Effects of recruitment maneuvers with PEEP on lung volume distribution in canine models of direct and indirect lung injury

Lung recruitment maneuvers can help open collapsed lung units for sufficient oxygenation, and positive end expiratory pressure (PEEP) is used to keep the lung open after recruitment. However, the application of high PEEP levels may play a significant role in causing regional lung hyperinflation during mechanical ventilation. The authors sought to study the effects of PEEP targeting optimal oxygenation on regional lung volume distribution in a direct and an indirect acute respiratory distress syndrome (ARDS) model. ARDS was induced by either surfactant depletion or oleic acid injection in dogs. After lung recruitment, PEEP was decreased from 20 to 10 cmH₂O in 2 cmH₂O steps every 10 min to examine regional lung aeration by using computed tomography. Lung injury appeared to be localized in the model of surfactant depletion while it widely diffused after oleic acid infusion. At PEEP levels that achieved optimal oxygenation, nonaerated lung units decreased and normally aerated lung units enhanced, but hyperinflated areas increased significantly in both models (P < 0.05). Hyperinflated areas were greater in the surfactant depletion model than in the oleic acid model at PEEP levels applied (P < 0.05). Optimal oxygenation guided PEEP may cause hyperinflated in both focal lung injury and diffused lung injury post lung recruitment. Hyperinflation was more susceptible in focal lung injury than in diffused lung injury post lung recruitment.     

Mechanisms of interaction between oxygen and granulocytes in hyperoxic lung injury

Hyperoxia and infused granulocytes act synergistically in producing a nonhydrostatic high-permeability lung edema in the isolated perfused rabbit lung within 4 h, which is substantially greater than that seen with hyperoxia alone. We hypothesized that the interaction between hyperoxia and granulocytes was principally due to a direct effect of hyperoxia on the lung itself. Isolated perfused rabbit lungs that were preexposed to 2 h of hyperoxia (95% O2-5% CO2) prior to the infusion of unstimulated granulocytes (under normoxic conditions) developed significant nonhydrostatic lung edema (P = 0.008) within 2 h when compared with lungs that were preexposed to normoxia (15% O2-5% CO2) prior to granulocyte perfusion. The edema in the hyperoxic-preexposed lungs was accompanied by significant increases in bronchoalveolar lavage (BAL) protein, BAL granulocytes, BAL thromboxane and prostacyclin levels, perfusate chemotactic activity, and lung lipid peroxidation. These findings suggest that the synergistic interaction between hyperoxia and granulocytes in producing acute lung injury involves a primary effect of hyperoxia on the lung itself.     

Positron emission tomography with [18F]fluorodeoxyglucose to evaluate neutrophil kinetics during acute lung injury

We measured neutrophil glucose uptake with positron emission tomographic imaging and [18F]fluorodeoxyglucose ([18F]FDG-PET) in anesthetized dogs after intravenous oleic acid-induced acute lung injury (ALI; OA group, n = 6) or after low-dose intravenous endotoxin (known to activate neutrophils without causing lung injury) followed by OA (Etx + OA group, n = 7). The following two other groups were studied as controls: one that received no intervention (n = 5) and a group treated with Etx only (n = 6). PET imaging was performed 1.5 h after initiating experimental interventions. The rate of [3H]deoxyglucose ([3H]DG) uptake was also measured in vitro in cells recovered from bronchoalveolar lavage (BAL) performed after PET imaging. Circulating neutrophil counts fell significantly in animals treated with Etx but not in the other two groups. The rate of [18F]FDG uptake, measured by the influx constant Ki, was significantly elevated (P < 0.05) in both Etx-treated groups (7.9 +/- 2.6 x 10(-3) ml blood x ml lung(-1) x min(-1) in the Etx group, 9.3 +/- 4.8 x 10(-3) ml blood x ml lung(-1) x min(-1) in the Etx + OA group) but not in the group treated only with OA (3.4 +/- 0.8 x 10-3 ml blood x ml lung(-1) x min(-1)) when compared with the normal control (1.6 +/- 0.4 x 10(-3) ml blood x ml lung(-1) x min(-1)). [3H]DG uptake was increased (73 +/- 7%) in BAL neutrophils recovered from the Etx + OA group (P < 0.05) but not in the OA group. Ki and [3H]DG uptake rates were linearly correlated (R2 = 0.65). We conclude that the rate of [18F]FDG uptake in the lungs during ALI reflects the state of neutrophil activation. [18F]FDG-PET imaging can detect pulmonary sequestration of activated neutrophils, despite the absence of alveolar neutrophilia. Thus [18F]FDG-PET imaging may be a useful tool to study neutrophil kinetics during ALI.     

