Cyclophosphamide prevents systemic keratinocyte growth factor-induced up-regulation of surfactant protein A after allogeneic transplant in mice.
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 microg) 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.
Yang
S
S
Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Panoskaltsis-Mortari
A
A
Ingbar
D H
DH
Matalon
S
S
Zhu
S
S
Resnik
E R
ER
Farrell
C L
CL
Lacey
D L
DL
Blazar
B R
BR
Haddad
I Y
IY
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003520:Cyclophosphamide / Q000494:pharmacology*; D005260:Female; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006133:Growth Substances / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism; D015603:Keratinocytes; D008171:Lung Diseases / Q000209:etiology / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D008212:Lymphocyte Depletion; D051379:Mice; D008815:Mice, Inbred Strains; D011510:Proteolipids / Q000378:metabolism*; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000378:metabolism*; D013601:T-Lymphocytes / Q000637:transplantation; D019172:Transplantation Conditioning; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis; D015854:Up-Regulation / Q000187:drug effects
C496454:Fgf7 protein, mouse; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D051523:Fibroblast Growth Factor 7; C002744:3-nitrotyrosine; D014443:Tyrosine; D005346:Fibroblast Growth Factors; D003520:Cyclophosphamide