Cyclophosphamide prevents systemic keratinocyte growth factor-induced up-regulation of surfactant protein A after allogeneic transplant in mice

S. Yang, A. Panoskaltsis-Mortari, D. H. Ingbar, S. Matalon, S. Zhu, E. R. Resnik, C. L. Farrell, D. L. Lacey, B. R. Blazar, I. Y. Haddad

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17 Scopus citations

Abstract

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 hypothe-sized 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.

Original languageEnglish (US)
Pages (from-to)1884-1890
Number of pages7
JournalAmerican journal of respiratory and critical care medicine
Volume162
Issue number5
DOIs
StatePublished - Jan 1 2000

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