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The Role of CIH Mediated by NF-α-regulated Fractalkine in OSAHS-induced Liver Injury

Author: WangZuoNa
Tutor: ChenPing
School: Central South University
Course: Internal Medicine
Keywords: OSAHS CIH liver injury fractalkine TNF-α
CLC: R766
Type: PhD thesis
Year: 2012
Downloads: 160
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Abstract


Objective:To observe the liver injury and serum fractalkine, TNF-α in OSAHS patients and the effect of nCPAP intervention. The expression of fractalkine, TNF-α and hepatic injury will be observed in OSAHS style CIH rat model and HepG2cells. The possible pathogenesis of hepatic injury induced by CIH will be approached in the research, which may be helpful to prevention and cure of NAFLD related to OSAHS.Methods:1.30patients with OSAHS (10mild,10moderate and10sever) and15control subjects were recruited. The two groups were matched for sex, age, body mass index (BMI) and diseases. Liver function, lipid, HOMA-IR, liver ultrasound and serum level of fractalkine, TNF-α were measured. In addition, the effects of3month of nCPAP on liver function, lipid, HOMA-IR, liver ultrasound and serum level of fractalkine, TNF-α were studied in moderate and sever OSAHS patients.2. OSAHS style CIH rats were randomly allocated into4groups:10%CIH,5%CIH,5%CIH+RH (Removal of hypoxia), control group. Each group’s liver function, lipid were measured and compared. To observe and compare the liver pathology, fractalkine, TNF-α in CIH rats’ liver tissue detected by immunohistochemical method.3. HepG2cells were randomly allocated into5groups:control group(A),10%CIH(B),5%CIH(C),5%CIH+TNF-a antibody (10mg/L)(D),5%CIH+TNF-α antibody (20mg/L)(E). Significant fat accumulation was documented by oil red O staining. RT-PCR method was adopted to detect the fractalkine, TNF-a mRNA. Western-blotting method was adopted to detect the fractalkine, TNF-α protein. Results:Part1:1. The level of ALT, GGT, TG were significantly higher in patients with OSAHS than in control subjects (P<0.05). The level of fractalkine, TNF-α were higher in patients with OSAHS than in control subjects (P<0.05). There were no difference in the level of AST、CHOL、HDL-C、LDL-C、HOMA-IR between two groups (P>0.05). There were more NAFLD patients in OSAHS group than control.2. There were significant positive correlation between AHI and ALT, GGT, TG, fractalkine, TNF-α in OSAHS patients (P<0.05), there were significant negtive correlation between the mean nocturnal SaO2and ALT, GGT, TG, fractalkine, TNF-α in OSAHS patients (P<0.05), there were significant negtive correlation between the lowest nocturnal SaO2and ALT, GGT, TG, fractalkine, TNF-α in OSAHS patients (P<0.05).3. There were significant positive correlation between fractalkine and ALT、GGT、TG (P<0.001), and significant positive correlation between TNF-α and ALT、GGT、TG (P<0.001). There were significant positive correlation between fractalkine and TNF-α (r=0.536, P<0.001). Stepwise regression analysis showed the good correlation between fractalkine and ALT, GGT, the mean nocturnal SaO2, the good correlation between TNF-α and GGT, ALT (P<0.01).4. nCPAP decreased the serum level of ALT, TG, fractalkine, TNF-α in moderate and sever OSAHS patients (P<0.05). The severity of fatty liver in moderate and sever OSAHS patients were decreased after nCPAP.Part2:1. For the serum aminopherase detection, ALT and AST lever in10%CIH,5%CIH,5%CIH+RH groups were higher than that in control group (p<0.001), GGT lever in10%CIH,5%CIH groups were higher than that in control group (p<0.001, p<0.01), while there was no difference in GGT between5%CIH+RH and control group (p>0.05). Compared with10%CIH group, the lever of ALT, AST in5%CIH group significant higher (p<0.001), the lever of GGT in5%CIH group higher(p<0.05), the lever of ALT in5%CIH+RH group higher (p<0.05), while there was no difference in AST and GGT between5%CIH+RH and10%CIH (p>0.05). Compared with5%CIH group, the lever of ALT, AST, and GGT in5%CIH+RH group dramatically reduced (p<0.01).2. For the serum lipid detection, there was no significant difference in TG among10%CIH,5%CIH+RH and control groups (p>0.05), with TG increase in5%CIH compared with control group (P<0.05). There were no significant difference in CHOL、HDL-C、LDL-C among4groups (p>0.05).3. Compared with control group, the hepatic steatosis and inflammatory activities in10%CIH,5%CIH and5%CIH+RH group were more severe(p<0.01), which in5%CIH group were more severe than which in10%CIH (p<0.01). Compared with5%CIH group, the hepatic steatosis and inflammatory activities in5%CIH+RH group were dramatically reduced (p<0.01, p<0.05).4. Compared with control group, expression of fractalkine and TNF-a in10%CIH,5%CIH and5%CIH+RH group increased (p<0.01). The expression of fractalkine and TNF-a in5%CIH group were more obvious than which in10%CIH group (p<0.05). The expression of fractalkine and TNF-α in5%CIH+RH group were dramatically downregulated compared with that in5%CIH group (p<0.01).Part3:1. HepG2cells cultured in CIH groups grew slowly, ratio of steatosis in CIH groups were higher than control group, which were related to the severity of CIH. The cell survival rate in D,E group were higher than C group and the ratio of steatosis in D,E group were lower than C group (p<0.05). The cell survival rate in E group were higher than D group and the ratio of steatosis in E group were lower than D group (p<0.05).2. Compared with control group, expression of fractalkine and TNF-α mRNA in B,C group increased (p<0.01), The expression of fractalkine and TNF-α in C group were more obvious than which in B group (p<0.05). The expression of fractalkine mRNA in D,E groups were dramatically downregulated compared with that in C group (p<0.05) or in B group (p<0.05), but increased than that in A group (p<0.05). The expression of fractalkine mRNA in E group was lower than D group (p<0.05).3. Compared with control group, protein expression of fractalkine and TNF-α in B and C group increased (p<0.01), protein expression of fractalkine and TNF-α in C group were more obvious than which in B group (p<0.01). Protein expression of fractalkine in D,E groups were dramatically downregulated compared with that in C group (p<0.05) or in B group (p<0.05), but increased than that in A group (p<0.05). Protein expression of fractalkine in E group was lower than D group (p<0.05).Conclusion:1. There is a high prevalence of liver injury, especially NAFLD among OSAHS patients.2. The level of fractalkine and TNF-α are higher in patients with OSAHS, which is related to the severity of OSAHS and liver injury.3. nCPAP can effectively reduce the level of fractalkine and TNF-α and apparently alleviate the liver injury in OSAHS patients.4. OSAHS style CIH induces the damage of liver function, hepatic steatosis and inflammation in rats, which are related to the severity of CIH.5. OSAHS style CIH induces the expression of fractalkine and TNF-α in rats’ liver tissue, which are coincident with the rats’ hepatic steatosis and inflammatory activities.6. OSAHS style CIH participate liver injury by effect on fractalkine though TNF-α.

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