Prostaglandin E2 attenuation of sheep lung responses to endotoxin

Prostaglandin (PG) E2 can inhibit inflammatory responses of neutrophils and lymphocytes, including eicosanoid release. Diffuse lung injury after endotoxemia in sheep is accompanied by sequestration of neutrophils and lymphocytes in the lungs, and eicosanoids mediate some of the pathophysiology of the response. To determine whether exogenous PGE2 could prevent the endotoxin response, we measured pulmonary hemodynamics, gas exchange, and lung lymph responses to infusion of Escherichia coli endotoxin (0.5 micrograms/kg iv over 30 min) in unanesthetized sheep in the presence and absence of PGE2 (0.5 micrograms.kg-1.min-1) infused intravenously for 4 h beginning 0.5 h before endotoxin infusion. We also measured lung lymph concentrations of thromboxane B2 (TxB2) and prostacyclin metabolite, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), by radioimmunoassay and leukotriene B4 (LTB4) by gas chromatography-mass spectrometry. PGE2 decreased endotoxin-induced pulmonary hypertension and hypoxemia and markedly attenuated the lymph flow and lymph protein clearance responses. PGE2 also attenuated endotoxin-induced increases in lung lymph TxB2 and 6-keto-PGF1 alpha and decreased lymph LTB4 flow after endotoxin without decreasing lymph LTB4 concentrations. We conclude that PGE2 infusion attenuates lung dysfunction caused by endotoxemia, possibly by preventing endogenous release of other eicosanoids.     

Role of histamine in acute oleic acid-induced lung injury

The action of histamine in oleic acid (OA)-induced injury was investigated using the isolated guinea pig lung perfused with blood-free media. OA infusion caused a significant increase in pulmonary arterial pressure, airway inspiratory pressure, lung weight, and protein flux across the alveolar-capillary barrier. These changes were dose dependent and caused injury regardless of the chemical form of OA (salt or free acid). Triolein (a neutral fat) infused at comparable emulsion particle size did not alter lung weight or bronchoalveolar lavage protein concentration in the perfused lung, suggesting that mechanical obstruction or emboli per se is not responsible for initiating early events in OA-induced injury. Infusion of OA caused a significant early histamine release into the venous effluent in the presence of aminoguanidine, a histamine catabolism inhibitor. Pretreatment with H1-receptor antagonists significantly attenuated OA-induced increase in lung weight and protein leak. These data support the link between OA-induced mast cell degranulation, histamine release, and OA-induced edema.     

Endotoxin-induced lung injury in mice: structural, functional, and biochemical responses

Acute lung injury is usually a complication of sepsis, and endotoxin treatment of mice is a frequently used experimental model. To define this model and to clarify pathogenesis of the lung injury, we injected with 1 mg/kg endotoxin ip and measured pulmonary function, pulmonary edema, serum concentrations of cytokines and growth factors, and lung histology over 48 h. During the first 6 h, tidal volume and minute volume increased and respiratory frequency decreased. Serum concentrations of cytokines showed three patterns: 10 cytokines peaked at 2 h and declined rapidly, two peaked at 6 h and declined, and two had biphasic peaks at 2 and 24 h. Growth factors increased later and remained elevated longer. Both collagen and fibronectin were deposited in the lungs beginning within hours of endotoxin and resolving over 48 h. Histologically, lungs showed increased cellularity at 6 h with minimal persistent inflammation at 48 h. Lung water peaked at 6 h and gradually decreased over 48 h. We conclude that intraperitoneal administration of endotoxin to mice causes a transient systemic inflammatory response and transient lung injury and dysfunction. The response is characterized by successive waves of cytokine release into the circulation, early evidence of lung fibrogenesis, and prolonged increases in growth factors that may participate in lung repair.     

