Early growth response gene-1 promotes airway allograft rejection.
Chronic airway rejection, characterized by lymphocytic bronchitis, epithelial cell damage, and obliterative bronchiolitis (OB), limits long-term survival after lung transplantation. The transcription factor early growth response gene-1 (Egr-1) induces diverse inflammatory mediators, some involved in OB pathogenesis. An orthotopic mouse tracheal transplant model was used to determine whether Egr-1 promotes development of airway allograft rejection. Significantly higher Egr-1 mRNA levels were seen in allografts (3.2-fold increase vs. isografts, P = 0.012). Allografts revealed thickening of epithelial and subepithelial airway layers (51 +/- 4% luminal encroachment for allografts vs. 20 +/- 3% for isografts, P < 0.0001) marked by significant lymphocytic infiltration. Absence of the Egr-1 gene in donor (but not recipient) tissue resulted in significant reduction in luminal narrowing (34 +/- 4%, P = 0.0001) with corresponding diminution of T cell infiltration. Egr-1 null allografts exhibited a striking reduction in inducible nitric oxide synthase (iNOS) expression. Effector cytokines previously implicated in OB pathogenesis with known Egr-1 promoter motifs (IL-1beta and JE/monocyte chemoattractant protein-1) were reduced in Egr-1 null allografts. These data suggest a paradigm wherein local induction of Egr-1 in tracheal allografts drives expression of inflammatory mediators responsible for lymphocyte recruitment and tissue destruction characteristic of airway rejection.
Harada
Hiroaki
H
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Lama
Vibha N
VN
Badri
Linda N
LN
Ohtsuka
Takashi
T
Petrovic-Djergovic
Danica
D
Liao
Hui
H
Yoshikawa
Yasushi
Y
Iwanaga
Koichiro
K
Lau
Chris L
CL
Pinsky
David J
DJ
D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D051766:Early Growth Response Protein 1 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D016040:Lung Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014184:Transplantation, Homologous
D017252:CD3 Complex; D016207:Cytokines; D051766:Early Growth Response Protein 1; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II