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Cytosolic phospholipase A(2) in hypoxic pulmonary vasoconstriction
Fumito Ichinose1, Roman Ullrich, Adam Sapirstein
1Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. ichinose@etherdome.mgh.harvard.edu
The Journal of Clinical Investigation
|June 5, 2002
Summary
Cytosolic phospholipase A(2) (cPLA(2)) plays a key role in hypoxic pulmonary vasoconstriction (HPV). Mice lacking cPLA(2) activity showed impaired HPV, but this could be restored by interventions that augment pulmonary vascular tone.
Area of Science:
- Physiology
- Biochemistry
- Pulmonary Medicine
Background:
- Cytosolic phospholipase A(2) (cPLA(2)) is crucial for releasing arachidonic acid (AA) from cell membranes.
- Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to low oxygen levels in the lungs.
Purpose of the Study:
- To investigate the specific role of cPLA(2) in mediating HPV.
- To determine if cPLA(2) activity is essential for the pulmonary vascular resistance increase during hypoxia.
Main Methods:
- Comparison of HPV response in wild-type and cPLA(2alpha) gene-deleted mice using left main stem bronchus occlusion (LMBO).
- Assessment of pulmonary vascular resistance (PVR) and systemic oxygenation.
- Pharmacological inhibition of cPLA(2) and administration of exogenous AA.
- Evaluation of HPV after chronic hypoxia and interventions targeting cyclooxygenase and nitric oxide synthase pathways.
Main Results:
- LMBO-induced increase in left lung pulmonary vascular resistance (LPVR) was abolished in cPLA(2alpha)(-/-) mice.
- Wild-type mice maintained better systemic oxygenation during LMBO compared to cPLA(2alpha)(-/-) mice.
- cPLA(2) inhibition blocked HPV in wild-type mice, while exogenous AA restored HPV in knockout mice.
- Chronic hypoxia restored HPV in cPLA(2alpha)(-/-) mice, independent of cPLA(2) activity, and reduced right ventricular hypertrophy.
Conclusions:
- cPLA(2) activity significantly contributes to the development of HPV in mice.
- Augmenting pulmonary vascular tone can restore HPV even in the absence of cPLA(2) activity.
- These findings highlight cPLA(2) as a potential therapeutic target for conditions involving abnormal HPV.
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