Sequential recruitment of neutrophils into lung and bronchoalveolar lavage fluid in LPS-induced acute lung injury

Infiltration of activated neutrophils [polymorphonuclear leukocytes (PMN)] into the lung is an important component of the inflammatory response in acute lung injury. The signals required to direct PMN into the different compartments of the lung have not been fully elucidated. In a murine model of LPS-induced lung injury, we investigated the sequential recruitment of PMN into the pulmonary vasculature, lung interstitium, and alveolar space. Mice were exposed to aerosolized LPS and bronchoalveolar lavage fluid (BAL), and lungs were harvested at different time points. We developed a flow cytometry-based technique to assess in vivo trafficking of PMN in the intravascular and extravascular lung compartments. Aerosolized LPS induced consistent PMN migration into all lung compartments. We found that sequestration in the pulmonary vasculature occurred within the first hour. Transendothelial migration into the interstitial space started 1 h after LPS exposure and increased continuously until a plateau was reached between 12 and 24 h. Transepithelial migration into the alveolar air space was delayed, as the first PMN did not appear until 2 h after LPS, reaching a peak at 24 h. Transendothelial migration and transepithelial migration were inhibited by pertussis toxin, indicating involvement of Galphai-coupled receptors. These findings confirm LPS-induced migration of PMN into the lung. For the first time, distinct transmigration steps into the different lung compartments are characterized in vivo.     

Fluid filtration coefficient of isolated goat lungs was unchanged by endotoxin

The Starling fluid filtration coefficient (Kf) of blood-perfused excised goat lungs was examined before and after infusion of Escherichia coli endotoxin. Kf was calculated from rate of weight gain as described by Drake et al. [Am. J. Physiol. 234 (Heart Circ. Physiol. 3): H266-H274, 1978]. These calculations were made twice during base line and then at hourly intervals for 5 h after infusion of 5 mg (approximately 250 micrograms/kg) of E. coli endotoxin or after injection of oleic acid (47 microliter/kg). All lungs were perfused at constant arterial and venous pressure under zone 3 conditions. Base-line Kf averaged 27 +/- 10 and 20 +/- 4 (SD) microliter.min-1.cmH2O-1.g dry wt-1 for endotoxin and oleic acid groups, respectively. It was unchanged in the endotoxin group throughout the experiment but approximately doubled in the oleic acid lungs. Pulmonary arterial and venous pressures were not changed significantly during the course of these experiments in either group. Lung wet-to-dry weight ratios of these lungs were 5.6 +/- 0.6 and 6.1 +/- 0.5 ml/g for the endotoxin and oleic acid groups, respectively. This compares with 4.6 +/- 0.5 ml/g for normal, freshly excised but not perfused goat lungs. The small change in lung water and unchanged pulmonary pressures after both endotoxin and oleic acid suggest that lung injury was minimal. We conclude that 1) endotoxin does not cause a direct injury to the endothelium of isolated lungs during the first 5 h of perfusion, and 2) neutrophils are not sufficient to cause increased Kf after endotoxin infusion in this preparation.     

