The role of endothelin-1 in hyperoxia-induced lung injury in mice.
BACKGROUND
As prolonged hyperoxia induces extensive lung tissue damage, we set out to investigate the involvement of endothelin-1 (ET-1) receptors in these adverse changes.


METHODS
Experiments were performed on four groups of mice: control animals kept in room air and a group of mice exposed to hyperoxia for 60 h were not subjected to ET-1 receptor blockade, whereas the dual ETA/ETB-receptor blocker tezosantan (TEZ) was administered via an intraperitoneal pump (10 mg/kg/day for 6 days) to other groups of normal and hyperoxic mice. The respiratory system impedance (Zrs) was measured by means of forced oscillations in the anesthetized, paralyzed and mechanically ventilated mice before and after the iv injection of ET-1 (2 microg). Changes in the airway resistance (Raw) and in the tissue damping (G) and elastance (H) of a constant-phase tissue compartment were identified from Zrs by model fitting.


RESULTS
The plasma ET-1 level increased in the mice exposed to hyperoxia (3.3 +/- 1.6 pg/ml) relative to those exposed to room air (1.6 +/- 0.3 pg/ml, p < 0.05). TEZ administration prevented the hyperoxia-induced increases in G (13.1 +/- 1.7 vs. 9.6 +/- 0.3 cmH2O/l, p < 0.05) and H (59 +/- 9 vs. 41 +/- 5 cmH2O/l, p < 0.05) and inhibited the lung responses to ET-1. Hyperoxia decreased the reactivity of the airways to ET-1, whereas it elevated the reactivity of the tissues.


CONCLUSIONS
These findings substantiate the involvement of the ET-1 receptors in the physiopathogenesis of hyperoxia-induced lung damage. Dual ET-1 receptor antagonism may well be of value in the prevention of hyperoxia-induced parenchymal damage.
Pediatric Anesthesia Unit, Geneva Children's Hospital, University Hospitals of Geneva, 6, Rue Willy Donze, CH-1205, Geneva, Switzerland. Walid.Habre@hcuge.ch
Walid
W
Habre
Ferenc
F
Peták
Isabelle
I
Ruchonnet-Metrailler
Yves
Y
Donati
Jean-Francois
JF
Tolsa
Eniko
E
Lele
Gergely
G
Albu
Morice
M
Beghetti
Constance
C
Barazzone-Argiroffo
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D019332:Endothelin-1 / Q000097:blood / Q000494:pharmacology*; D005260:Female; D018496:Hyperoxia / Q000097:blood* / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008171:Lung Diseases / Q000097:blood* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011725:Pyridines / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D011725:Pyridines; D017466:Receptors, Endothelin; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan