Heat shock response decreases endotoxin-induced acute lung injury in rats

OBJECTIVE: Transient whole-body hyperthermia was reported to reduce lung damage in a rat with intra-abdominal sepsis produced by caecal perforation. METHODOLOGY: In order to determine the effect of heat shock response on acute lung injury induced by endotoxin, which plays a central role in the pathogenesis of sepsis, we instilled either saline or lipopolysaccharide (LPS) intravenously with and without heat pretreatment in rats. The heated rats had their rectal temperature raised to more than 40 degrees C for 13 min 18 h before intravenous administration of saline or LPS. RESULTS: We found that the lung leak was significantly increased among the rats given LPS intravenously with (median, 0.17; range, 0.15-0.22; n = 10) and without heat pretreatment (0.23; 0.17-0.30; n = 10) compared with those of saline-treated rats (0.13; 0.10-0.14; n = 10) (P < 0.05 in each). However, rats given LPS after heat pretreatment had significantly decreased lung leak index compared with those of LPS-treated rats without heat pretreatment (P < 0.05). Rats administered LPS intravenously showed increased myeloperoxidase activity without heat pretreatment (19.01; 9.34-28.00 U/g; n = 10) compared with that of saline-treated rats (7.09; 4.49-10.56 U/g; n = 5) (P < 0.05) (Fig. 2). Myeloperoxidase activity of the rats treated with LPS with heat pretreatment (5.57; 2.87-8.96 U/g; n = 10) was significantly decreased to the level of normal control compared with that of LPS-treated rats without heat pretreatment (P < 0.05). The levels of heat shock proteins (HSP72) in lung tissue, which were examined by western blot analysis, were increased over baseline levels at 23 h after hyperthermic stress. CONCLUSIONS: These observations show that brief heat shock response is associated with the induction of HSP72 protein synthesis and attenuated neutrophil recruitment and acute lung leak is induced by endotoxin in rats.     

Effects of continuous infusion of nitroglycerin on pulmonary hemodynamics,lung lymph balance,and prostanoid products in the response to endotoxin in awake sheep

We examined the effects of continuous intravenous infusion of nitroglycerin (NTG) on lung dysfunction induced by endotoxemia in awake sheep chronically instrumented with lung lymph fistula. We measured the responses of hemodynamics, lung lymph balance, and thromboxane (Tx)B₂ and 6-keto-prostaglandin (PG) Fla levels in plasma and lung lymph to endotoxin administration (1 µg/kg, intravenously [IV], over 30 min) with and without continuous infusion of NTG (1 µg/kg/min). Continuous infusion of NTG alone (n = 5) over 5 hr did not significantly alter systemic, pulmonary hemodynamics, and/or lung lymph fluid filtration. Infusion of endotoxin alone (n = 7) caused remarkable increases in pulmonary artery pressure (Ppa) and lung lymph flow (Qlym) in the early phase. Continuous infusion of NTG (n = 6) significantly prevented the early increases in Ppa and Qlym after endotoxin. The increased values of TxB₂ and 6-keto-PGF₁ in both plasma and lung lymph after endotoxemia showed the same increases in groups with and without NTG. These findings suggest that the reduction of pulmonary artery pressure induced by NTG decreased the filtration of fluid into the lungs associated with endotoxemia in sheep, and that the mechanism of vasodilating action of NTG is not due to modifications of constrictive-dilated cyclo-oxygenase products of arachidonate, such as TxA₂ and PGI₂. Offprint requests to: K. Kubo     

Effects of continuous infusion of nitroglycerin on pulmonary hemodynamics, lung lymph balance, and prostanoid products in the response to endotoxin in awake sheep

We examined the effects of continuous intravenous infusion of nitroglycerin (NTG) on lung dysfunction induced by endotoxemia in awake sheep chronically instrumented with lung lymph fistula. We measured the responses of hemodynamics, lung lymph balance, and thromboxane (Tx)B₂ and 6-keto-prostaglandin (PG) F1α levels in plasma and lung lymph to endotoxin administration (1 μg/kg, intravenously [IV], over 30 min) with and without continuous infusion of NTG (1 μg/kg/min). Continuous infusion of NTG alone (n=5) over 5 hr did not significantly alter systemic, pulmonary hemodynamics, and/or lung lymph fluid filtration. Infusion of endotoxin alone (n=7) caused remarkable increases in pulmonary artery pressure (Ppa) and lung lymph flow ( Qlym) in the early phase. Continuous infusion of NTG (n=6) significantly prevented the early increases in Ppa and Qlym after endotoxin. The increased values of TxB₂ and 6-keto-PGF_1α in both plasma and lung lymph after endotoxemia showed the same increases in groups with and without NTG. These findings suggest that the reduction of pulmonary artery pressure induced by NTG decreased the filtration of fluid into the lungs associated with endotoxemia in sheep, and that the mechanism of vasodilating action of NTG is not due to modifications of constrictive-dilated cyclo-oxygenase products of arachidonate, such as TxA₂ and PGI₂.     

A review of pulmonary coagulopathy in acute lung injury,acute respiratory distress syndrome and pneumonia

Enhanced bronchoalveolar coagulation is a hallmark of many acute inflammatory lung diseases such as acute lung injury, acute respiratory distress syndrome and pneumonia. Intervention with natural anticoagulants in these diseases has therefore become a topic of interest. Recently, new data on the role of pulmonary coagulation and inflammation has become available. The aim of this review is to summarize these findings. Furthermore, the results of anticoagulant therapeutic interventions in these disorders are discussed.     

Effect of dobutamine on lung aquaporin 5 in endotoxine shock-induced acute lung injury rabbit

Background

Dobutamine, a commonly used vasoactive drug, has been reported to reduce pulmonary edema and protect against acute lung injury (ALI) by up-regulating aquaporin 5 (AQP₅) expressions. However, the underlying mechanism is still elusive.

Methods

ALI was induced by intravenous injection of LPS. Seventy male New Zealand white rabbits were randomly divided into seven groups: sham group, ALI group, dobutamine low-dose group [group ALI + Dob (L)], dobutamine medium-dose group [group ALI + Dob (M)], dobutamine high-dose group [group ALI + Dob (H)], ALI + Dob (H) + ICI group and sham + ICI group. ICI 118,551, a potent and specific beta-2 antagonist, could block the effect of dobutamine. The animals were sacrificed at 3 h after endotoxic shock and lungs were removed. The arterial blood gas was analyzed. The lung wet to dry (W/D) ratio was determined. The level of cyclic AMP (cAMP) in lung tissue was assessed by ELISA. The expression of AQP₅ protein was determined by western blotting and immunohistochemistry. The pathological alteration in lung tissue was evaluated by optical microscopy and electron microscope, and lung injury score was assessed.

Results

Dobutamine increased AQP₅ protein expression and cAMP level in a dose-dependent manner. Meanwhile, the degree of lung pathological and ultrastructural lesion was ameliorated and arterial blood gas was improved obviously. Additionally, W/D ratio and histological scores decreased significantly. However, the AQP₅ protein expression and cAMP level were significantly decreased in group ALI + Dob (H) + ICI than that in group ALI + Dob (H), the degree of lung pathological and ultrastructural lesion was more serious in group ALI + Dob (H) + ICI than that in group ALI + Dob (H) and the arterial blood gas was not obviously improved.

Conclusions

These results suggested that protective effect of dobutamine against endotoxin shock-induced ALI may be due to its ability of up-regulating AQP₅ protein expression via increasing intracellular cAMP concentration.     

Mechanical ventilation modulates Toll-like receptors 2, 4, and 9 on alveolar macrophages in a ventilator-induced lung injury model

Objective

To investigate the role of Toll-like receptor 2 (TLR2), TLR4, TLR9 and myeloid differentiation factor 88 (MyD88) on alveolar macrophages in ventilator-induced lung injury (VILI).

Methods

Male, adult pathogen-free Sprague-Dawley rats weighing 300-350 g were used in this study. Animals were tracheotomized and allowed to breathe spontaneously for 4 h or mechanically ventilated for 4 h with low or high tidal volume (7 or 40 mL/kg). TLR2, TLR4, and TLR9, MyD-88 and NF-κΒ of alveolar macrophages’ expression under the different ventilation conditions were detected. Pulmonary permeability, lung inflammatory, IL-6 and IL-1β were assessed as well.

