title: Absence of Smad3 induces neutrophil migration after cutaneous irradiation: possible contribution to subsequent radioprotection.
abstract: Our previous work showed that 6 weeks after cutaneous irradiation, mice null (knockout, KO) for Smad3, a cytoplasmic downstream mediator of transforming growth factor-beta, demonstrate less epidermal acanthosis and dermal inflammation than wild-type (WT) Smad3 mice. Analysis of the kinetics of inflammation showed that 6 to 8 hours after skin irradiation, there was a transient sevenfold increase in neutrophil influx in Smad3 KO mice compared with WT. Herein we describe bone marrow transplantation and skin grafting between WT and KO mice to assess the contribution of the neutrophil genotype compared with that of irradiated skin to the induction of neutrophil migration after irradiation. Results from bone marrow transplantation showed that WT marrow transplanted into KO mice enhanced neutrophil migration 6 to 8 hours after irradiation by 3.2-fold compared with KO marrow in WT mice. KO skin grafted onto either WT or KO animals showed a sixfold elevation of neutrophils after irradiation compared with grafted WT skin. These results suggest that the genotype of the irradiated skin, rather than the inflammatory cell, controls neutrophil influx. Circulating neutrophils, increased in WT mice after injection of granulocyte colony-stimulating factor, resulted in increased neutrophil migration to the skin 6 to 8 hours after irradiation and less skin damage 6 weeks after irradiation compared with untreated WT mice. Thus, early responses, including enhanced neutrophil influx, appear to contribute to subsequent cutaneous radioprotection.
authors.affiliation: Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA. flanderk@dce41.nci.nih.gov
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Flanders
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Ho
authors.forename: Praveen R
authors.initials: PR
authors.lastname: Arany
authors.forename: Christina
authors.initials: C
authors.lastname: Stuelten
authors.forename: Mizuko
authors.initials: M
authors.lastname: Mamura
authors.forename: Miya Okada
authors.initials: MO
authors.lastname: Paterniti
authors.forename: Anastasia
authors.initials: A
authors.lastname: Sowers
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Anita B
authors.initials: AB
authors.lastname: Roberts
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology / Q000528:radiation effects*; D012867:Skin / Q000276:immunology / Q000528:radiation effects*; D016038:Skin Transplantation; D051900:Smad3 Protein / Q000172:deficiency* / Q000235:genetics*
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse