Down-regulation of the inhibitor of growth family member 4 (ING4) in different forms of pulmonary fibrosis.
BACKGROUND
Recent evidence has underscored the role of hypoxia and angiogenesis in the pathogenesis of idiopathic fibrotic lung disease. Inhibitor of growth family member 4 (ING4) has recently attracted much attention as a tumor suppressor gene, due to its ability to inhibit cancer cell proliferation, migration and angiogenesis. The aim of our study was to investigate the role of ING4 in the pathogenesis of pulmonary fibrosis both in the bleomycin (BLM)-model and in two different types of human pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and cryptogenic organizing pneumonia (COP).


METHODS
Experimental model of pulmonary fibrosis was induced by a single tail vein injection of bleomycin in 6- to 8-wk-old C57BL/6mice. Tissue microarrays coupled with qRT-PCR and immunohistochemistry were applied in whole lung samples and paraffin-embedded tissue sections of 30 patients with IPF, 20 with COP and 20 control subjects.


RESULTS
A gradual decline of ING4 expression in both mRNA and protein levels was reported in the BLM-model. ING4 was also found down-regulated in IPF patients compared to COP and control subjects. Immunolocalization analyses revealed increased expression in areas of normal epithelium and in alveolar epithelium surrounding Masson bodies, in COP lung, whereas showed no expression within areas of active fibrosis within IPF and COP lung. In addition, ING4 expression levels were negatively correlated with pulmonary function parameters in IPF patients.


CONCLUSIONS
Our data suggest a potential role for ING4 in lung fibrogenesis. ING4 down-regulation may facilitate aberrant vascular remodelling and fibroblast proliferation and migration leading to progressive disease.
Tzouvelekis
Argyris
A
Department of Pneumonology, University Hospital of Alexandroupolis, Medical school, Democritus University of Thrace, Greece. atzouvelekis@yahoo.gr
Aidinis
Vassilis
V
Harokopos
Vagelis
V
Karameris
Andreas
A
Zacharis
George
G
Mikroulis
Dimitrios
D
Konstantinou
Fotios
F
Steiropoulos
Paschalis
P
Sotiriou
Ioannis
I
Froudarakis
Marios
M
Pneumatikos
Ioannis
I
Tringidou
Rodoula
R
Bouros
Demosthenes
D
D000818:Animals; D001761:Bleomycin; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D018549:Cryptogenic Organizing Pneumonia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D006115:Greece; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014109:Total Lung Capacity; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014797:Vital Capacity
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; C483230:ING4 protein, human; C540680:ING4 protein, mouse; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D001761:Bleomycin