Pulmonary hypoxia and venous admixture correlate linearly to the kinetic energy from porcine high velocity projectile behind armor blunt trauma.

Purpose. Behind armor blunt trauma (BABT) is a non-penetrating injury caused by the rapid deformation of body armor, by a projectile, which may in extreme circumstances cause death. The understanding of the mechanisms is still low, in relation to what is needed for safety threshold levels. High velocity projectile BABT causes immediate and severe hypoxia by increased venous admixture (Q's/Q't), but it is not known whether the level of hypoxia correlates to the kinetic energy (Ek) of the projectile.Materials and Methods. We constructed a 65 mm BABT-simulator to measure the Ek absorbed by the thorax. The simulator was validated to 7.62 mm high velocity BABT (swine with removed organs) for 7.62 mm (n = 7) and 65 mm (n = 12). Physiological measurements during 60 minutes were performed in 40 anesthetized swine in groups control (n = 9), 7.62 mm (n = 7), 65 mm weight variation (n = 24), 65 mm speed variation (n = 12, included in the weight variation group). New calculations were done for a previously studied group of 7.62 mm with backing (n = 9).Results. 65 mm BABT simulation and 7.62 mm BABT had similar back-face signatures (24 mm), and maximum thoracic impression speed (24-34 m/s). Back-face signatures correlated linearly to Ek (R2=0.20). Rib fractures had a 50% likelihood at back-face signature 23.0 mm (95% CI 18.5 to 29.0 mm, area under ROC curve 0.93). Ek correlated linearly to pO2 (R2=0.34, p = 0.0026) and venous admixture (R2=0.37, p = 0.0046). The extrapolated Ek at 5 minutes for pO2=0 kPa was 587 J and for venous admixture = 100% 574 J.Conclusions. Hypoxia and venous admixture correlated linearly to Ek, allowing for a calculated predicted lethal Ek to ≥574 J, which should be verified in survival studies. Lethality predictions from lung physiology is an alternative to clay impressions and may facilitate the development of ballistic safety equipment and new BABT safety criteria.Supplemental data for this article is available online at https://doi.org/10.1080/01902148.2021.1950869 .

Severe, transient pulmonary ventilation-perfusion mismatch in the lung after porcine high velocity projectile behind armor blunt trauma.

BACKGROUND: Behind armor blunt trauma (BABT) is a non-penetrating injury caused by the rapid deformation of body armor, by a projectile, which may in extreme circumstances cause death. Although there is not a high incidence of high energy BABT, the understanding of the mechanisms is still low, in relation to what is needed for safety threshold levels. BABT is also useful as a model for blunt thoracic trauma, with a compressive speed between traffic accidents and blast caused by explosives. High velocity projectile BABT causes severe hypoxia. The mechanisms are not fully known. We investigated the acute pulmonary consequences in the individual lungs, and the effects of alveolar recruitment. METHODS: 12 swine (mean weight 62.5 kg) were randomized to groups BABT by 7.62 × 51 mm NATO-type bullets (mean velocity 803 m/s) to a military grade ceramic plate armor (n = 7) or control (n = 5). Modified double lumen tracheal tubes provided respiratory dynamics in the lungs separately/intermittently for two hours, with alveolar recruitment after one hour. RESULTS: Venous admixture increased 5 min after BABT (p < .05) and correlated with increased cardiac output. Static compliance decreased 5 minutes after BABT (p < .05) and further by recruitment (p < .005). Physiological dead space decreased 5 minutes after BABT (p < .01) and further by recruitment (p < .01), while not in the contralateral lung. V'A/Q' decreased 5 minutes after BABT (p < .05), also shown in phase III volumetric capnography (p < .05). Most effects regressed after one hour. CONCLUSIONS: High velocity projectile BABT caused hypoxia by a severe and transient decrease in V'A/Q' to <1 and increased venous admixture in the exposed lung. Alveolar recruitment was hemodynamically and respiratory tolerable and increased V'A/Q'. Body armor development should aim at ameliorating severe pulmonary consequences from high projectile velocities which also needs to include further understanding of how primary and secondary effects are distributed between the lungs.

Feasibility of pleural and perilesional subcutaneous microdialysis to assess porcine experimental pulmonary contusion.

Background: Severe thoracic trauma affects 55% of patients with multiple traumatic injuries and may lead to acute lung injury or acute respiratory distress syndrome. Pulmonary trauma differs clinically and biologically from lung injury of other origins and carries a mortality rate of 10%. Treatment options are limited, and it is not possible to monitor the progression of lung injury with specific biomarkers. Microdialysis of pleural fluid may offer a viable entry to monitor the lung directly and specifically. Bronchial microdialysis has been described, but not pleural microdialysis. We therefore investigated the feasibility of microdialysis of pleural fluid, and its ability to detect pulmonary injury and inflammation in the pleural cavity after traumatic acute lung injury.Methods: 16 pigs (mean weight 64 kg) were randomized to groups "exposed with MD", receiving a focally severe pulmonary contusion and microdialysis (n = 7), "control with MD", receiving only microdialysis and no pulmonary contusion (n = 5), "normal no MD" receiving only anesthesia (n = 2) and "naïve no MD" (no instrumentation) (n = 2). Microdialysate from the pleura and the perilesional subcutis, plasma and bronchoalveolar lavage were collected for 5 hours.Results: Pleura lactate, plasma lactate and pleura lactate/pyruvate ratio increased in injured lungs (p < 0.05). Subcutis and plasma glucose increased after trauma (p < 0.05). Pleura glycerol increased although not reaching statistical significance. IL-6 and IL-8 were dissimilar in plasma, bronchoalveolar lavage and pleural fluid, while IL-1 did not differ. Neutrophils increased in bronchoalveolar lavage (p < 0.001) after trauma, and in pleural fluid, although not when the microdialysis catheter was omitted.Conclusion: Pleural microdialysis was technically feasible and detected signs of cellular injury and anaerobic metabolism after focally severe pulmonary contusion and may be of interest for future clinical applications. The microdialysis catheter triggered a recruitment of neutrophils to the pleura which needs to be elucidated further before taking the technique into clinical practice.

Abdominal Aortic and Junctional Tourniquet release after 240 minutes is survivable and associated with small intestine and liver ischemia after porcine class II hemorrhage.

BACKGROUND: Uncontrolled hemorrhage is a leading cause of tactical trauma-related deaths. Hemorrhage from the pelvis and junctional regions are particularly difficult to control due to the inability of focal compression. The Abdominal Aortic and Junctional Tourniquet (AAJT) occludes aortic blood flow by compression of the abdomen. The survivability of tourniquet release beyond 120 minutes is unknown and fluid requirements to maintain sufficient blood pressure during prolonged application are undetermined. We therefore compared 60-minute and 240-minute applications and release of the AAJT for 30 minutes, with crystalloid fluid therapy, after a Class II hemorrhage. METHODS: Sixty-kilogram anesthetized pigs were subjected to 900-mL hemorrhage and AAJT application for 60 minutes (n = 5), 240 minutes (n = 5), and fluid therapy only for 240 minutes (n = 5) and reperfusion for 30 minutes. RESULTS: The AAJT application was hemodynamically and respiratory tolerable for 60 minutes and 240 minutes. Cumulative fluid requirements decreased by 64%, comparable to 3000 mL of crystalloids. Mechanical ventilation was impaired. AAJT increased the core temperature by 0.9°C compared with fluid therapy. Reperfusion consequences were reversible after 60 minutes but not after 240 minutes. A 240-minute application resulted in small intestine and liver ischemia, persisting hyperkalemia, metabolic acidosis, and myoglobinemia, suggesting rhabdomyolysis. CONCLUSION: The AAJT application for 240 minutes with reperfusion was survivable in an intensive care setting and associated with abdominal organ damage. Long time consequences and spinal cord effects was not assessed. We propose an application time limit within 60 minutes to 240 minutes, though further studies are needed to increase the temporal resolution. The AAJT application may be considered as a rescue option to maintain central blood pressure and core temperature in cases of hemorrhagic shock from extremity bleedings, if fluid therapy is unavailable or if the supply is limited. LEVEL OF EVIDENCE: Therapeutic study, level II.

Brain metabolism and oxygenation in healthy pigs receiving hypoventilation and hyperoxia.