Effects of inhaled carbon monoxide on acute lung injury in mice

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of morbidity and mortality in the intensive care unit, but despite continuing research few effective therapies have been identified. In recent years, inhaled carbon monoxide (CO) has been reported to have cytoprotective effects in several animal models of tissue injury. We therefore evaluated the effects of inhaled CO in three different in vivo mouse models of ALI. Anesthetized C57BL/6 mice were ventilated with oxygen in the presence or absence of CO (500 parts per million) for 1 h before lung injury was induced by lipopolysaccharide (LPS) or oleic acid (OA) administration. Ventilation was then continued with the same gases for a further 2-3 h, with hemodynamic and respiratory parameters monitored throughout. Intratracheal LPS administration induced lung injury with alveolar inflammation (increased lavage fluid neutrophils, total protein, and cytokines). In contrast, intravenous LPS induced a predominantly vascular lung injury, with increased plasma TNF and increased neutrophil activation (surface Mac-1 upregulation and L-selectin shedding) and sequestration within the pulmonary vasculature. Intravenous OA produced deteriorations in lung function, reflected by changes in respiratory mechanics and blood gases and lavage fluid neutrophil accumulation. However, addition of CO to the inspired gas did not produce significant changes in the measured physiological or immunological parameters in the mouse models used in this study. Thus the results do not support the hypothesis that use of inhaled CO is beneficial in the treatment of ALI and ARDS.     

Injury,inflammation, and remodeling in fetal sheep lung after intra-amniotic endotoxin

Chorioamnionitis is frequent in preterm labor and increases the risk of bronchopulmonary dysplasia. We hypothesized that intra-amniotic endotoxin injures the lung in utero, causing a sequence of inflammation and tissue injury similar to that which occurs in the injured adult lung. Preterm lamb lungs at 125 days gestational age were evaluated for indicators of inflammation, injury, and repair 5 h, 24 h, 72 h, and 7 days after 4 mg of intra-amniotic endotoxin injection. At 5 h, the epithelial cells in large airways expressed heat shock protein 70, and alveolar interleukin-8 was increased. Surfactant protein B (SP-B) decreased in alveolar type II cells at 5 h, and SP-B in lung tissue and alveolar lavage fluid increased by 72 h. By 24 h, neutrophils were recruited into the large airways, and cell death was the highest. Alveolar type II cells decreased by 25% at 24 h, and proliferation was highest at 72 h, consistent with tissue remodeling. Intra-amniotic endotoxin caused surfactant secretion, inflammation, cell death, and remodeling as indications of lung injury. The recovery phase was accompanied by maturational changes in the fetal lung.     

Intrapleural delivery of MSCs attenuates acute lung injury by paracrine/endocrine mechanism

Two different repair mechanisms of mesenchymal stem cells (MSCs) are suggested to participate in the repair of acute lung injury (ALI): (i) Cell engraftment mechanism, (ii) Paracrine/endocrine mechanism. However, the exact roles they play in the repair remain unclear. The aim of the study was to evaluate the role of paracrine/endocrine mechanism using a novel intrapleural delivery method of MSCs. Either 1 × 10⁶ MSCs in 300 μl of PBS or 300 μl PBS alone were intrapleurally injected into rats with endotoxin‐induced ALI. On days 1, 3 or 7 after injections, samples of lung tissues and bronchoalveolar lavage fluid (BALF) were collected from each rat for assessment of lung injury, biochemical analysis and histology. The distribution of MSCs was also traced by labelling the cells with 4′,6‐diamidino‐2‐phenylindole dihydrochloride (DAPI). MSCs intrapleural injection significantly improved LPS‐induced lung histopathology compared with PBS‐treated group at day 3. There was also a significant decrease in total cell counts and protein concentration in BALF at day 7 in the MSCs ‐treated rats compared to PBS control group. Tracking the DAPI‐marked MSCs showed that there were no exotic MSCs in the lung parenchyma. MSCs administration resulted in a down‐regulation of pro‐inflammatory response to endotoxin by reducing TNF‐α both in the BALF and in the lung, while up‐regulating the anti‐inflammatory cytokine IL‐10 in the lung. In conclusion, treatment with intrapleural MSCs administration markedly attenuates the severity of endotoxin‐induced ALI. This role is mediated by paracrine/endocrine repair mechanism of MSCs rather than by the cell engraftment mechanism.     

