Response to inhaled nitric oxide in acute lung injury depends on distribution of pulmonary blood flow prior to its administration

Responses to inhaled nitric oxide (iNO) in acute lung injury (ALI), as evidenced by improvements in oxygenation, are variable. We hypothesized that the effect of iNO may be related to the pre-iNO distribution of pulmonary blood flow (PBF). In the present study we evaluated the effect of iNO on PBF in normal healthy dogs and in a canine model of ALI induced by oleic acid (OA). In Group "OA only" (n = 5), ALI was induced by central venous injection of 0.08 ml/kg OA. In Group "E+OA" (n = 5), hypoxic pulmonary vasoconstriction after ALI was blocked with low-dose endotoxin (15 microg/kg of Escherichia coli endotoxin) administered 30 min before giving the same dose of OA. Measurements of regional PBF and lung water concentration (LWC) using positron emission tomography (PET) and H215O were performed before and after OA or placebo, and then again at concentrations of 10, 40, and 0 ppm iNO. One hundred twenty minutes after OA injury, PaO2/FIO2 fell significantly in Group OA only, from 567 +/- 32 to 437 +/- 67 mm Hg. In these animals, PBF redistributed from the dorsal edematous regions of the lungs to the nondependent zones, thus partially preserving normal ventilation/ perfusion relationships. As in the normal animals, in Group OA only, iNO did not significantly change either PBF or oxygenation. In Group E+OA, the administration of low-dose endotoxin eliminated perfusion redistribution from the dorsal edematous lung regions. As a result, PaO2/FIO2 fell from 558 +/- 70 to 119 +/- 53 mm Hg, a decrease that was significantly greater than that in Group OA only. In Group E+OA, administration of iNO restored perfusion redistribution to a similar level as in Group OA only, which was associated with a significant improvement in PaO2/FIO2, from 119 +/- 53 to 251 +/- 159 (10 ppm iNO), and 259 +/- 165 mm Hg (40 ppm iNO). We conclude that the effect of iNO on oxygenation after ALI depends on the pre-iNO perfusion pattern, which may help explain the variable response to iNO often observed in patients with acute respiratory distress syndrome.     

Effect of lung volume on lung resistance and elastance in awake subjects measured during sinusoidal forcing

BACKGROUND: Although lung volume may be changed by certain procedures during anesthesia and mechanical ventilation, dependence of the dynamic mechanical properties of the lungs on lung volume are not clear. Based on studies in dogs, the authors hypothesized that changes in lung mechanics caused by anesthesia in healthy humans could be accounted for by immediate changes in lung volume and that lung resistance will not be decreased by positive end-expiratory airway pressure if tidal volume and respiratory frequency are in the normal ranges. METHODS: Lung resistance and dynamic lung elastance were measured in six healthy, relaxed, seated subjects during sinusoidal volume oscillations at the mouth (5 mL/kg; 0.4 Hz) delivered at mean airway pressure from -9 to +25 cmH2O. Changes in lung volume from functional residual capacity were measured with inductance plethysmographic belts. RESULTS: Decreases in mean mean airway pressure that caused decreases in lung volume from functional residual capacity comparable to those typically observed during anesthesia were associated with significant increases in both dynamic lung elastance and lung resistance. Increases in mean mean airway pressure that caused increases in lung volume from functional residual capacity did not increase lung resistance and increased dynamic lung elastance only above about 15 cmH2O. CONCLUSIONS: Increases in dynamic lung elastance and lung resistance with anesthesia can be explained by the accompanying, acute decreases in lung volume, although other factors may be involved. Increasing lung volume by increasing mean airway pressure with positive end-expiratory pressure will decrease lung resistance only if the original lung volume is low compared to awake, seated functional residual capacity.     

Factors influencing the tracheal fluctuation of inhaled nitric oxide in patients with acute lung injury

BACKGROUND: Inhaled nitric oxide (NO) improves arterial oxygenation in patients with acute lung injury (ALI) by selectively dilating pulmonary vessels perfusing ventilated lung areas. It can be hypothesized that NO uptake from the lung decreases with increasing ventilation perfusion mismatch. This study was undertaken to determine the factors influencing the fluctuation of tracheal NO concentration over the respiratory cycle as an index of NO pulmonary uptake in patients with ALI. METHODS: By using a prototype system (Opti-NO) delivering a constant flow of NO only during the inspiratory phase, 3 and 6 ppm of NO were administered during controlled mechanical ventilation into a lung model and to 11 patients with ALI. All patients had a thoracic computed tomography (CT) scan. Based on an analysis of tomographic densities, lungs were divided into three zones: normally aerated (-1.000 to -500 Hounsfield units [HU]), poorly aerated (-500 to -100 HU), and nonaerated (-100 to +100 HU), and the volume of each zone was computed. Concentrations of NO in the inspiratory limb and trachea were continuously measured by a fast-response chemiluminescence apparatus. RESULTS: In the lung model, tracheal NO concentration was stable with minor fluctuation. In contrast, in patients, tracheal NO concentration fluctuated widely during the respiratory cycle (55 +/- 10%). Because uptake of NO from the lungs was absent in the lung model but present in the patients, this fluctuation was considered as an index of pulmonary uptake of NO. This was further substantiated by (1) the coincidence of the peak and minimum tracheal NO concentration with the end-inspiratory and end-expiratory phases, respectively, and (2) continued decrease of tracheal NO concentration during prolonged expiratory phase. In patients with ALI, the fluctuation of tracheal NO concentration expressed as the difference between inspiratory and expiratory NO concentrations divided by inspiratory NO concentration was greater at 6 ppm than at 3 ppm (P < 0.01), was linearly correlated with normally aerated lung volume, inversely correlated with alveolar dead space and with poorly aerated lung volume. CONCLUSION: In patients with ALI, fluctuation of tracheal NO concentration over the respiratory cycle can be considered as an index of NO uptake from the lungs that depends on aerated lung volume and perfusion of ventilated lung areas. At bedside, it may be used to follow the evolution of ventilation-perfusion mismatch.     

Mediators of ischemia-reperfusion injury of rat lung

In rats, we characterized the mediators of lung reperfusion injury after ischemia. Animals underwent left lung ischemia. After 90 minutes of ischemia, reperfusion for up to 4 hours was evaluated. Lung injury, as determined by vascular leakage of serum albumin, increased in ischemic-reperfused animals when compared with time-matched sham controls. Injury was biphasic, peaking at 30 minutes and 4 hours of reperfusion. The late but not the early phase of reperfusion injury is known to be neutrophil dependent. Bronchoalveolar lavage of ischemic-reperfused lungs at 30 minutes and 4 hours of reperfusion demonstrated increased presence of serum albumin, indicative of damage to the normal vascular/airway barrier. Lung mRNA for rat monocyte chemoattractant protein-1 and tumor necrosis factor-alpha peaked very early (between 0.5 and 1.0 hour) during the reperfusion process. Development of injury was associated with a decline in serum complement activity and progressive intrapulmonary sequestration of neutrophils. Administration of superoxide dismutase before reperfusion resulted in reduction of injury at 30 minutes of reperfusion. Complement depletion decreased injury at both 30 minutes and 4 hours of reperfusion. Requirements for tumor necrosis factor-alpha, interferon-gamma, and monocyte chemoattractant protein-1 for early injury were shown whereas only tumor necrosis factor-alpha was involved at 4 hours. We propose that acute (30-minute) lung injury is determined in large part by products of activated lung macrophages whereas the delayed (4-hour) injury is mediated by products of activated and recruited neutrophils.     

Respiratory function and surgical reduction of lung volume

Emphysema is characterised by an enlargement of the terminal air spaces. Destructions of alveolar walls lead to a loss of the lung elastic recoil. The driving pressure for expiration is decreased and the outward forces acting on the bronchioles are lost, leading to bronchiolar collapse and airflow limitation. Hyperinflation of the lungs and overdistension of the chest wall cause the respiratory muscles to operate in unfavourable conditions. Patients with advanced emphysema have decreased quality of live: they are dyspneic at rest and are unable to perform exercise. Surgical excision of parts of diffusely emphysematous lungs (Lung Volume Reduction Surgery, LVRS) has been proposed since many years. Expansion of the remaining lung should increase lung elastic recoil and restore the outward forces on the bronchioles. It has been demonstrated that LVRS reduces dyspnea symptoms, improves exercise tolerance and enhances the quality of live. LVRS increases lung elastic recoil, airway conductance and maximal expiratory flow, reduces dynamic hyperinflation and improves the efficiency of the respiratory muscles. These improvements are maintained for at least 12 to 18 months. Preoperative evaluation, surgical-induced modifications of pulmonary functions and postoperative exercise training are exposed.     

Role of inducible nitric oxide synthase in endotoxin-induced acute lung injury

The role of nitric oxide (NO) in lung injury remains unclear. Both beneficial and detrimental roles have been proposed. In this study, we used mutant mice lacking the inducible nitric oxide synthase (iNOS) to assess the role of this isoform in sepsis-associated lung injury. Wild-type and iNOS knockout mice were injected with either saline or Escherichia coli endotoxin (LPS) 25 mg/kg and killed 6, 12, and 24 h later. Lung injury was evaluated by measuring lactate dehydrogenase activity in the bronchoalveolar lavage, pulmonary wet/dry ratio, and immunostaining for nitrotyrosine formation. In the wild-type mice, LPS injection elicited more than a 3-fold rise in lactate dehydrogenase activity, a significant rise in lung wet/dry ratio and extensive nitrotyrosine staining in large airway and alveolar epithelium, macrophages, and pulmonary vascular cells. This was accompanied by induction of iNOS protein and increased lung nitric oxide synthase activity. By comparison, LPS injection in iNOS knockout mice elicited no iNOS induction and no significant changes in lung NOS activity, lactate dehydrogenase activity, lung wet/dry ratio, or pulmonary nitrotyrosine staining. These results indicate that mice deficient in iNOS gene are more resistant to LPS-induced acute lung injury than are wild-type mice.     

Effects of pretreatment with SDZ MRL 953, a novel immunostimulatory lipid A analog, on endotoxin-induced acute lung injury in guinea pigs

SDZ MRL 953 (SDZ), a novel immunostimulatory lipid A analog, has been reported to have immunopharmacological activities similar to those of lipopolysaccharide (LPS) but to have little of the toxicity of LPS. We investigated the effects of pretreatment with SDZ on Escherichia coli endotoxin-induced acute lung injury in guinea pigs. Four experimental groups consisted of saline control (n = 16), SDZ (-12 h) plus LPS (2 mg/kg of SDZ per kg of body weight injected intravenously 12 h before intravenous injection of 2 mg of LPS per kg; n = 15), SDZ (-10 min) plus LPS (SDZ injected 10 min before LPS injection; n = 10), and LPS alone (n = 16). The animals were sacrificed, and lung tissue was sampled 4 h after LPS or saline infusion. Lung injury was assessed by measuring the wet weight-to-dry weight ratio and the level of 125I-labeled albumin accumulation in bronchoalveolar lavage fluid relative to that in plasma. In the SDZ (-12 h) plus LPS group, these two parameters of acute lung injury were decreased compared with those in the LPS alone group. However, they were not decreased in the SDZ (-10 min) plus LPS group. We conclude that SDZ attenuates endotoxin-induced acute lung injury when it is administered 12 h before LPS injection. The attenuating effects of SDZ are speculated to be due to down regulation of the response to endotoxin rather than to receptor blocking.     

Effect of lung lavage on the stress relaxation of the respiratory system

To test the hypothesis that lowering the concentrations of surfactant molecules at the gas-liquid interface increases viscoelastic dissipation in the lungs, the amplitude and time course of stress relaxation were quantified before and after lavage of the lungs with warm saline in five newborn and five 8-wk-old anesthetized piglets. Stress relaxation was separated from other dissipative pressure losses by fitting the pressure decays that follow airway occlusions performed during a period of constant inspiratory flow to a double-exponential regression. The amplitude of stress relaxation (defined by the term of the regression with the longest time constant) related linearly to the changes in respiratory system volume and elastic recoil preceding the occlusions both before and after the lavage. Lung lavage increased the slope of both relationships without altering the time course of the relaxations. In addition to being consistent with the proposed hypothesis, these results suggest that viscoelastic pressure losses remain linked to the elastic stresses generated during lung inflation, as proposed by Fredberg and Stamenovic's structural dumping theory (J. Appl. Physiol. 67: 2408-2419, 1989).     

