Abstract
Endothelin-1 (ET-1) mediates the development of pulmonary hypertension (PHT) in newborn rats exposed to 60% O2 for 14 days, a model for human chronic neonatal lung iniury. ET-1 production by d-14 rat pulmonary artery smooth muscle cells in vitro was markedly increased by thromboxane (TX) A2 receptor agonists and inhibited by a competitive antagonist. We hypothesized that stimulation of the TX A2 receptor contributed to O2-mediated PHT in vivo. Newborn rat pups received daily intraperitoneal injections of L670596, a competitive TX A2 receptor antagonist, or 5,5-dimethyl-3-(3-fluorophenyl)4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 inhibitor, during 14 days of 60% O2 or air exposure. L670596, but not DFU, prevented 60% O2-mediated right ventricular and small pulmonary vessel smooth muscle hypertrophy. Lung ET-1 content was significantly reduced by L670596 in 60% O2-exposed animals. We conclude that TX A2 receptor activation, though not by TX A2, caused upregulation of ET-1 and PHT in this model. A likely mediator is the stable lipid peroxidation product, 8-iso-prostane, which acts as an incidental ligand of the TX A2 receptor and is a potent inducer of ET-1 production by cultured d-14 rat pulmonary artery smooth muscle cells in vitro.
| Original language | English |
|---|---|
| Pages (from-to) | 208-214 |
| Number of pages | 7 |
| Journal | American Journal of Respiratory and Critical Care Medicine |
| Volume | 166 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 15 Jul 2002 |
| Externally published | Yes |
Fingerprint
Keywords
- 8-isoprostane
- Endothelin-1
- Pulmonary oxygen toxicity
- Reactive oxygen species
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Critical Care and Intensive Care Medicine
Cite this
Thromboxane A2 receptors mediate pulmonary hypertension in 60% oxygen-exposed newborn rats by a cyclooxygenase-independent mechanism. / Jankov, Robert P.; Belcastro, Rosetta; Ovcina, Emira; Lee, Julia; Massaeli, Hamid; Lye, Stephen J.; Keith Tanswell, A.
In: American Journal of Respiratory and Critical Care Medicine, Vol. 166, No. 2, 15.07.2002, p. 208-214.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Thromboxane A2 receptors mediate pulmonary hypertension in 60% oxygen-exposed newborn rats by a cyclooxygenase-independent mechanism
AU - Jankov, Robert P.
AU - Belcastro, Rosetta
AU - Ovcina, Emira
AU - Lee, Julia
AU - Massaeli, Hamid
AU - Lye, Stephen J.
AU - Keith Tanswell, A.
PY - 2002/7/15
Y1 - 2002/7/15
N2 - Endothelin-1 (ET-1) mediates the development of pulmonary hypertension (PHT) in newborn rats exposed to 60% O2 for 14 days, a model for human chronic neonatal lung iniury. ET-1 production by d-14 rat pulmonary artery smooth muscle cells in vitro was markedly increased by thromboxane (TX) A2 receptor agonists and inhibited by a competitive antagonist. We hypothesized that stimulation of the TX A2 receptor contributed to O2-mediated PHT in vivo. Newborn rat pups received daily intraperitoneal injections of L670596, a competitive TX A2 receptor antagonist, or 5,5-dimethyl-3-(3-fluorophenyl)4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 inhibitor, during 14 days of 60% O2 or air exposure. L670596, but not DFU, prevented 60% O2-mediated right ventricular and small pulmonary vessel smooth muscle hypertrophy. Lung ET-1 content was significantly reduced by L670596 in 60% O2-exposed animals. We conclude that TX A2 receptor activation, though not by TX A2, caused upregulation of ET-1 and PHT in this model. A likely mediator is the stable lipid peroxidation product, 8-iso-prostane, which acts as an incidental ligand of the TX A2 receptor and is a potent inducer of ET-1 production by cultured d-14 rat pulmonary artery smooth muscle cells in vitro.
AB - Endothelin-1 (ET-1) mediates the development of pulmonary hypertension (PHT) in newborn rats exposed to 60% O2 for 14 days, a model for human chronic neonatal lung iniury. ET-1 production by d-14 rat pulmonary artery smooth muscle cells in vitro was markedly increased by thromboxane (TX) A2 receptor agonists and inhibited by a competitive antagonist. We hypothesized that stimulation of the TX A2 receptor contributed to O2-mediated PHT in vivo. Newborn rat pups received daily intraperitoneal injections of L670596, a competitive TX A2 receptor antagonist, or 5,5-dimethyl-3-(3-fluorophenyl)4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 inhibitor, during 14 days of 60% O2 or air exposure. L670596, but not DFU, prevented 60% O2-mediated right ventricular and small pulmonary vessel smooth muscle hypertrophy. Lung ET-1 content was significantly reduced by L670596 in 60% O2-exposed animals. We conclude that TX A2 receptor activation, though not by TX A2, caused upregulation of ET-1 and PHT in this model. A likely mediator is the stable lipid peroxidation product, 8-iso-prostane, which acts as an incidental ligand of the TX A2 receptor and is a potent inducer of ET-1 production by cultured d-14 rat pulmonary artery smooth muscle cells in vitro.
KW - 8-isoprostane
KW - Endothelin-1
KW - Pulmonary oxygen toxicity
KW - Reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=0037099166&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037099166&partnerID=8YFLogxK
U2 - 10.1164/rccm.200112-124OC
DO - 10.1164/rccm.200112-124OC
M3 - Article
C2 - 12119234
AN - SCOPUS:0037099166
VL - 166
SP - 208
EP - 214
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 2
ER -