[Role of macrophage migration inhibitory factor in septic shock-induced cardiovascular dysfunction: experiment with rats].
OBJECTIVE
To investigate the role of macrophage migration inhibitory factor (MIF) in septic shock-induced cardiovascular dysfunction.


METHODS
56 SD rats were randomly divided into 7 equal groups: CLP group (undergoing cecal ligation and puncture so as to cause septic shock), CLP + ISO-1 group (ISO-1, was injected before and after CLP), CLP + MIF antibody group (MIF-Ab was injected before and after CLP), CLP + dexamethasone (DEX)-1, 5, and 20 groups [I, 5, or 20 mg/kg was injected 1 h after CLP), and sham operation group. Echocardiography was performed 6 h after CLP to measure the LVEDD, LVESD, FS%, CO, and PP. Catheters were inserted into the femoral artery and vein to measure the mean arterial pressure (MAP) and to be used as the route of drug administration. Phenylephrine (PE) of the concentrations of 0.5, 1, 2, and 2.5 microg/kg was injected intravenously and then the MAP increase percentage (DeltaMAP%) was calculated. Then the rats were euthanized with their hearts and aortas taken out. The aortas were cut into rings, and bathed in Krebs solution. PE of the concentrations of 1 mol/L to 30 micromol/L was added into the solution cumulatively to produce the dose-reaction curve of PE. The maximum energy (Emax) and median effective concentration (EC50) of PE were calculated. Western blotting was used to examine the protein expression of MIF in the myocardium and aorta. Another 70 SD rats were divided into 7 groups as mentioned above to observe the cumulative survival rates within 72 h.


RESULTS
The LVEDD and LVESD of the CLP group decreased by 56% and 54% respectively 6 h after CLP, and the LVEDD and LVESD of the ISO-1, MOF-Ab, and DEX-20 groups were all significantly higher than that of the CLP group (all P < 0.05) The FS% of the CLP group was significantly lower than that of the Sham groups, and the FS% of the ISO-1, MOF-Ab, and DEX-20 groups were all significantly higher than that of the CLP group (all P < 0.05). The PP value of the ISO-1, MIF-Ab, and DEX-20 groups were all significantly higher than that of the CLP group (all P < 0.06). The CO of the CLP group was significantly lower than that of the Sham group, and those of the ISO-1, MIF-Ab, and DEX-20 groups were all significantly higher than that of the CLP group (all P < 0.001). The DeltaMAP% of different group all increased after the addition of PE dose-dependently, however, the DeltaMAP% was significantly lower in the CLP group than in the Sham group (P < 0.05), and t significantly higher in the ISO-1, MIF-Ab, and DEX-20 groups than in the CLP group (all P < 0.05). The values of PE-induced maximum aorta tension of the SO-1 and MIF-Ab groups were both significantly higher than that of the CLP group (both P < 0.05). The values of PE-induced maximum aorta tension of the DEX-20 group were all higher than those of the CLP group when the PE concentration was between 1.0 x 10(-6) - 1.0 x 10(-5) mol/L (all P < 0.05), however, were not significantly different those of the CLP group when the PE concentration was over 1.0 x 10(-5) mol/L. The values of Emax were significantly lower in the 6 experimental groups than in the Sham group (all P < 0.05), however, were all significantly higher in the ISO-1, MIF-Ab, and DEX-20 groups than in the CLP group (all P < 0.05). The values of EC50 were significantly higher in the 6 experimental groups than in the Sham group (all P < 0.05), however, were significantly lower in the ISO-1, MIF-Ab, and DEX-20 groups than in the CLP group (all P < 0.05). The protein expression levels of MIF in the heart and aorta were significantly higher in the 6 experimental groups than in the Sham group (all P < 0.05), however, the DEX-1 and DEX-5 groups showed significantly higher MIF expression than DEX-20 group (both P < 0.05). The 72 h survival rates of the ISO-1 and MIF-Ab groups were both significantly higher than that of the CLP group (0%, both P < 0.05). DEX of different dose failed to increase the survival rate.


CONCLUSIONS
MIF plays a pivotal role in the circulation dysfunction in septic ambience. Antagonism and blockade of MIF improve corresponding hemodynamics, vascular responsiveness, and prognosis. Glycocorticoid of high and low dose are poles apart in effects on septic hemodynamics and vaso-reactivity, however, fails to improve the prognosis of sepsis no matter how high is the dose.
Wang
Fu-Zhou
FZ
Department of Anesthesia, Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, China.
Jing
Liang
L
Chen
Jian
J
Huang
Yao-Yao
YY
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis / Q000502:physiology*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D005938:Glucocorticoids; D008263:Macrophage Migration-Inhibitory Factors; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D003907:Dexamethasone