The bulbar respiratory centre in the rabbit. I. Changes of respiratory parameters caused by intermittent electrical bulbar stimulation during inspiration or expiration

In anesthetized rabbits, spirogram and diaphragmatic activity were examined during electrical stimulation of regions of the medulla oblongata. The stimulating volleys were triggered by the phase transitions of the animal's own respiration. 1. Each early inspiratory volley of 120 ms duration at 100 pulses per second caused an immediate and transient inhibition of the diaphragmatic activity. Respiration was slowed down due to prolongation of inspiration. The tidal volume increased above control. Stimuli delivered after 30-40% of a control inspiration had elapsed cut short this phase and entailed a shortening of the following expiration, too. Respiration was thus accelerated. 2. Each early expiratory volley caused an inspiratory twitch after a short latency. The respiratory rate was slightly increased due to shortening of expiration. The spirogram exhibited a distinct inspiratory effect (elevation of the end-inspiratory and end-expiratory levels). Stimuli delivered after 60--70% of a control expiration had elapsed slowed down respiration due to prolongation of inspiration but did not alter the end-expiratory level. The expiration remained almost unaltered. The effects were still observed while an artificial state of lung distension or collapse was maintained. 3. Volleys of increasing duration were delivered, starting with onset of expiration. The initial respiratory acceleration (shortening of both phases) and elevation of the end-expiratory level, observed when short volleys were applied, changed into slowing down of respiration (prolongation of both phases) and a shift of the end-expiratory level towards active expirations when the duration of the volley was somewhat longer than a normal expiration. The end-inspiratory level remained slightly elevated. Results suggest that during inspiration a progressively increasing inhibitory state is built up. During expiration, both an increasing inspiratory and an expiratory tendency are present as revealed by mixed inexpiratory stimulation effects.     

Kinetics and quantitation of eosinophil and neutrophil recruitment to allergic lung inflammation in a brown Norway rat model

We quantitated neutrophil and eosinophil migration into lung parenchyma using specific peroxidase enzyme assays, and into the bronchoalveolar compartment by bronchoalveolar lavage (BALF), in sensitized brown Norway (BN), Fischer, and Lewis rats and also assessed the lungs by histopathology. Fourteen days after sensitization with ovalbumin (OA in alum [given subcutaneously] and OA with Bordetella pertussis [given intraperitoneally]), rats were challenged with an OA aerosol for 1 h. In BN rats, there was marked perivascular and peribronchial edema, focal hemorrhages, and increase in lung wet weight and BALF protein content, accompanied by neutrophilic infiltration at 3-14 h postchallenge. Few eosinophils were seen at 14 h in lung tissue or in BALF. Neutrophils peaked at 24 h in parenchyma ([94 +/- 7] x 10[6]) and in BALF ([2.7 +/- 0.4] x 10[6]) and declined rapidly thereafter. Marked eosinophil infiltration into parenchyma was apparent by 24 h. Eosinophil accumulation peaked at 48 h in parenchyma ([127 +/- 18] x 10[6]) and at 72 h in BALF ([10 +/- 2.4] x 10[6]), comprising up to 85% of lavage cells at this time. Lung eosinophilia persisted for at least 6 d with only a slow decline or clearance, not approximating baseline until day 13 after challenge. Histopathology showed peribronchial and interstitial eosinophilic pneumonia, most severe on day 3. In contrast to the BN rats, essentially no pulmonary inflammation was observed in Lewis and Fischer rats. This model in the BN rat, and the specific peroxidase assays for quantitating tissue eosinophils and neutrophils, should be useful for investigating the regulation of allergen-induced eosinophil and neutrophil migration into and clearance from the lung.     

Regional lung hematocrit variation and assessment of acute lung injury

Estimating blood content in the lung remains a key step in calculating lung water volume and microvascular permeability. We studied the effect of regional lung hematocrit (Hct) variation on assessment of acute lung injury. Escherichia coli endotoxin was administered in guinea pigs intravenously. Lung injury was evaluated by measuring the wet-to-dry weight ratio (W/D) and transvascular 125I-labeled albumin leakage for 3 h [tissue-to-plasma 125I-albumin ratio (T/P)] in five tissue samples from each animal. Residual blood content was corrected using either 51Cr-red blood cells as a blood cell marker, 99mTc-albumin as a plasma marker, or both, injected 10 min before the guinea pigs were killed. Lung Hct, estimated from the marker counts of lung and peripheral blood samples, was lower than peripheral blood Hct; intraindividual variation, represented by the standard deviation in each subject, was 0.024 +/- 0.015 for the control group (coefficient of variation 8.0 +/- 5.1%) and 0.026 +/- 0.013 for the endotoxin group (coefficient of variation 8.5 +/- 4.1%). Uncorrected W/D for residual blood content was greater than the corrected W/D. 99mTc-albumin correction gave values closer to the W/D corrected by both markers. T/P corrected by 99mTc-albumin showed smaller data variations than the values obtained with 51Cr-red blood cell correction, which was affected by variations in lung Hct. We recommend using a plasma marker to correct for blood content in assessing acute lung injury by W/D and T/P.     

Mechanical ventilation of patients with acute lung injury

Ventilatory management of patients with acute lung injury (ALI), particularly its most severe subset, acute respiratory distress syndrome (ARDS), is complex. Newer lung protective strategies emphasize measures to enhance alveolar recruitment and avoid alveolar overdistention, thus minimizing the risk of ventilator-induced lung injury (VILI). Key components of such strategies include the use of smaller-than-conventional tidal volumes which maintain peak transpulmonary pressure below the pressure associated with overdistention, and titration of positive end-expiratory pressure to promote maximal alveolar recruitment. Novel techniques, including prone positioning, inverse ratio ventilation, tracheal gas insufflation, and high frequency ventilation, are considerations in severe ARDS. No single approach is best for all patients; adjustment of ventilatory parameters to individual characteristics, such as lung mechanics and gas exchange, is required.     

Effects of magnetic field exposure on the development of lung fibrosis elicited by industrial pollutants

Lung injury elicited by a single intratracheal instillation of fibrogenic (quartz) and nuisance (anatase) dusts and/or weekly repeated instillation of CdCl2 solution combined with sinusoidal (50 Hz, 10 mT) magnetic field (MF) exposure was studied in male rats. Combined effects in bronchoalveolar lavage (BAL), rat lungs and regional lymph nodes after 4 months of MF exposure (1 h/5 days per week) were evaluated biochemically and by cytological and histopathological examination. Damage of cell membranes in the cell part of BAL due to MF exposure was not observed in the examined animal groups. Following MF exposure, decreased synthesis of collagen proteins (incorporation of [14C]proline) was demonstrated in lungs with quartz dust burden. Histological examination revealed differences in the lung tissue reaction suggesting the modification of the repair process due to MF exposure following experimental injury in both quartz and cadmium groups.     

Percutaneous direct-puncture acrylic embolization of a pseudoaneurysm after failed carotid stenting for the treatment of acute carotid blowout

OBJECTIVES: To compare four widely used animal models of acute lung injury and to determine the changes in physiologic variables associated with each model. DESIGN: A prospective, controlled animal study. SETTING: An animal laboratory of a university-affiliated children's hospital. SUBJECTS: Four groups of anesthetized, paralyzed, and ventilated young Yorkshire pigs, weighing 35 to 45 kg. INTERVENTIONS: Acute lung injury was generated by four different methods: a) intrapulmonary arterial infusion of endotoxin of Escherichia colt; b) bronchoalveolar instillation of 0.05N of hydrochloric acid; c) repeated bronchoalveolar warm saline lavage; and d) intrapulmonary arterial infusion of oleic acid. After each acute lung injury procedure, the temporal changes in various physiologic variables were measured, starting at 60 mins and at 15-min intervals thereafter for a total of 165 mins. Systemic and mixed venous serum immunoreactive tumor necrosis factor (TNF)-alpha concentrations were also measured at the same time points. Analysis of variance for repeated measures was employed to determine the absolute and relative significance of the changes observed. MEASUREMENTS AND MAIN RESULTS: Systemic and mixed venous immunoreactive TNF-alpha did not change following any of the acute lung injury procedures. The animals' heart rates and systemic vascular resistances also did not change. Hydrochloric acid instillation as well as bronchoalveolar lavage resulted in significant hypoxemia with no other hemodynamic effects. Endotoxin infusion did not result in hypoxemia but caused significant increases in mean pulmonary arterial pressure and pulmonary vascular resistance and decreases in mean arterial pressure and cardiac output. Oleic acid infusion resulted in a marked hypoxemia with a pronounced increase in mean pulmonary arterial pressure and pulmonary vascular resistance. It also markedly reduced the mean arterial pressure, cardiac output, and the mixed venous PO2. CONCLUSIONS: The surfactant depletion and hydrochloric acid instillation models produce acute hypoxemia in an otherwise hemodynamically stable animal. A brief endotoxin infusion provides a model for cardiovascular instability and pulmonary hypertension but fails to produce hypoxemia in the pig. The oleic acid infusion creates a model of marked cardiovascular instability, pulmonary hypertension, and profound hypoxemia. However, none of the acute lung injury models described was associated with the production of tumor necrosis factor.     

