Hsing I. Chen

Mechanism of Fulminant Pulmonary Edema Caused by Enterovirus 71

Abstract Pulmonary edema (PE) may occur with enterovirus 71 (EV71) infection. We monitored arterial pressure (AP) and heart rate (HR) in patients with EV71 infection and analyzed the variability of AP and HR. Sympathetic activity, AP, and HR increased with respiratory stress. Thereafter, parasympathetic activity increased with decreases in AP and HR. The lungs showed edema with inducible nitric oxide synthase (iNOS) expression. Destruction of the medial, ventral, and caudal medulla may lead to sympathetic overactivation, causing blood to shift to the lungs. The pathogenesis of PE may also involve iNOS and nitric oxide.

Sympathetic and parasympathetic activities evaluated by heart-rate variability in head injury of various severities

OBJECTIVE To investigate the autonomic function in patients with brain damage of various extents. The purposes were to correlate the parameters derived from spectral analysis of the heart-rate variability (HRV) with the classic Glasgow coma scale (GCS), and to evaluate the possible clinical application of HRV in the autonomic functions in patients with various severities of brain-stem injury. METHODS A total of 90 patients was divided into 5 groups based on the GCS: I: 15, II: 9-14, III: 4-8, no pupil dilatation, IV: 4-8, pupil dilatation, and V: 3, brain death. Electrocardiogram was recorded for frequency-domain analysis of RR intervals. HRV were categorized into the low-frequency (LF, 0.04-0.15Hz) and high-frequency power (HF, 0.15-0.40Hz), LF to HF power ratio (LF/HF), normalized powers (LF and HF%). These HRV parameters were correlated with the severity of brain damage. RESULTS The LF, HF, LF%, and LF/HF in Group I were essentially similar to those in the normal subjects. LF and HF decreased from Group I to IV. All parameters were nearly absent in Group V. CONCLUSIONS The increases in LF% and LF/HF with the decrease in HF indicate augmented sympathetic and attenuated parasympathetic drive. These changes were related to the severity of brain-stem damage. Both LF and HF were nearly abolished in brain death. SIGNIFICANCE Our analysis indicates that HRV may be an useful tool for evaluating the autonomic functions in patients with brain damage of various degrees.

The Lung Is The Major Site That Produces Nitric Oxide To Induce Acute Pulmonary Oedema In Endotoxin Shock

1. The present study was undertaken to determine the locus of nitric oxide (NO) production that is toxic to the lung and produces acute pulmonary oedema in endotoxin shock, to examine and compare the effects of changes in lung perfusate on endotoxin‐induced pulmonary oedema (EPE) and to evaluate the involvement of constitutive and inducible NO synthase (cNOS and iNOS, respectively).

Inhibition of inducible nitric oxide synthase attenuates acute endotoxin-induced lung injury in rats

1 In the present study, we investigated the effects of the inducible nitric oxide (iNOS) inhibitors S‐methylisothiourea (SMT) and l‐N6‐(1‐iminoethyl)‐lysine (l‐Nil) on endotoxin‐induced acute lung injury (ALI), as well as the associated physiological, biomedical and pathological changes, in anaesthetized Sprague‐Dawley rats and in rat isolated perfused lungs. 2 Endotoxaemia was induced by an intravenous (i.v.) infusion of lipopolysaccharide (LPS; Escherichia coli 10 mg/kg). Lipopolysaccharide produced systemic hypotension and tachycardia. It also increased the lung weight/bodyweight ratio, lung weight gain, exhaled nitric oxide (NO), the protein concentration in bronchoalveolar lavage and microvascular permeability. 3 Following infusion of LPS, plasma nitrate/nitrite, methyl guanidine, pro‐inflammatory cytokines (tumour necrosis factor‐α and interleukin‐1β) were markedly elevated. Pathological examination revealed severe pulmonary oedema and inflammatory cell infiltration. Pretreatment with SMT (3 mg/kg, i.v.) or l‐Nil (3 mg/kg, i.v.) significantly attenuated the LPS‐induced changes and ALI. 4 The results suggest that the inflammatory responses and ALI following infusion of LPS are due to the production of NO, free radicals and pro‐inflammatory cytokines through the iNOS system. Inhibition of iNOS is effective in mitigating the endotoxaemic changes and lung pathology. Inhibitors of iNOS may be potential therapeutic agents for clinical application in patients with acute respiratory distress syndrome.

Insulin attenuates endotoxin-induced acute lung injury in conscious rats.

Objectives:To investigate the effects of insulin on the acute lung injury induced by lipopolysaccharide using a conscious rat model. Design:Prospective, randomized, controlled animal study. Setting:University research laboratory. Subjects:A total of 190 adult male Sprague-Dawley rats weighing 250–300 g. Interventions:Endotoxemia was induced by intravenous infusion of lipopolysaccharide. Lipopolysaccharide at various doses (0, 1, 5, 10, 20, and 30 mg/kg, n = 10 for each dose) was administered intravenously in 20 mins. Insulin infusion at doses of 0.5, 1, and 5 &mgr;U/kg/min was given 5 mins before lipopolysaccharide administration. Plasma glucose was clamped at 90–110 mg/dL by infusion of 10–80% glucose solution. Insulin and glucose infusion (0.01 mL/min) was started 5 mins before lipopolysaccharide and continued for 120 mins. The rats received a total of 60, 120, and 600 &mgr;U/kg insulin as well as 0.12, 0.36, and 0.96 g of glucose in respective groups. The animals were then observed for 4 hrs. Measurements and Main Results:The extent of acute lung injury was evaluated by lung weight/body weight ratio, lung weight gain, protein concentration in bronchoalveolar lavage, and exhaled nitric oxide. We also measured plasma nitrate/nitrite and methyl guanidine. In addition, histopathologic changes of the lung were examined. Lipopolysaccharide caused systemic hypotension and severe acute lung injury with increases in plasma nitrate/nitrite and methyl guanidine. Pretreatment with insulin infusion at doses of 0.5, 1, and 5 &mgr;U/kg/min mitigated or prevented systemic hypotension and the development of acute lung injury, depending on the dose. Insulin also attenuated the lipopolysaccharide-induced increases in nitrate/nitrite and methyl guanidine. Conclusions:Insulin is effective in reducing or preventing the lipopolysaccharide-induced increases in plasma nitrate/nitrite and methyl guanidine and the occurrence of acute lung injury.

Physiological and Chemical Indicators for Early and Late Stages of Sepsis in Conscious Rats

Endotoxin shock is a major cause of death in patients with septicemia. Endotoxin induces nitric oxide (NO) production and causes tissue damage. In addition, the release of oxygen free radicals has also been observed in endotoxin shock and was found to be responsible for the occurrence of multiple organ failure. The purpose of the present study was to evaluate suitable indicators for early and late stages of endotoxin shock. The experiments were designed to induce endotoxin shock in conscious rats by means of an Escherichia coli lipopolysaccharide (LPS) injection. Arterial pressure (AP) and heart rate (HR) were continuously monitored for 72 h after LPS administration. The maximal decrease in AP and increase in HR and nitrate/nitrite level occurred at 9-12 h following LPS administration. The white blood cell (WBC) count had decreased at 3 h. Hydroxyl radical (methyl guanidine, MG) decreased rapidly after LPS administration. Plasma levels of blood urea nitrogen (BUN), creatinine (Cr), lactic dehydrogenase (LDH), creatine phosphokinase (CPK), and glutamic oxaloacetic transaminase increased before the rise of amylase. Our results suggest that changes in AP, HR, WBC, free radicals, and chemical substances (BUN, Cr) can possibly serve as approximate indicators for the early stage of endotoxin shock. Severe multiple organ damage may be caused by amylase release in the late stage of endotoxin shock.

N-acetylcysteine abrogates acute lung injury induced by endotoxin

1 Acute lung injury (ALI) or acute respiratory distress syndrome is a serious clinical problem with high mortality. N‐Acetylcysteine (NAC) is an anti‐oxidant and a free radical scavenger. It has been reporeted recently that NAC ameliorates organ damage induced by endotoxin (lipopolysaccharide; LPS) in conscious rats. The present study was designed to evaluate the effects of NAC on LPS‐induced ALI and other changes in anaesthetized rats. 2 Sprague‐Dawley rats were anaesthetized with pentobarbital (40 mg/kg, i.p.). Endotracheal intubation was performed to provide artificial ventilation. Arterial pressure and heart rate were monitored. The extent of ALI was evaluated with the lung weight (LW)/bodyweight ratio, LW gain, exhaled nitric oxide (NO) and protein concentration in bronchoalveolar lavage (PCBAL). Haematocrit, white blood cells, plasma nitrate/nitrite, methyl guanidine (MG), tumour necrosis factor (TNF)‐a and interleukin (IL)‐1b were measured. Pathological changes in the lung were examined and evaluated. 3 Endotoxaemia was produced by injection of 10 mg/kg, i.v., LPS (Escherichia coli). Animals were randomly divided into three groups. In the vehicle group, rats received an i.v. drip of physiological saline solution (PSS) at a rate of 0.3 mL/h. The LPS group received an i.v. drip of PSS for 1 h, followed by LPS (10 mg/kg by slow blous injection, i.v., over 1–2 min). Rats in the LPS + NAC group received NAC by i.v. drip at a rate of 150 mg/kg per h (0.3 mL/h) for 60 min starting 10 min before LPS administration (10 mg/kg by slow blous injection, i.v., over 1–2 min). Each group was observed for a period of 6 h. 4 N‐Acetylcysteine treatment improved the LPS‐induced hypotension and leukocytopenia. It also reduced the extent of ALI, as evidenced by reductions in LW changes, exhaled NO, PCBAL and lung pathology. In addition, NAC diminished the LPS‐induced increases in nitrate/nitrite, MG, TNF‐a and IL‐1b. 5 In another series of experiments, LPS increased the mortality rate compared with the vehicle group (i.v. drip of PSS at a rate of 0.3 mL/h) during a 6 h observation period. N‐Acetylcysteine, given 10 min prior to LPS, significantly increased the survival rate. 6 The results of the present study suggest that NAC exerts a protective effect on the LPS‐induced ALI. The mechanisms of action may be mediated through the reduction of the production of NO, free radicals and pro‐inflammatory cytokines.

Protective effects of propofol on acute lung injury induced by oleic acid in conscious rats.

Objectives:Oleic acid has been used to induce acute lung injury (ALI) in animals. In patients with acute respiratory distress syndrome (ARDS), the blood level of oleic acid was increased. The mechanism and therapeutic regimen of ARDS and oleic acid-induced ALI remain undefined. In the present study, we investigated the oleic acid-induced changes in lung variables for the measure of ALI, inflammatory mediators, and neutrophil-derived substances. We evaluated the effects of pretreatment and posttreatment with propofol. Design:Randomized, controlled animal study. Setting:University research laboratory. Subjects:Fifty adult male Sprague-Dawley rats weighing 250–300 g. Interventions:We employed a conscious and unrestrained rat model. Oleic acid at a dose of 100 mg/kg was administered intravenously. Propofol (30 mg/kg) was given by intravenous infusion (6 mg/kg/min for 5 mins) 30 mins before (pretreatment) and 30 mins after (posttreatment) oleic acid. Measurements and Main Results:We monitored the arterial pressure, heart rate, and blood gas. The lung weight changes, exhaled nitric oxide, protein concentration in bronchoalveolar lavage, and Evans blue content in lung tissue were determined. The plasma nitrate/nitrite, methylguanidine, cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6, and interleukin-10), neutrophil elastase, myeloperoxidase, malondialdehyde, and sodium- and potassium-activated adenosine triphosphatase (Na+-K+-ATPase) were detected. Histopathological examination of the lung was performed. Oleic acid caused systemic hypotension and severe ALI as evidenced by the increases in the extent of ALI, impairment of pulmonary functions (blood gas variables), and lung pathology. In addition, oleic acid significantly increased inflammatory mediators and neutrophil-derived factors but depressed Na+-K+-ATPase. The inducible nitric oxide synthase was up-regulated. Pre- or posttreatment with propofol was capable of reversing the oleic acid-induced changes and attenuating the extent of ALI. Conclusions:Oleic acid resulted in sepsis-like responses including ALI, inflammatory reaction, and increased neutrophil-derived factors. It depressed the Na+-K+-ATPase activity but up-regulated inducible nitric oxide synthase. Treatment with propofol abrogated or reversed the oleic acid-induced changes.

Effects of post-treatment with low-dose propofol on inflammatory responses to lipopolysaccharide-induced shock in conscious rats

1. In the present study, we used a low dose of propofol (5 mg/kg per h) to investigate its effects on the pro‐inflammatory cytokines (tumour necrosis factor (TNF)‐α, interleukin (IL)‐1β and IL‐10) and changes in nitric oxide (NO) following lipopolysaccharide (LPS) for a period of 12 h in conscious rats.

Nitric oxide in mesenteric vascular reactivity: A comparison between rats with normotension and hypertension

1. Nitric oxide (NO) plays an important role in various physiological functions. The continuous formation of endogenous NO from endothelial cells maintains a vasodilator tone and regulates blood flow and pressure. However, the role of NO in hypertension remains controversial.