Results

Rats subjected to high tidal volume showed significantly greater pulmonary permeability and lung inflammatory than the control rats. Alveolar macrophages from rats subjected to high tidal volume also showed significantly higher protein expression of TLR2 (0.59±0.049 vs. 0.35±0.036 and 0.36±0.031, both P<0.001), TLR4 (0.845±0.0395 vs. 0.401±0.026 and 0.403±0.020, both P<0.001), TLR9 (0.727±0.074 vs. 0.383±0.039 and 0.367±0.043, both P<0.001), MyD-88 (1.01±0.060 vs. 0.485±0.045 and 0.507±0.046, both P<0.001) and NF-κΒ (0.776±0.067 vs. 0.448±0.043 and 0.481±0.047, both P<0.001), as well as significantly higher concentrations of IL-6 (7.32±0.24 vs. 2.42±0.13 and 2.44±0.32, both P<0.001) and IL-1β (139.95±9.37 vs. 53.63±5.26 and 53.55±6.63, both P<0.001) than the control and low tidal volume group.

Conclusions

The overexpression of TLR2, TLR4, and TLR9 on alveolar macrophages and release of pro-inflammatory cytokines play a role in VILI.     

A sensitive model for prediction of relapse in adult acute myeloid leukaemia with t(8;21) using white blood cell count, CD56 and MDR1 gene expression at diagnosis

Acute myeloid leukaemia (AML) carrying t(8;21) has an overall favourable prognosis. However, relapse occurs and the impact of multidrug resistance gene (MDR1) expression on recurring disease in this group of patients is not known. We determined quantifiable MDR1 expression in the bone marrow of 28 AML patients with t(8;21) by a validated real-time polymerase chain reaction assay. Using MDR1 expression, white blood cell count and CD56 expression at diagnosis we observed complete concordance of predicted and observed relapses. A calculated logit out of these three variables was a strong independent prognostic factor for overall (P = 0.007) and disease-free survival (P = 0.002).     

Fresh-frozen plasma and platelet transfusions are associated with development of acute lung injury in critically ill medical patients

BACKGROUND: Transfusion has long been identified as a risk factor for acute lung injury (ALI)/ARDS. No study has formally evaluated the transfusion of specific blood products as a risk factor for ALI/ARDS in critically ill medical patients. METHOD: In this single-center retrospective cohort study, 841 consecutive critically ill patients were studied for the development of ALI/ARDS. Patients who received blood product transfusions were compared with those who did not, in univariate and multivariate propensity analyses. RESULTS: Two hundred ninety-eight patients (35%) received blood transfusions. Transfused patients were older (mean [+/- SD] age, 67 +/- 17 years vs 62 +/- 19 years; p < 0.001) and had higher acute physiologic and chronic health evaluation (APACHE) III scores (74 +/- 32 vs 58 +/- 23; p < 0.001) than those who had not received transfusions. ALI/ARDS developed more commonly (25% vs 18%; p = 0.025) in patients exposed to transfusion. Seventeen patients received massive RBC transfusions (ie, > 10 U of blood transfused within 24 h), of whom 13 also received fresh-frozen plasma (FFP) and 11 received platelet transfusions. When adjusted for the probability of transfusion and other ALI/ARDS risk factors, any transfusion was associated with the development of ALI/ARDS (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.24 to 3.75). Among those patients receiving individual blood products, ALI/ARDS was more likely to develop in patients who received FFP transfusions (OR, 2.48; 95% CI, 1.29 to 4.74) and platelet transfusions (OR, 3.89; 95% CI, 1.36 to 11.52) than in those who received only RBC transfusions (OR, 1.39; 95% CI, 0.79 to 2.43). CONCLUSION: Transfusion is associated with an increased risk of the development of ALI/ARDS in critically ill medical patients. The risk is higher with transfusions of plasma-rich blood products, FFP, and platelets, than with RBCs.