Protective role of scutellarin on LPS induced – Acute lung injury and regulation of apoptosis,oxidative stress and reduction of mitochondrial dysfunction

Lung fluid accumulation was determined using wet/dry lung mass ratio. Rats subjected to LPS-induced acute lung injury (2.8 ± 0.33, P < 0.05) presented with a significantly higher wet to dry lung weight ration ratio than sham rats (1.6 ± 0.23, P < 0.05). These results demonstrate that acutely inured rats' lungs were oedematous. On the other hand, treatment with scutellarin alone and in combination with a JNK inhibitor, SP600125, both significantly attenuated pulmonary edema as shown via reduced wet/dry lung mass ratios (1.7 ± 0.09 and 1.8 ± 0.23; P < 0.05, respectively). These results showed that the interventions were effective against LPS-induced edema of the lungs. However, the difference between treatment groups' weight ratios was not statistically significant (P > 0.05). In the sham control rats, the levels of ROS and SOD production were maintained at a low and at a high concentration, respectively (P < 0.05). However, following LPS infusion, the ROS levels skyrocketed while that of SOD decreased significantly relative to the control rats (P < 0.05). Furthermore, we noted that pre-treatment with scutellarin reduced the ROS levels in LPS-injured rats while the SOD was increased to near control levels (P < 0.05). Moreover, the combined effect of scutellarin and JNK inhibitor SP600125 on the levels of ROS and the SOD activity followed a similar trend to that of scutellarin alone albeit with a lower magnitude of change. Our results also showed that the combinatorial treatment was not significantly different from scutellarin alone in terms of influence on the levels of ROS production and SOD activity (P > 0.05). The effect of Scutellarin on broncho-alveolar lavage fluid (BALF) cytokine secretion The expression of interleukins-1β, ?18 and ?6 in the broncho-alveolar lavage fluid were significantly upregulated by LPS infusion (P < 0.05). The rise was, however, attenuated via pre-treatment with scutellarin only or in conjunction with SP600125, a JNK inhibitor (all P < 0.05). On the contrary, we observed that LPS injection caused a reduction of interlekins ?4 and ?10 secreted in the BALF. Pre-treatment with scutellarin alone (P < 0.05) and not in combination with SP600125 or SP600125 was able to significantly reverse this noted down-regulation (all P > 0.05).     

A new porcine model of reperfusion injury after lung transplantation

Rodent models have been described to investigate lung preservation and reperfusion injury but have significant disadvantages. In large animals single lung transplant studies are probably optimal but problems remain over the ability to rigorously separate the lungs for assessment while promoting medium to long-term animal survival for meaningful investigation. Our aim was to develop a novel and refined large animal model to assess reperfusion injury in the transplanted lung, overcoming the difficulties associated with existing models. Specifically, small animal models of lung transplantation usually have short perfusion times (often one hour) and include extracorporeal circuits while larger animal models often require the contralateral lung to be excluded after transplantation-an unphysiological situation under which to evaluate the graft. A porcine model of left lung allotransplantation was developed in which native and donor lungs are individually ventilated. Sampling catheters placed within the graft lung allowed specimen withdrawal without mixing of blood from the contralateral lung after reimplantation. The model permits a variety of clinical scenarios to be simulated with the native lung supporting the animal irrespective of function in the graft. This model has been used in over 60 transplant procedures with a postoperative survival time of 12 h being readily achieved. The mean operating time was 2.6 h. The mortality rate is 4% in our series. We have found the model to be reliable, reproducible and flexible. We propose this model as an adaptable investigation for evaluating lung reperfusion injury and preservation.     