Effects of partial liquid ventilation on lung injury in a model of acute respiratory failure: a histologic and morphometric analysis

OBJECTIVE: To compare the histopathologic changes observed in a sheep model of oleic acid-induced acute respiratory failure during partial liquid ventilation with perflubron with gas ventilation. DESIGN: Randomized, controlled study. SETTING: Animal laboratory and pathology laboratories of a university hospital. SUBJECTS: Fourteen healthy adult sheep, weighing 64.9 +/- 6.4 kg. INTERVENTIONS: Lung injury was induced with oleic acid (0.15 mL/kg). A tracheostomy tube was inserted, along with systemic and pulmonary artery monitoring catheters. Animals were randomized to undergo either partial liquid ventilation (n = 7) or gas ventilation (n = 7). Animals underwent euthanasia at the end of the 90-min study period, after which the endotracheal tube was clamped with the lungs in expiratory hold at a positive end-expiratory pressure of 5 cm H2O. En bloc excision of the heart and lungs was performed by thoracotomy. Perfusion of the isolated lung vasculature with 2.5% paraformaldehyde and 0.25% glutaraldehyde in a 0.1-M phosphate buffer was performed. Histologic analysis followed. MEASUREMENTS AND MAIN RESULTS: Gas exchange increased markedly in the animals that underwent partial liquid ventilation compared with the gas-ventilated animals (PaO2 at 90 mins: gas ventilation-treatment group, 40 +/- 8 torr [5.3 +/- 1.1 kPa]; partial liquid ventilation-treatment group, 108 +/- 60 torr [14.4 +/- 8.0 kPa]; p = .004). Lung histologic analysis demonstrated a better overall diffuse alveolar damage score (partial liquid ventilation-treatment group, 12.4 +/- 1.4; gas ventilation-treatment group, 15.0 +/- 1.7; p = .01). In the partial liquid ventilation-treatment group, we observed an increase in mean alveolar diameter (partial liquid ventilation-treatment group, 82.4 +/- 2.9 microm; gas ventilation-treatment group, 67.7 x 3.9 microm; p = .0022) and a decrease in the number of alveoli per high-power field (partial liquid ventilation-treatment group, 25.7 +/- 0.9, gas ventilation-treatment group, 31.4 +/- 2.5; p = .0022), in septal wall thickness (partial liquid ventilation-treatment group, 6.0 +/- 0.6 microm; gas ventilation-treatment group, 8.3 +/- 1.0 microm; p = .0033), and in mean capillary diameter (partial liquid ventilation-treatment group, 13.0 +/- 0.8 microm; gas ventilation-treatment group, 19.9 +/- 1.4 microm; p = .0022). CONCLUSIONS: Partial liquid ventilation is associated with notable improvement in gas exchange and with a reduction in the histologic and morphologic changes observed in an oleic acid model of acute lung injury.     

