4][5] and pneumonia remains the leading infectious cause of death following stem cell transplantation despite the implementation of numerous prophylactic strategies and advances in diagnosis and treatment [6]. These transplant patients manifest increased susceptibility to infections for periods of time (months to years) post transplantation, extending long after engraftment of leukocytes from donor sources [2,7].We have previously established a murine model of gram-negative bacterial infection following bone marrow transplantation (BMT) and have shown that these mice are more susceptible to pulmonary infection with the gram-negative pathogen Pseudomonas aeruginosa due to defects in innate immune cells. these studies involved 13 Gy of total body irradiation (TBI) followed by reconstitution with 5 × 10 6 whole bone marrow (BM) cells + 1 × 10 6 syngeneic splenic T cells. We demonstrated that AMs from these mice were >87% donor-derived by 3 weeks post BMT [4]. Despite the fact that the alveolar macrophages (AMs) were largely donor derived, the AMs were defective in their ability to both phagocytose and kill bacteria [4,8]. In this model, AMs post BMT produced elevated amounts of prostaglandin E 2 (PGE 2 ), which is known to inhibit host defense [4,8,9]. However, one caveat to the extrapolation of these findings is that the experimental conditioning regimen utilized in our previous studies does not mimic human clinical practice. Thus, to determine the applicability of these findings to BMT performed following different conditioning regimens, we compared the level of AM reconstitution and prostaglandin production following multiple TBI and chemotherapy preparative regimens. Our results demonstrate that significant reconstitution of AMs from donor BM following either TBI or c...