Submitted on March 26, 2003
Accepted on May 6, 2003
Surfactant Protein A is a Required Mediator of Keratinocyte Growth Factor after Experimental Marrow Transplantation
Imad Y. Haddad1*, Carlos Milla2, Shuxia Yang2, Angela Panoskaltsis-Mortari1, Samuel Hawgood3, David L. Lacey4, and Bruce R. Blazar5
1 Department of Pediatrics, Division of Pulmonary and Critical Care, University of Minnesota, Minneapolis, MN, USA; Division of Bone Marrow Transplantation, and Cancer Center, University of Minnesota, Minneaoplis, MN, USA
2 Department of Pediatrics, Division of Pulmonary and Critical Care, University of Minnesota, Minneapolis, MN, USA
3 Department of Pediatrics, University of California San Francisco, USA
4 Amgen Inc., Thousand Oaks, CA, USA
5 Division of Bone Marrow Transplantation, and Cancer Center, University of Minnesota, Minneaoplis, MN, USA
* To whom correspondence should be addressed. E-mail: hadda003{at}tc.umn.edu.
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 prior to irradiation to SP-A-sufficient (SP-A+/+) and SP-A-deficient (SP-A-/-) mice given inflammation-inducing allogeneic spleen T cells at time of BMT. In contrast to SP-A+/+ mice, rHuKGF failed to suppress the high levels of TNF-
, IFN-
, and nitric oxide contained in bronchoalveolar lavage fluids collected on day 7 after BMT from SP-A-/- mice. rHuKGF attenuated early post-BMT weight loss 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 month after allogeneic BMT. In further experiments, the addition of cyclophosphamide to conditioning regimen, known to cause severe injury to the alveolar epithelium in donor T cell-recipient mice, 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.