Cardiovascular changes associated with aging: the anesthetic implications

PURPOSE: Elevated arterial lactate concentrations in patients with sepsis have been interpreted as evidence of peripheral, nonpulmonary tissue hypoxia. These patients often develop pulmonary failure manifested by the acute respiratory distress syndrome (ARDS). As the result of tissue hypoxia or inflammation, the lungs of patients with sepsis and ARDS may become a source of lactate release into the circulation. MATERIALS AND METHODS: Pulmonary lactate release was measured in 19 patients with sepsis, arterial lactate > or = 2.2 mm, and gastric mucosal pH > 7.30. A normal gastric mucosal pH served as a marker of adequate splanchnic oxygenation. Pulmonary lactate release was computed as the product of the cardiac index and the difference in plasma L-lactate concentration in simultaneously obtained arterial and mixed venous blood samples. Lung injury was graded with the Lung Injury Score using radiographic and physiologic data. RESULTS: The lungs of patients with minimal or no lung injury (lung injury score <1) produced significantly less lactate than those with moderate or severe lung injury (lung injury score > or = 1) (P < .005). The Lung Injury Score correlated with pulmonary lactate release (r2 = .73; P < .0001). This relationship resulted primarily from increases in mixed venous-arterial lactate differences (r2 = .59). The Lung Injury Score correlated weakly with the cardiac index (r2 = .32). Arterial lactate concentration did not correlate with pulmonary lactate release, systemic oxygen transport, or systemic oxygen consumption. CONCLUSIONS: The lungs of patients with sepsis and ARDS may produce lactate. Pulmonary lactate release correlates with the severity of lung injury. The contribution of pulmonary lactate release should be considered when interpreting arterial lactate concentration as an index of systemic hypoxia.     

Purification and characterization of aminopeptidase P from Lactococcus lactis subsp. cremoris

BACKGROUND: Neutrophils, platelets, and cytokines are thought to play a pivotal role in the pathogenesis of endotoxin-induced lung injury which resembles features of acute respiratory distress syndrome (ARDS). For initiation of this pathological process, neutrophils and platelets are activated and adhere to pulmonary endothelium. Nitric oxide (NO) inhibits adhesion and activation of these cells and decreases the cytokine level in bronchoalveolar lavage (BAL) fluid obtained from patients with ARDS. Limited data are available on the effect of NO treatment before and after endotoxin on the development and advance of ARDS. The aim of the current study was to determine whether NO inhalation prevents acute lung injury. METHODS: Thirty-two male anaesthetized rabbits were randomly assigned to receive one of four treatments (n = 8 each); Group S-N received saline with nitrogen (N2), Group S-NO received saline infusion with NO (20 p.p.m.) inhalation, Group E-N received an infusion of Escherichia coli endotoxin 100 micrograms/ kg over 60 min with inhalation of N2, and Group E-NO received endotoxin with NO (20 p.p.m.) inhalation. The lungs of the rabbits were ventilated with 40% oxygen until 6 h after the start of endotoxin or saline administration. Haemodynamics and PaO2 were recorded during the ventilation period. After observation, the lung wet-to dry-(W/D) weight ratio, lung mechanics, and cell fraction, activated complements, cytokines, arachidonic acid metabolites, and albumin concentrations in the BAL fluid were measured and analysed. Light microscopic findings were compared among the four groups. RESULTS: Pulmonary hypertension and deterioration of oxygenation by endotoxin were less pronounced in rabbits receiving NO. The lung compliance after endotoxin was similar in Groups E-NO and E-N. The W/D weight ratio and neutrophils and albumin concentrations in the BAL fluid increased in Groups E-NO and E-N. The BAL fluid concentrations of interleukin-8, thromboxane A2, and prostacyclin were similar in the two endotoxin-treated groups. Endotoxin caused extensive morphologic lung damage regardless of NO inhalation. CONCLUSIONS: The increase in pulmonary arterial pressure and deterioration of oxygenation were less in endotoxin-exposed rabbits receiving NO inhalation compared with those receiving N2. Accumulation of neutrophils and platelets in the lung, morphological lung damage, and the release of cytokines and prostanoids were observed in the E-NO group. However, we are unable to extrapolate these results directly to the human clinical setting because of the short observation period, the use of only one dose of NO, and the species difference.     

Factors affecting the uptake of 99mTc-sulfur colloid by the lung and kidney

Occasionally patients injected with 99mTc-sulfur colloid (TSC) for liver--spleen imaging show increased uptake by the lungs or kidneys. In animals, increased lung uptake of TSC can be produced by injecting endotoxin intraperitoneally. Using an intraperitoneal endotoxin model, we studied the effect of heparin on dose-response curves for TSC uptake by the lungs and kidneys. Over a dose range of 1 mug to 10 mg of endotoxin, TSC uptake by the lungs increased progressively; heparin had no effect. In the kidneys, endotoxin in doses from 1 mug to 1 mg resulted in an increased TSC uptake which was less marked than that in the lungs and which was also unaffected by heparin. However, at a dose of 10 mg of endotoxin, a marked increase occurred in TSC uptake by the kidneys, and this could be prevented by heparin. Although the increased TSC uptake by the kidneys at lower doses of endotoxin and by the lungs at all doses is probably not related to intraavascular coagulation, the marked increase in TSC uptake by the kidneys at 10 mg of intraperitoneal endotoxin probably is related to intravascular coagulation, possibly by entrapment in fibrin deposits in the renal capillaries.     

The fetal inflammatory response syndrome

A mathematical model of the ARDS lung, with simulated gravitational superimposed pressure, evaluated the effect of varying alveolar threshold opening pressures (TOP), PEEP and peak inspiratory pressure (PIP) on the static pressure-volume (PV) curve. The lower inflection point (Pflex) was affected by SP and TOP, and did not accurately indicate PEEP required to prevent end-expiratory collapse. Reinflation of collapsed lung units (recruitment) continued on the linear portion of the PV curve, which had a slope at any volume greater than the total compliance of aerated alveoli. As recruitment diminished, the reduced PV slope could produce an upper Pflex at 20 to 30 cm H2O pressure. An upper Pflex caused by alveolar overdistension could be modified or eliminated by recruitment with high TOP. With constant PIP as PEEP increased, and TOP range of 5 to 60 cm H2O, PEEP to prevent end-expiratory collapse was indicated by minimum PV slope above 20 cm H2O, minimum hysteresis, and maximum volume at a pressure of 20 cm H2O. With constant inflation volume as PEEP increased, the effect on PV slope was unpredictable. Although increased PV slope indicated recruitment, maximum PV slope usually underestimated PEEP required to prevent end-expiratory collapse. Therefore, with this model the PV curve did not reliably predict optimal ventilator settings.     

Endothelin-1 and cell proliferation in lung organ cultures. Implications for lung allografts

Endothelin-1 (ET-1) is found in bronchoalveolar lavage fluid in patients following lung transplantation. ET-1 causes contraction of isolated pulmonary vessels and bronchi and stimulates proliferation of smooth muscle cells in culture. Therefore, ET-1 could contribute to the smooth muscle hyperplasia and stromal proliferation seen in chronic rejection of lung allografts. Experiments were designed to determine whether (1) ET-1 stimulates proliferation of pulmonary tissue, (2) proliferation is increased in rejecting allotransplanted lungs, (3) endothelin-A receptors mediate the proliferative response, and (4) ET-1 is produced by activated infiltrating immunocompetent cells. Lung organ cultures were prepared from unoperated dogs and dogs with rejecting single lung allografts. Incubation of organ cultures from unoperated dogs with ET-1 (10(-9) to 10(-7) M)) increased positive staining for proliferation cell nuclear antigen (PCNA) in lung parenchyma. PCNA staining was not decreased by the endothelin-A antagonist BQ123 (10(-6) M). In addition, immunostaining for endothelin-B receptors was present in sections of unoperated but not rejecting lungs. PCNA staining in lung cultures from rejecting allotransplanted dogs was significantly greater than that from unoperated dogs. Positive immunohistochemical staining for ET-1 was found in mononuclear cells infiltrating rejecting transplanted lungs. In conclusion, exogenous ET-1 is mitogenic in lung organ cultures through receptors other than endothelin-A. Proliferation in rejecting transplanted lungs is increased compared with unoperated lungs. Mononuclear cells may be a source of endothelin-1 in the rejecting lung. ET-1, therefore could, in synergism with other cytokines, contribute to acute and chronic pathological changes seen in pulmonary rejection.