Early administration of propofol protects against endotoxin-induced acute lung injury in rats by inhibiting the TGF-beta1-Smad2 dependent pathway.

OBJECTIVE: To assess the effects of propofol treatments at different time points on acute lung injury and on the expression of transforming growth factor (TGF)-beta1 and the downstream target of TGF-beta1, Smad 2, in the lung tissues in the endotoxic rats. METHODS: Seventy-six Wistar rats were randomly assigned to five groups: control group (saline only), endotoxemic group [lipopolysaccharide (LPS) 8 mg kg(-1), i.v.], and three propofol-treated groups. For the propofol-treated groups, propofol (5 mg kg(-1), i.v. bolus) was administered either 1 h before LPS, simultaneously with LPS, and 1 h after LPS, and all were followed by infusion of 10 mg kg(-1) h(-1) of propofol for 5 h after LPS. Lung tissues were sampled to measure myeloperoxidase activity and expression of TGF-beta1 and Smad2 and to assess pulmonary microvascular permeability and histopathological changes. RESULTS: The hemodynamics, arterial blood gases, 5 h survival rate, pulmonary microvascular permeability, and acute lung injury scores were significantly better, and expression of TGF-beta1 and Smad2 and myeloperoxidase activity in lung tissues was significantly lower in the pretreatment and simultaneous treatment groups compared to the endotoxemic group. However, there were no significant differences in all observed variables between the endotoxemic and postreatment groups. Except for TGF-beta1 expression in lung tissues, the other observed variables were also not significantly different between the pretreatment and simultaneous treatment groups. CONCLUSIONS: In the endotoxic rat model, pretreatment and simultaneous treatment with propofol provided protection against acute lung injury by inhibiting the TGF-beta1-Smad2 dependent pathway.

[Effects of different fluid resuscitation regimes on lung injury and expression of pulmonary aquaporin 1 and aquaporin 5 in uncontrolled hemorrhagic shock in rats].

OBJECTIVE: To investigate the effects of different fluid resuscitation regimes on lung injury and expression of pulmonary aquaporin 1 (AQP1) and AQP5 in rats with uncontrolled hemorrhagic shock. METHODS: Sixty Sprague-Dawley (SD) rats were randomly assigned to the following five groups: control group (C group), no fluid resuscitation group (NF group), lactated Ringer's solution group (LRS group), 7.5%NaCl group (HS group) and hydroxyethyl starch group (hydroxyethyl starch 130/0.4, HES group). A four-phased uncontrolled hemorrhagic shock model was reproduced. Uncontrolled hemorrhagic shock phase began with blood withdrawal extended over 15 minutes, in which animals were subjected to massive hemorrhage [mean arterial pressure (MAP)=40 mm Hg (1 mm Hg=0.133 kPa)] for 60 minutes and followed by intratracheal lipopolysaccharide 2 mg/kg and continuous bleeding with amputation of the tail. Then, animals were partially resuscitated with LRS of 3 times the volume of shed blood (LRS group), followed by a bolus dose of 4 ml/kg body weight of 7.5%NaCl (HS), or hydroxyethyl starch (a volume equal to that of the shed blood), respectively, during different fluid resuscitation regimes. After that, comprehensive resuscitation phase of 60 minutes began with hemostasis, and transfusion of all the shed blood plus same amount of normal saline. Observation phase was continued for 3.5 hours. At the end the experiment, the lung tissue was sampled to measure wet-to-dry lung weight ratio (W/D), and the expression of AQP1 and AQP5 were determined with immunohistochemistry. The paraffin-embedded lungs were stained with hematoxylin and eosin for pathological analysis. RESULTS: When compared with NF and LRS groups, the lung W/D ratio was significantly decreased, and the shock induced decreased expression of AQP1 and AQP5 in lung tissue were attenuated in HES group, but these beneficial effects were blunted in the HS group. CONCLUSION: Uncontrolled hemorrhagic shock may induce lung injury and pulmonary edema as well as down regulation of the expression of AQP1 and AQP5 in rats. Resuscitation with hypertonic fluids, especially with HES, can reduce lung damage and pulmonary edema in this kind of shock. The cause may be due in part to maintenance of the expression of AQP1 and/or AQP5 in the lung. Pulmonary AQP1 and AQP5 play an important role in fluid transportation.

[Changes in pulmonary transforming growth factor-beta1/smad2 signaling pathway in a two-hit pulmonary injury as a result of uncontrolled hemorrhagic shock and lipopolysaccharide in rats].

OBJECTIVE: To investigate the changes in pulmonary transforming growth factor-beta1 (TGF-beta1)/smad2 signaling pathway in pulmonary injury as a result of hemorrhagic shock followed by lipopolysaccharide challenge. METHODS: Twenty-four Sprague-Dawley (SD) rats were randomly assigned to the following two groups: sham operation group (sham group, surgery, no hemorrhage and no resuscitation), and two-hit model group (HS group), each n=12. Three-phased uncontrolled hemorrhagic shock model was reproduced in rats. Hemorrhagic shock phase I began with blood withdrawal over 15 minutes, i.e. animals were subjected to massive hemorrhage [mean arterial pressure (MAP)=35-40 mm Hg (1 mm Hg=0.133 kPa) for 60 minutes], followed by intratracheal lipopolysaccharide 2 mg/kg (two-hit model). Ninety minutes after blood shedding, resuscitation phase II of 60 minutes began with hemostasis, return of all the blood initially shed, plus fluids. Observation phase III was 210 minutes. After phase III, blood gas analysis with carotid artery blood was performed. Lung tissue was sampled to measure values of wet-to-dry lung weight (W/D) ratio and pulmonary microvascular permeability. Immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR) were used to assess the expression of TGF-beta1 protein and mRNA, and the protein content of the smad2 was determined by Western blotting. RESULTS: Compared with sham group, MAP was significantly lowered after 60 minutes in phase I, and lactic acid content was increased significantly, while partial pressure of oxygen in artery (PaO2), blood pH, HCO(-)3, arterial oxygen saturation (SaO2) and negative base excess (BE) showed a significant decrease in HS group. Concomitantly, values of pulmonary microvascular permeability and W/D ratio were significantly increased in HS group (all P<0.01). In sham group, weak TGF-beta1 staining was detected in the alveolar epithelial cells. However, intense positive immunostaining for TGF-beta1 was observed in alveolar epithelial cells, pulmonary interstitial inflammatory cell as well as macrophage cells of alveolar space of the HS group. Lung tissue in HS group demonstrated a marked increase in TGF-beta1 mRNA and smad2 protein expression in the lung tissue compared with those of sham group (all P<0.01). CONCLUSION: The expression of TGF-beta1/smad2 signaling pathway may play an important role in regulation of pulmonary permeability and development of pulmonary edema in acute lung injury induced by uncontrolled hemorrhagic shock followed by lipopolysaccharide challenge.