Surfactant protein A is a required mediator of keratinocyte growth factor after experimental marrow transplantation.
We reported an association between the ability of recombinant human keratinocyte growth factor (rHuKGF) to upregulate the expression of surfactant protein A (SP-A) and to downregulate pulmonary inflammation that occurs after allogeneic bone marrow transplantation (BMT). To establish a causal relationship, rHuKGF (5 mg/kg) was administered subcutaneously for three consecutive days before irradiation to SP-A-sufficient and -deficient [SP-A(+/+) and SP-A(-/-), respectively] mice given inflammation-inducing allogeneic spleen T cells at the time of BMT. In contrast with SP-A(+/+) mice, rHuKGF failed to suppress the high levels of TNF-alpha, IFN-gamma, and nitric oxide contained in bronchoalveolar lavage fluids collected on day 7 after BMT from SP-A(-/-) mice. Early post-BMT weight loss was attenuated by rHuKGF in both SP-A(+/+) and SP-A(-/-) recipients. In the absence of supportive respiratory care, however, SP-A deficiency eventually abolished the ability of rHuKGF to prevent weight loss and to improve survival monitored for 1 mo after allogeneic BMT. In further experiments, the addition of cyclophosphamide (which is known to cause severe injury to the alveolar epithelium in donor T cell-recipient mice) to the conditioning regimen prevented rHuKGF-induced upregulation of SP-A and suppression of lung inflammation in both SP-A(+/+) and SP-A(-/-) mice. We conclude that endogenous baseline SP-A levels and optimal upregulation of SP-A are required for the anti-inflammatory protective effects of KGF after allogeneic transplantation.
Univ. of Minnesota, Dept. of Pediatrics, 420 Delaware St. S.E., Minneapolis, MN 55455, USA. hadda003@tc.umn.edu
Imad Y
IY
Haddad
Carlos
C
Milla
Shuxia
S
Yang
Angela
A
Panoskaltsis-Mortari
Samuel
S
Hawgood
David L
DL
Lacey
Bruce R
BR
Blazar
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000401:mortality; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008170:Lung Compliance / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000276:immunology; D015431:Weight Loss
C496454:Fgf7 protein, mouse; D037662:Pulmonary Surfactant-Associated Protein A; D011994:Recombinant Proteins; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors