Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice.
The pulmonary endothelin (ET) system has been implicated in the pathogenesis of chronic lung diseases such as pulmonary hypertension, asthma, chronic obstructive lung disease, idiopathic pulmonary fibrosis, and bronchiolitis obliterans. However, the etiologic role of ET-1 in these diseases has not yet been established. We recently demonstrated that ET-1 transgenic mice, generated using the human prepro-ET-1 expression cassette including the cis-acting transcriptional regulatory elements, had predominant transgene expression in lung, brain, and kidney. We used these mice in the present study to analyze the pathophysiologic consequences of long-term pulmonary overexpression of ET-1. We found that ET-1 overexpression in the lungs did not result in significant pulmonary hypertension, but did result in development of a progressive pulmonary fibrosis and recruitment of inflammatory cells (predominantly CD4-positive cells). Our study provides evidence that a long-term activated pulmonary ET system, without any other stimuli, produces chronic lymphocytic inflammation and lung fibrosis. This suggests that overexpression of ET-1 may be a central event in the pathogenesis of lung diseases associated with fibrosis and chronic inflammation, such as pulmonary fibrosis and bronchiolitis.
Hocher
B
B
Department of Nephrology and Institute of Pharmacology and Toxicology, University Hospital Charité, Humboldt University of Berlin, Germany. berthold.hocher@charite.de
Schwarz
A
A
Fagan
K A
KA
Thöne-Reineke
C
C
El-Hag
K
K
Kusserow
H
H
Elitok
S
S
Bauer
C
C
Neumayer
H H
HH
Rodman
D M
DM
Theuring
F
F
D000818:Animals; D017209:Apoptosis; D001784:Blood Gas Analysis; D001980:Bronchi / Q000098:blood supply / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D002908:Chronic Disease; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D009929:Organ Size; D009928:Organ Specificity; D011651:Pulmonary Artery / Q000254:growth & development; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D017725:Ventricular Pressure
D019332:Endothelin-1; D017466:Receptors, Endothelin