Modulation in ventilatory settings is one of the approaches and interventions used to treat and prevent secondary brain damage after traumatic brain injury (TBI). Here we investigate the effect of hyperoxia in combination with hypoventilation on brain oxygenation, metabolism and intracranial pressure. Twelve pigs were divided into three groups; group1-100% hyperoxia (n=4), group 2-100% hyperoxia and 20% decrease in minute volume (MV) (n=4) and group 3-100% hyperoxia and 50% decrease in MV (n=4). Neither of the ventilator settings affected the lactate/pyruvate ratio significantly. However, there was a significant decrease of brain lactate (2.6±1.7 to 1.8±1.6mM) and a rapid and marked increase in brain oxygenation (7.9±0.7 to 61.3±17.6mmHg) in group 3. Intracranial pressure (ICP) was not significantly affected in this group, however, the ICP increased significantly in group 2 with 100% hyperoxia plus 20% reduction in minute volume. We conclude that hyperoxia in combination with 50% decrease in MV showed pronounced increase in partial brain oxygen tension (pbrO2) and decrease in brain lactate. The ventilatory modification, used in this study should be considered for further investigation as a possible therapeutic intervention for TBI patients.

Mobile decontamination units-room for improvement?

INTRODUCTION: Mobile decontamination units are intended to be used at the accident site to decontaminate persons contaminated by toxic substances. A test program was carried out to evaluate the efficacy of mobile decontamination units. OBJECTIVE: The tests included functionality, methodology, inside environment, effects of wind direction, and decontamination efficacy. METHODS: Three different types of units were tested during summer and winter conditions. Up to 15 test-persons per trial were contaminated with the imitation substances Purasolve ethyl lactate (PEL) and methyl salicylate (MES). Decontamination was carried out according to standardized procedures. During the decontamination trials, the concentrations of the substances inside the units were measured. After decontamination, substances evaporating from test-persons and blankets as well as remaining amounts in the units were measured. RESULTS: The air concentrations of PEL and MES inside the units during decontamination in some cases exceeded short-term exposure limits for most toxic industrial chemicals. This was a problem, especially during harmful wind conditions, i.e., wind blowing in the same direction as persons moving through the decontamination units. Although decontamination removed a greater part of the substances from the skin, the concentrations evaporating from some test-persons occasionally were high and potentially harmful if the substances had been toxic. The study also showed that blankets placed in the units absorbed chemicals and that the units still were contaminated five hours after the end of operations. CONCLUSIONS: After decontamination, the imitation substances still were present and evaporating from the contaminated persons, blankets, and units. These results indicate a need for improvements in technical solutions, procedures, and training.

Pathophysiological effects and changes in potassium, ionised calcium, glucose and haemoglobin early after severe blunt chest trauma.

BACKGROUND: Severe lung contusion is often observed after blunt chest trauma due to traffic accidents or fall from heights, but may also occur after a non-penetrating ballistic impact against body armour. Such trauma has been designated behind armour blunt trauma (BABT). Our aim in the present study has been to evaluate pathophysiological changes and compensatory mechanisms that occur early after such severe lung contusion. METHODS: Twelve pigs wearing body armour were shot with a 7.62mm assault rifle to produce a standardised pulmonary contusion. Exposed animals were compared with five control animals shot with blank ammunition. Physiological parameters and levels of potassium, glucose, haemoglobin, calcium, lactate and pH were monitored for two hours after the shot. RESULTS: The impact induced severe pulmonary contusion with apnoea, desaturation and hypotension in all exposed animals. Increased haemoglobin, glucose and severe hyperkalaemia were seen shortly after impact. Seven of twelve animals died due to the trauma. Dense cardiac tissue was observed during post mortem examination in six of the animals that died during the experimental course. CONCLUSION: In conclusion, this study has shown that life-threatening hyperkalaemia occurs early after severe lung contusion. Moreover, dense cardiac tissue and early increase of haemoglobin and glucose are intriguing findings that should be investigated in future studies.

Cardiac changes after simulated behind armor blunt trauma or impact of nonlethal kinetic projectile ammunition.

BACKGROUND: Cardiac-related injuries caused by blunt chest trauma remain a severe problem. The aim of this study was to investigate pathophysiological changes in the heart that might arise after behind armor blunt trauma or impacts of nonlethal projectiles. METHODS: Sixteen pigs were shot directly at the sternum with "Sponge Round eXact I Mpact" (nonlethal ammunition; diameter 40 mm and weight 28 g) or hard-plastic ammunition (diameter 65 mm and weight 58 g) to simulate behind armor blunt trauma. To evaluate the influence of the shot location, seven additional pigs where exposed to an oblique heart shot. Physiologic parameters, electrocardiography, echocardiogram, the biochemical marker troponin I (TnI), and myocardial injuries were analyzed. RESULTS: Nonlethal kinetic projectiles (101-108 m/s; 143-163 J) did not cause significant pathophysiological changes. Five of 18 pigs shot with 65-mm plastic projectiles (99-133 m/s; 284-513 J) to the front or side of the thorax died directly after the shot. No major physiologic changes could be observed in surviving animals. Animals shot with an oblique heart shot (99-106 m/s; 284-326 J) demonstrated a small, but significant decrease in saturation. Energy levels over 300 J caused increased TnI and myocardial damages in most of the pigs. CONCLUSION: This study indicates that nonlethal kinetic projectiles "eXact iMpact" does not cause heart-related damage under the examined conditions. On impact, sudden heart arrest may occur independently from the cardiac's electrical cycle. The cardiac enzyme, TnI, can be used as a reliable diagnostic marker to detect heart tissue damages after blunt chest trauma.

Effects of fluid resuscitation with hypertonic saline dextrane or Ringer's acetate after nonhemorrhagic shock caused by pulmonary contusion.

BACKGROUND: Injured lungs are sensitive to fluid resuscitation after trauma. Such treatment can increase lung water content and lead to desaturation. Hypertonic saline with dextran (HSD) has hyperosmotic properties that promote plasma volume expansion, thus potentially reducing these side effects. The aim of this study was to (1) evaluate whether fluid treatment counteracts hypotension and improves survival after nonhemorrhagic shock caused by lung contusion and (2) analyze whether resuscitation with HSD is more efficient than treatment with Ringer's acetate (RA) in terms of blood oxygenation, the amount of lung water, circulatory effects, and inflammatory response. METHODS: Twenty-nine pigs, all wearing body armor, were shot with a 7.62-mm assault rifle to produce a standardized pulmonary contusion. These animals were allocated into three groups: HSD, RA, and an untreated shot control group. Exposed animals were compared with animals not treated with fluid and shot with blank ammunition. For 2 hours after the shot, the inflammatory response and physiologic parameters were monitored. RESULTS: The impact induced pulmonary contusion, desaturation, hypotension, increased heart rate, and led to an inflammatory response. No change in blood pressure was observed after fluid treatment. HSD treatment resulted in significantly less lung water (p < 0.05) and tended to give better Pao2 (p = 0.09) than RA treatment. Tumor necrosis factor-α release and heart rate were significantly lower in animals given fluids. CONCLUSION: Fluid treatment does not affect blood pressure or mortality in this model of nonhemorrhagic shock caused by lung contusion. However, our data indicate that HSD, when compared with RA, has advantages for the injured lung.

Trauma attenuating backing improves protection against behind armor blunt trauma.

BACKGROUND: Body armor is used by military personnel, police officers, and security guards to protect them from fatal gunshot injuries to the thorax. The protection against high-velocity weapons may, however, be insufficient. Complementary trauma attenuating backings (TAB) have been suggested to prevent morbidity and mortality in high-velocity weapon trauma. METHODS: Twenty-four Swedish landrace pigs, protected by a ceramid/aramid body armor without (n = 12) or with TAB (n = 12) were shot with a standard 7.62-mm assault rifle. Morphologic injuries, cardiorespiratory, and electroencephalogram changes as well as physical parameters were registered. RESULTS: The bullet impact caused a reproducible behind armor blunt trauma (BABT) in both the groups. The TAB significantly decreased size of the lung contusion and prevented hemoptysis. The postimpact apnea, desaturation, hypotension, and rise in pulmonary artery pressure were significantly attenuated in the TAB group. Moreover, TAB reduced transient peak pressures in thorax by 91%. CONCLUSIONS: Our results indicate that ordinary body armor should be complemented by a TAB to prevent thoracic injuries when the threat is high-velocity weapons.

Treatment with dexamethasone or liposome-encapsuled vitamin E provides beneficial effects after chemical-induced lung injury.

The pathogenesis of lung injury by exposure to highly toxic sulfur and nitrogen mustards involves alkylating damage of the respiratory epithelium followed by an acute inflammatory response and lung edema. The acute phase is followed by long-term respiratory complications characterized by bronchitis, lung fibrosis, and airway hyperreactivity. In this study, we utilized a mouse model for airway inflammation induced by inhalation exposure to the alkylating nitrogen mustard melphalan, in order to investigate possible beneficial treatment effects by the corticosteroid dexamethasone. In addition, we investigated therapeutic efficacy of liposome-encapsuled vitamin E, an antioxidant formulation previously shown to be efficient in counteracting inflammatory conditions. Influx of inflammatory cells to airways, edema formation, and expression of different cytokines were analyzed 6 and 18 hours after exposure to melphalan. In order to evaluate long-term lung effects, we also investigated collagen deposition and accumulation of lymphocytes at 2 and 4 weeks after exposure. A single intraperitoneal injection of dexamethasone (10 mg/kg body weight) 1 hour after melphalan exposure significantly reduced interleukin (IL)-1 and IL-6 in bronchoalveolar lavage fluid (BALF) and diminished the acute airway inflammation. Our results also indicate that early single-dose treatment with dexamethasone protects against long-term effects observed 2-4 weeks after melphalan exposure, as indicated by reduced lymphocytic response in airways and decreased collagen deposition. Furthermore, our results indicate that also vitamin E (50 mg/kg) reduces acute inflammatory cell influx, and suppresses collagen formation in lung tissue, indicating that this drug could be used in combination with corticosteroids for protection against chemical-induced lung injury.

An animal model to study health effects during continuous low-dose exposure to the nerve agent VX.

In the present study, we have developed an animal model to study long-term health effects of continuous exposure of toxic chemical agents, in awake, freely moving rats. The aim was to evaluate the effect of low-dose exposure of the nerve agent VX, and to find specific biomarkers for intoxication. To exclude the influence of stress, we used an implanted radio-telemetric device for online registration of physiological parameters, and an osmotic pump, implanted subcutaneously, for continuous exposure of the toxic agent. Our results showed that the lowest observable effect dose of VX in Wistar rats was 5 microg/kg/24 h, after continuous exposure by the osmotic pump. Although we observed significant inhibition of acetylcholinesterase (AChE) in blood and a significant decrease in body weight gain at this dose, no change in blood pressure, heart rate or respiratory rate was registered. However, a significant decrease in the thyroid hormone, free T4, was measured in blood after 8 weeks, indicating that low doses of VX might affect the thyroid function. Rats given repeated daily injections were more sensitive to VX and needed only 1/10 of the concentration to reach a similar level of AChE inhibition, compared to animals exposed by the osmotic pump. Moreover, the results showed that exposure of VX in our experimental design, does not induce an increase in corticosterone blood levels. Thus, the model used in this investigation renders minimal stress and will not cause unnecessary pain to the animals, indicating that this model could be a useful tool to study long-term effects of various toxic substances in freely moving rats.

Bilateral vagotomy inhibits apnea and attenuates other physiological responses after blunt chest trauma.

BACKGROUND: Behind armor blunt trauma (BABT) is defined as the nonpenetrating injury resulting from a ballistic impact on body armor. Some of the kinetic energy is transferred to the body, causing internal injuries and, occasionally, death. The aim of this study was to investigate if apnea and other pathophysiological effects after BABT is a vagally mediated reflex. METHODS: Sixteen anesthetized pigs wearing body armor, of which five were vagotomized, were shot with a standard 7.62 mm assault rifle. These animals were compared with control animals (n = 8), shot with blank ammunition. We performed bilateral vagotomy before the shot and assessed the outcome on the apnea period, respiration, circulation, and brain function. Animals were monitored during a 2-hour period after the shot. RESULTS: Nonvagotomized animals had a mean apnea period of 22 (6-44) seconds. This group also showed a significant decrease in oxygen saturation compared with control animals. Furthermore, electroencephalogram-changes were more pronounced in nonvagotomized animals. In contrast, vagotomized animals were protected from apnea and showed only a minor decrease in oxygen saturation. All exposed animals showed impaired circulation, and postmortem examination revealed a pulmonary contusion. CONCLUSION: This study shows that apnea after BABT is a vagally mediated reflex that can be inhibited by bilateral vagotomy. Our results indicate that the initial apnea period is an important factor for hypoxia after BABT. Supported ventilation should begin immediately if the affected person is unconscious and suffers from apnea. It should continue until the neurologic paralysis disappears and sufficient spontaneous breathing begins.

Severe lung contusion and death after high-velocity behind-armor blunt trauma: relation to protection level.

The most-used safety recommendation for protective vests is that the impact should not cause more than a 44-mm impression in plasticine. The aim of this study was to investigate whether this criterion was sufficient if the vest was exposed to a high-velocity projectile. We tested the hypothesis with pigs divided into a 40-mm group (n = 10) and a 34-mm group (n = 8) protected by a vest allowing a 40-mm or 34-mm impression in plasticine, respectively. Five (50%) of 10 animals in the 40-mm group and 2 (25%) of 8 in the 34-mm group died due to the trauma. We observed severe lung hematoma, impaired circulation, desaturation, and electroencephalogram changes. These effects were more aggravated in the 40-mm group compared to the 34-mm group. Based on our results, the overall judgment is that the safety criterion of 44-mm impression is insufficient when a vest is exposed to a high-velocity projectile.

Electroencephalogram, circulation, and lung function after high-velocity behind armor blunt trauma.

BACKGROUND: Behind armor blunt trauma (BABT) is defined as the nonpenetrating injury resulting from a ballistic impact on personal body armor. The protective vest may impede the projectile, but some of the kinetic energy is transferred to the body, causing internal injuries and occasionally death. The aim in this study was to investigate changes in electroencephalogram (EEG) and physiologic parameters after high-velocity BABT. METHODS: Eight anesthetized pigs, wearing body armor (including a ceramic plate) on the right side of their thorax, were shot with a 7.62-mm assault rifle (velocity approximately 800 m/s). The shots did not penetrate the armor and these animals were compared with control animals (n = 4), shot with blank ammunition. EEG and several physiologic parameters were thereafter monitored during a 2-hour period after the shot. RESULTS: All animals survived during the experimental period. Five of the exposed animals showed a temporary effect on EEG. Furthermore, exposed animals displayed decreased cardiac capacity and an impaired oxygenation of the blood. Postmortem examination revealed subcutaneous hematomas and crush injuries to the right lung. CONCLUSION: The results in our animal model indicate that high-velocity BABT induce circulatory and respiratory dysfunction, and in some cases even transient cerebral functional disturbances.

Intestinal circulation, oxygenation and metabolism is not affected by oleic acid lung injury.

This study was performed to establish a platform for further studies on effects of ventilatory treatment modalities on the intestines during mechanical ventilation of acute lung injury (ALI). We tested the hypotheses that oleic acid (OA) infusion causes changes in intestinal circulation, oxygenation and metabolism, and that OA is distributed to tissues outside the lung. This was performed as an experimental, prospective and controlled study in an university animal research laboratory. Thirteen juvenile anaesthetized pigs were used in the main study, where seven were given an intravenous infusion of 0.1 ml kg(-1) OA and six served as control (surgery only). In a separate study, four animals were given an intravenous infusion of 0.1 ml kg(-1) (3)H-labelled OA. We measured systemic and mesenteric (portal venous blood flow, jejunal mucosal perfusion) haemodynamic parameters, mesenteric oxygenation (jejunal tissue oxygen tension) and systemic cytokines (tumour necrosis factor-alpha and interleukin-6). We calculated mesenteric lactate flux and mesenteric oxygen delivery, uptake and extraction ratio. In the animals given 3H-OA, we measured 3H-OA in different tissues (lungs, heart, liver, kidney, stomach, jejunum, colon and arterial blood). We found that OA given intravenously is distributed in small amounts to the intestines. This intestinal exposure to OA does not cause intestinal injury when evaluating mesenteric blood flow, metabolism or oxygenation. OA infusion induced a moderate increase in mean pulmonary arterial pressure and a decrease in PaO2/Fraction inspired O2 (P/F) ratio, giving evidence of severe lung injury. Consequently, the OA lung injury model is suitable for studies on intestinal effects of ventilatory treatment modalities during mechanical ventilation of ALI.

Lipopolysaccharide-induced pulmonary inflammation is not accompanied by a release of anandamide into the lavage fluid or a down-regulation of the activity of fatty acid amide hydrolase.

The effect of lipopolysaccharide inhalation upon lung anandamide levels, anandamide synthetic enzymes and fatty acid amide hydrolase has been investigated. Lipopolysaccharide exposure produced a dramatic extravasation of neutrophils and release of tumour necrosis factor alpha into the bronchoalveolar lavage (BAL) fluid, which was not accompanied by epithelial cell injury. The treatment, however, did not change significantly the levels of anandamide and the related compound palmitoylethanolamide in the cell-free fraction of the BAL fluid. The activities of the anandamide synthetic enzymes N-acyltransferase and N-acylphosphatidylethanolamine phospholipase D and the activity of fatty acid amide hydrolase in lung membrane fractions did not change significantly following the exposure to lipopolysaccharide. The non-selective fatty acid amide hydrolase inhibitor phenylmethylsulfonyl fluoride was a less potent inhibitor of lung fatty acid amide hydrolase than expected from the literature, and a dose of 30 mg/kg i.p. of this compound, which produced a complete inhibition of brain anandamide metabolism, only partially inhibited the lung metabolic activity.

Lung effects during a generalized Shwartzman reaction and therapeutic intervention with dexamethasone or vitamin E.

We investigated if a two-hit shock model, commonly referred to as generalized Shwartzman reaction (GSR), can prime for indirect acute respiratory distress syndrome (ARDS) in mice. The GSR was provoked in C57BL/6 mice by two consecutive i.p. injections of 100 microg lipopolysaccharide (LPS) at t = 0 and t = 20 h. These mice demonstrated a dramatic decrease in respiratory capacity and 80% mortality after the second injection. No such effect was observed when LPS was given as a single 200 microg dose at t = 0. Increased expression of proinflammatory cytokines in serum (interleukin-1beta, interleukin-6 and interferon-gamma), lung neutrophilia, and edema formation were observed in mice injected with one dose of LPS, but notably, mice exposed twice did not further increase their inflammatory response. Early treatment 1 h after the first LPS injection (t = 1 h) with either dexamethasone (10 mg/kg) or vitamin E (50 mg/kg) improved respiratory function and down-modulated the induction of proinflammatory cytokines in serum. In conclusion, mice with a generalized Shwartzman reaction exhibited features resembling some aspects of the pathophysiology in septic ARDS, i.e., neutrophilic inflammation, edema formation, impaired respiratory capacity, and mortality. Our data indicate that a systemic cytokine response and lung neutrophilia may prime for the GSR but that other mechanisms account for the rapid decline in lung function after the second challenge. We suggest that this model can be used for studies of pathogenesis and therapeutic prevention of acute respiratory failure.

Vitamin E reduces transendothelial migration of neutrophils and prevents lung injury in endotoxin-induced airway inflammation.

We investigated the pharmacologic effects of the antioxidant Vitamin E (alpha-tocopherol [alpha-toc]) in airway inflammation induced by inhaled endotoxin. A preparation of alpha-toc incorporated in liposomes was administered intraperitoneally in mice 1 h after exposure of aerosolized endotoxin. Injection of 50 mg alpha-toc/kg significantly decreased the number of neutrophils in airspaces and prevented lung injury, monitored both as decreased lactate dehydrogenase activity in airways and reduced lung edema when compared with animals treated with plain liposomes. Immunofluorescence staining of lung tissue revealed that treatment with alpha-toc decreased the number of neutrophils in lung interstitium, whereas the number in lung blood vessels and peripheral blood did not differ between mice treated with alpha-toc and control mice. Our results indicate that alpha-toc downmodulates the migration of neutrophils across the endothelial barrier, but in contrast to strong anti-inflammatory drugs such as corticosteroids, without inhibition of transcription factors involved in the early inflammatory response (nuclear factor-kappaB/activator protein-1). Neither was the endotoxin-induced expression of proinflammatory cytokines in lung tissue downregulated. Treatment with a combination of alpha-toc and a suboptimal dose of 0.5 mg/kg dexamethasone enhanced the effect, suggesting that alpha-toc, in combination with low doses of corticosteroids, might be effective for therapeutic treatment of acute lung injury.