Differential expression of cytochrome P450 isoforms in the lungs of septic animals.
OBJECTIVE
Sepsis is characterized by an early, hyperdynamic phase and a late, hypodynamic phase. Although studies have shown that cytochrome P450 (CYP) plays an important role in the regulation of vascular reactivity, alterations of vascular CYP isoforms in sepsis remain unknown. Since CYP2C11 and CYP2J4 convert arachidonic acid to vasodilative epoxyeicosatrienoic acids, and CYP4A3 metabolizes arachidonic acid to both epoxyeicosatrienoic acids and vasoconstrictive 19,20-hydroxyeicosatetraenoic acid, the aim of this study was to examine the expression of these isoforms in sepsis and their association with hemodynamic changes.


METHODS
Prospective, controlled, and randomized animal study.


METHODS
An institute research laboratory.


METHODS
Male adult Sprague-Dawley rats were subjected either to polymicrobial sepsis by cecal ligation and puncture or to sham operation followed by the administration of normal saline solution (i.e., fluid resuscitation).


METHODS
At 5 hrs (early sepsis) or 20 hrs (late sepsis) after cecal ligation and puncture, blood vessel-rich tissues (i.e., lungs) were harvested. The expression of CYP isoforms at both messenger RNA and protein levels was determined by reverse transcription polymerase chain reaction and Western blot analysis (CYP2C11), respectively. Hemodynamic variables were measured by radioactive microspheres.


RESULTS
The results indicate that the gene expression of CYP2C11 and CYP2J4 was significantly down-regulated at 20 hrs after cecal ligation and puncture, whereas the expression of CYP4A3 was markedly up-regulated at 5 hrs. The protein concentrations of CYP2C11 also decreased significantly at 20 hrs after cecal ligation and puncture. Although total peripheral resistance markedly increased, mean arterial pressure did not change significantly at 20 hrs after the onset of sepsis. In contrast, cardiac output and pulmonary perfusion markedly decreased in late sepsis.


CONCLUSIONS
Since the up-regulated CYP4A3 is associated with the early, hyperdynamic phase of sepsis and the down-regulated CYP2C11 and CYP2J4 are associated with the late, hypodynamic phase, vascular CYP isoforms that metabolize arachidonic acid may be involved in regulating the cardiovascular response during the progression of sepsis.
Cui
Xiaoxuan
X
Division of Surgical Research, Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, NY 11030, USA.
Wu
Rongqian
R
Zhou
Mian
M
Simms
H Hank
HH
Wang
Ping
P
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D001794:Blood Pressure / Q000502:physiology; D002302:Cardiac Output / Q000502:physiology; D002432:Cecum / Q000293:injuries; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D000072470:Cytochrome P450 Family 4; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D008026:Ligation; D008168:Lung / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D020033:Protein Isoforms; D011677:Punctures; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000378:metabolism / Q000503:physiopathology; D039181:Steroid 16-alpha-Hydroxylase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology; D014655:Vascular Resistance / Q000502:physiology
D006893:Hydroxyeicosatetraenoic Acids; D020033:Protein Isoforms; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C112496:Cyp2j4 protein, rat; D000072467:Cytochrome P450 Family 2; D000072470:Cytochrome P450 Family 4; D039181:Steroid 16-alpha-Hydroxylase; C465389:Cyp4a3 protein, rat