Modulation of cyclophosphamide-induced early lung injury by curcumin,an anti-inflammatory antioxidant

Cyclophosphamide causes lung injury in rats through its ability to generate free radicals with subsequent endothelial and epithelial cell damage. In order to observe the protective effects of a potent anti-inflammatory antioxidant, curcumin (diferuloyl methane) on cyclophosphamide-induced early lung injury, healthy pathogen free male Wistar rats were exposed to 20 mg/100 g body weight of cyclophosphamide, intraperitoneally as a single injection. Prior to cyclophosphamide intoxication oral administration of curcumin was performed daily for 7 days. At various time intervals (2, 3, 5 and 7 days post insult) serum and lung samples were analyzed for angiotensin converting enzyme, lipid peroxidation, reduced glutathione and ascorbic acid. Bronchoalveolar lavage fluid was analyzed for biochemical constituents. The lavage cells were examined for lipid peroxidation and glutathione content. Excised lungs were analyzed for antioxidant enzyme levels. Biochemical analyses revealed time course increases in lavage fluid total protein, albumin, angiotensin converting enzyme (ACE), lactate dehydrogenase, N-acetyl--D-glucosaminidase, alkaline phosphatase, acid phosphatase, lipid peroxide levels and decreased levels of glutathione (GSH) and ascorbic acid 2, 3, 5 and 7 days after cyclophosphamide intoxication. Increased levels of lipid peroxidation and decreased levels of glutathione and ascorbic acid were seen in serum, lung tissue and lavage cells of cyclophosphamide groups. Serum angiotensin converting enzyme activity increased which coincided with the decrease in lung tissue levels. Activities of antioxidant enzymes were reduced with time in the lungs of cyclophosphamide groups. However, a significant reduction in lavage fluid biochemical constituents, lipid peroxidation products in serum, lung and lavage cells with concomitant increase in antioxidant defense mechanisms occurred in curcumin fed cyclophosphamide rats. Therefore, our results suggest that curcumin is effective in moderating the cyclophosphamide induced early lung injury and the oxidant-antioxidant imbalance was partly abolished by restoring the glutathione (GSH) with decreased levels of lipid peroxidation.     

A micro-CT analysis of murine lung recruitment in bleomycin-induced lung injury.

The effects of lung injury on pulmonary recruitment are incompletely understood. X-ray computed tomography (CT) has been a valuable tool in assessing changes in recruitment during lung injury. With the development of preclinical CT scanners designed for thoracic imaging in rodents, it is possible to acquire high-resolution images during the evolution of a pulmonary injury in living mice. We quantitatively assessed changes in recruitment caused by intratracheal bleomycin at 1 and 3 wk after administration using micro-CT in 129S6/SvEvTac mice. Twenty female mice were administered 2.5 U of bleomycin or saline and imaged with micro-CT at end inspiration and end expiration. Mice were extubated and allowed to recover from anesthesia and then reevaluated in vivo for quasi-static compliance measurements, followed by harvesting of the lungs for collagen analysis and histology. CT images were converted to histograms and analyzed for mean lung attenuation (MLA). MLA was significantly greater for bleomycin-exposed mice at week 1 for both inspiration (P<0.0047) and exhalation (P<0.0377) but was not significantly different for week 3 bleomycin-exposed mice. However, week 3 bleomycin-exposed mice did display significant increases in MLA shift from expiration to inspiration compared with either group of control mice (P<0.005), suggesting increased lung recruitment at this time point. Week 1 bleomycin-exposed mice displayed normal shifts in MLA with inspiration, suggesting normal lung recruitment despite significant radiographic and histological changes. Lung alveolar recruitment is preserved in a mouse model of bleomycin-induced parenchymal injury despite significant changes in radiographic and physiological parameters.     

Monitoring changes in lung air and liquid volumes with electrical impedance tomography

Adler, A., R. Amyot, R. Guardo, J. H. T. Bates, and Y. Berthiaume. Monitoring changes in lung air and liquid volumes withelectrical impedance tomography. J. Appl.Physiol. 83(5): 1762-1767, 1997.Electricalimpedance tomography (EIT) uses electrical measurements at electrodesplaced around the thorax to image changes in the conductivitydistribution within the thorax. This technique is well suited tostudying pulmonary function because the movement of air, blood, andextravascular fluid induces significant conductivity changes within thethorax. We conducted three experimental protocols in a total of 19 dogsto assess the accuracy with which EIT can quantify changes in thevolumes of both gas and fluid in the lungs. In the first protocol, lungvolume increments from 50 to 1,000 ml were applied with a largesyringe. EIT measured these volume changes with an average error of 27 ± 6 ml. In the second protocol, EIT measurements were made at endexpiration and end inspiration during regular ventilation with tidalvolume ranging from 100 to 1,000 ml. The average error in the EITestimates of tidal volume was 90 ± 43 ml. In the third protocol,lung liquid volume was measured by instilling 5% albumin solution intoa lung lobe in increments ranging from 10 to 100 ml. EIT measured thesevolume changes with an average error of 10 ± 10 ml and was alsoable to detect into which lobe the fluid had been instilled. These results indicate that EIT can noninvasively measure changes in thevolumes of both gas and fluid in the lungs with clinically usefulaccuracy.

     

In vitro effects of endotoxin on bovine and sheep lung microvascular and pulmonary artery endothelial cells

A single infusion of Escherichia coli endotoxin into sheep results in structural evidence of pulmonary endothelial injury, increases in both prostacyclin and prostaglandin E2 (PGE2) in lung lymph, and an increase in pulmonary microvascular permeability. Endotoxin-induced lung endothelial damage can also be induced in vitro, but to date these studies have utilized endothelium from large pulmonary vessels. In the present study, we have grown endothelial cells from peripheral lung vessels of cows and sheep and exposed these microvascular endothelial cells to endotoxin. Controls included lung microvascular endothelium without endotoxin and endothelial cells from bovine and sheep main pulmonary artery with and without addition of endotoxin. We found that endotoxin caused significant increases in release of prostacyclin and PGE2 from both bovine and sheep lung microvascular and pulmonary artery endothelium. Normal bovine and sheep pulmonary artery and bovine lung microvascular endothelium released greater levels of prostacyclin than PGE2 (ng/ng); release of PGE2 from the microvascular cells was greater than from the pulmonary artery endothelium in both species. Exposure of endothelial cells from cow and sheep main pulmonary artery to endotoxin results in endothelial cell retraction and pyknosis, a loss of barrier function, increased release of prostacyclin and PGE2 and eventual cell lysis. In lung microvascular cells, the increases in prostanoids were accompanied by changes in cell shape but occurred in the absence of either detectable alterations in barrier function or cytolysis. Thus, while endotoxin causes alterations to endothelial cells from both large and small pulmonary vessels, the effects are not identical suggesting site specific phenotypic expression of endothelial cells even within a single vessel. To determine whether the response of either the large or small pulmonary vessel endothelial cells in culture mimics most closely the in vivo response of the lung to endotoxin requires further study.     

Mechanisms of recruitment in oleic acid-injured lungs.

Lung recruitment strategies, such as the application of positive end-expiratory pressure (PEEP), are thought to protect the lungs from ventilator-associated injury by reducing the shear stress associated with the repeated opening of collapsed peripheral units. Using the parenchymal marker technique, we measured regional lung deformations in 13 oleic acid (OA)-injured dogs during mechanical ventilation in different postures. Whereas OA injury caused a marked decrease in the oscillation amplitude of dependent lung regions, even the most dependent regions maintained normal end-expiratory dimensions. This is because dependent lung is flooded as opposed to collapsed. PEEP restored oscillation amplitudes only at pressures that raised regional volumes above preinjury levels. Because the amount of PEEP necessary to promote dependent lung recruitment increased the end-expiratory dimensions of all lung regions (nondependent AND dependent ones) compared with their preinjury baseline, the "price" for recruitment is a universal increase in parenchymal stress. We conclude that the mechanics of the OA-injured lung might be more appropriately viewed as a partial liquid ventilation problem and not a shear stress and airway collapse problem and that the mechanisms of PEEP-related lung protection might have to be rethought.