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Am. J. Respir. Crit. Care Med., Volume 162, Number 5, November 2000, 1884-1890

Cyclophosphamide Prevents Systemic Keratinocyte Growth Factor-induced Up-Regulation of Surfactant Protein A after Allogeneic Transplant in Mice

SHUXIA YANG, ANGELA PANOSKALTSIS-MORTARI, DAVID H. INGBAR, SADIS MATALON, SHA ZHU, ERNESTO R. RESNIK, CATHERINE L. FARRELL, DAVID L. LACEY, BRUCE R. BLAZAR, and IMAD Y. HADDAD

Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, Minnesota; Department of Anesthesiology Research, University of Alabama, Birmingham, Alabama; and Amgen Inc., Thousand Oaks, California

We reported that systemic keratinocyte growth factor (KGF) given before bone marrow transplantation (BMT) prevents allogeneic T cell-dependent lung inflammation assessed on Day 7 post-BMT, but the antiinflammatory effects of KGF were impaired in mice injected with both T cells and conditioning regimen of cyclophosphamide (Cy). Intratracheal KGF is known to stimulate the expression of surfactant protein A (SP-A), an oxidant-sensitive T cell immunomodulator produced by alveolar type II cells. We hypothesized that systemic KGF up-regulates SP-A after allogeneic BMT, and the addition of Cy may interfere with the ability of KGF to enhance SP-A production. The subcutaneous administration of recombinant human KGF (5 mg/kg on Days -6, -5, and -4 pre-BMT) increased SP-A protein and mRNA in allogeneic T cell-recipient irradiated mice measured on Day 7 post-BMT. In contrast, the same KGF treatment in irradiated mice given T cells and Cy failed to up-regulate SP-A mRNA and protein expression. In mixed lymphocyte reaction experiments designed to simulate the in vivo model, the addition of human SP-A (5-50 µg) to alloactivated T cells suppressed the production of interleukin-2 in a dose-dependent fashion. We conclude that the systemic pre-BMT injection of KGF in recipients of allogeneic T cells up-regulates SP-A, which may contribute to the early antiinflammatory effects of KGF. The protective KGF-mediated SP-A production is abolished in mice given alloreactive T cells plus Cy.




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