| Recent studies have demonstrated that in acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), the extrinsic coagulation systems are activated by pathogen and its'metabolic product, especially by leukocytes emerged in the early stage of inflammatory reaction. Meanwhile, thrombin mostly produced in the early stage of ALI/ARDS may promote gathering and adhering of the platelets and neutrophilic leukocytes and strengthen interaction between endotheliocyte and neutrophilic leukocytes. Therefore, the balances are brokened between blood clotting and anticoagulation, inflammation and anti-inflammatory in the course of ALI/ARDS, which worsens patient's condition. So, anticoagulants should be used to prevent the progression of ALI/ARDS. Moreover, the over-reaction of inflammatory of ALI/ARDS has close association with activation of the p38 mutagen activated protein kinase (MAPK) signal transduction access and nuclear factor-κB. It has been testified that heparin has anti-inflammatory and anti-anaphylaxis effects besides anticoagulation effect.Objective: To investigate the potential beneficial effects and molecule mechanisms of heparin and low molecular weight heparin (LMWH) on ALI/ARDS.Methods: Forty-eight rabbits were randomly divided into four groups (n=12): normal control group (Group A),LPS group (Group B), heparin group (Group C) and LMWH group (Group D). 1. Rabbit ALI model was established by intravenous injection with lipopolysaccharide (LPS); 2. The blood gas analysis was performed by Nova Stst Profile; 3. Enzyme-linked immunosorbentassay was used to measure the level of serum TNF-α; 4. ELISA was used to measure the expression of sICAM-1; 5. Western blots was used to measure the expression of p38 MAPK; 6. Electrophoretic mobility shift assay (EMSA) was used to measure the activity of NF-κB in the lung tissue; 7. The ratio of dry weight and wet weight of the lung was calculated and the lung histopathology change was observed.Results1. The level of Pa02 was decreased progressively after injection of LPS. At one hour after injection, the levels of Pa02 in Group B, C and D were lower than those in Group A (P<0.05). At 4 and 6 hours after injection, the levels of Pa02 in Group C and D were higher than those in Group B (P<0.05). There was no significant difference in the level of Pa02 between Group C and D(P>0.05). 2. The level of TNF-αwas increased progressively after injection of LPS. At 4 and 6 hours after injection, the levels of TNF-αin Group C and D were lower than those in Group B (P<0.05). There was no significant difference in the level of TNF-αbetween Group C and D(P>0.05).3. The level of sICAM-1 was increased progressively after injection of LPS. At 4 and 6 hours after injection, the levels of sICAM-1 in Group C and D were lower than those in Group B (P<0.05). There was no significant difference in the level of sICAM-1 between Group C and D(P>0.05).4. The expression of p38 MAPK was increased after injection of LPS. At 4 and 6 hours after injection, the expressions of p38 MAPK in Group C and D were lower than those in Group B (P<0.05). There was no significant difference in the expression of p38 MAPK between Group C and D(P>0.05).5. The activity of NF-κB was comparatively weak in the lung in Group A. At 6 hours after injection of LPS, the activity of NF-κB in Group B, C and D was 3.58±0.31, 1.56±0.21 and 1.76±0.24 times of that in Group A , respectively(P<0.05). The activity of NF-κB in Group C and D were weaker than that in Group B(P<0.05). There was no significant difference in the activity of NF-κB between Group C and D(P>0.05).6. In Group B, there was significant correlation between p38 MAPK and TNF-αand sICAM-1 at hour 1, 2, 4 and 6 (r=0.722,0.792,0.808,0.793, P<0.05 and r=0.781,0.752,0.858,0.819,P<0.05; respectively). There was significant correlation between NF-κB and TNF-αand sICAM-1 at hour 6 (r=0.766,P<0.05 and r=0.778,P<0.05; respectively) in Group B.7. D/W of the lung in Group A, B, C and D were 0.2878±0.017,0.2338±0.015,0.2556±0.014 and 0.2503±0.012, respectively. D/W of the lung in Group B, C and D were lower than that in Group A (t=6.74,P<0.05;t=4.14,P<0.05 and t=5.10,P<0.05, respectively) and D/W of the lung in Group C and D were higher than that in Group B (t=3.01,P<0.05;t=2.43,P<0.05, respectively).8. The scores of lung injury in Group A, B, C and D were 0.1, 2.4±0.5, 1.7±0.5 and 1.8±0.4, respectively. The scores of lung injury in Group C and D were lower than that in Group B (P<0.05).Conclusion1. Heparin and LMWH show their beneficial effects on rabbit ALI/ARDS model in both functional and morphological aspects, including improving hypoxemia and lessening lung edema and inflammatory reaction.2. The expression of TNF-αand sICAM-1 was increased in ALI/ARDS, which was coincidence with the severity of the disease.3. The activity of p38 MAPK and NF-κB was increased in ALI/ARDS, which was coincidence with the expression of TNF-αand sICAM-1.4. The mechanism of lessening inflammatory reaction of heparin in ALI/ARDS may be as follows:⑴interrupt chain reaction between inflammatory and blood clotting by anticoagulation effect;⑵inhibit the expression of TNF-αand sICAM-1; and⑶inhibit the activity of p38 MAPK and NF-κB and then inhibit the overexpression of TNF-αand sICAM-1.
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