Bacterial lipopolysaccharide induction of the prostaglandin G/H synthase 2 gene causes thromboxane-dependent pulmonary hypertension in rabbits.
Two genes encode proteins with prostaglandin G/H synthase (PGHS) activity. PGHS-1 is primarily a constitutively expressed gene, whereas inflammatory agents such as bacterial lipopolysaccharide (LPS) endotoxin rapidly induce the PGHS-2 gene in leukocytes. Both PGHS-1 and PGHS-2 are rate-limiting enzymes for the production of prostaglandins and thromboxane following release of arachidonic acid by phospholipases. We previously reported that LPS perfusion into the circulation of isolated perfused rabbit lung (IPL) results in thromboxane-dependent pulmonary hypertension and lung edema when the LPS-primed lung is subsequently stimulated with platelet activating factor (PAF) (J. Clin. Invest. 1990;85:1135). In this study, we showed that the mechanism by which LPS primes IPL for enhanced production of thromboxane and pulmonary hypertension in response to PAF depends on specific upregulation of the PGHS-2 gene in the rabbit lung. LPS perfusion of IPL induced PGHS-2 gene expression, which correlated with the conversion of free arachidonic acid to thromboxane-B2 (TXB2) and the onset of pulmonary hypertension. LPS-induced PGHS-2 expression, TXB2 release, and pulmonary hypertension were inhibited by actinomycin D (an inhibitor of transcription) and cycloheximide (an inhibitor of protein synthesis). The constitutively expressed PGHS-1 remained unchanged with LPS perfusion, and did not convert free arachidonic acid to TXB2, suggesting that PGHS-1 does not contribute to the induction of pulmonary hypertension by LPS. These studies reveal a pathogenic role for induction of PGHS-2 in lung injury.
Delong
P
P
Section on Infectious Diseases, Department of Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157-1042, USA.
O'Sullivan
M G
MG
Huggins
E
E
Hubbard
C L
CL
McCall
C
C
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003609:Dactinomycin / Q000494:pharmacology; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000209:etiology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D010477:Perfusion; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011817:Rabbits; D013931:Thromboxanes / Q000378:metabolism*
D007527:Isoenzymes; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D013931:Thromboxanes; D003609:Dactinomycin; D016718:Arachidonic Acid; D003513:Cycloheximide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases