title: Egr1: a novel target for ameliorating acute allograft rejection in an experimental lung transplant model.
abstract: OBJECTIVE
  Acute allograft rejection is one of the significant complications occurring in lung transplant recipients. Early growth response-1 (Egr-1), zinc-finger-type transcription factor, is known as a master switch regulator of diverse chemical mediators. We used an orthotopic mouse model of left lung transplant to elucidate the function of Egr-1 in acute pulmonary rejection.
  
  
  METHODS
  Left lung grafts retrieved from C57BL/6 wild mice or C57BL/6 Egr-1-null mice were orthotopically transplanted into BALB/c mice; the lungs were harvested at day 1, 3, 5 or 7 after lung transplantation. The grade of acute rejection was histopathologically evaluated. The intragraft gene expression levels of Egr-1 and downstream target mediators were quantitatively measured by real-time polymerase chain reaction. Immunohistochemical analysis was used to determine the location and distribution of the Egr-1 protein in the pulmonary graft.
  
  
  RESULTS
  Severe acute rejection was observed in allografts from wild-type mice at 5 days after transplantation. Only minimal rejection was seen in the lung graft from Egr-1-null donor mice at 5 days after transplantation. Strong upregulation of Egr-1 mRNA transcripts was observed at day 1, which then decreased during the next 5 days. The mRNA of Egr-1 target mediators [interleukin-1-beta (IL-1β), monocyte chemotactic protein-1 (MCP-1) and plasminogen activator inhibitor-1] reached maximal levels at day 5. Egr-1-null allografts exhibited significantly lower expressions of IL-1β and MCP-1 mRNA (P < 0.05).
  
  
  CONCLUSIONS
  Our study showed that deletion of Egr-1 in lung allografts ameliorates severe acute rejection with the reduction of expression levels of chemical mediators, implying a new possible strategy for treating acute pulmonary allograft rejection.
authors.affiliation: Department of Cancer and Thoracic Surgery,  Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,  Okayama University, Okayama,  Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Waki
authors.forename: Masaomi
authors.initials: M
authors.lastname: Yamane
authors.forename: Sumiharu
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Mikio
authors.initials: M
authors.lastname: Okazaki
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Sugimoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsukawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oto
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Miyoshi
mesh_terms: D000208:Acute Disease; D000818:Animals; D016516:CD4-CD8 Ratio; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016040:Lung Transplantation / Q000276:immunology / Q000473:pathology* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D012333:RNA, Messenger