Effects of leukotriene inhibition on pulmonary morphology in rat pup lungs exposed to hyperoxia

Assisted ventilation is necessary for treating preterm infants with respiratory distress syndrome. Unfortunately, high and prolonged concentrations of oxygen associated with assisted ventilation often lead to pulmonary changes, such as hemorrhage and inflammation. The resulting chronic pulmonary condition is known as bronchopulmonary dysplasia. Pulmonary changes characteristic of this syndrome can be produced in rat pups exposed to high oxygen levels. We exposed 21-d-old rats to room air or continuous 95% oxygen for 7 d and then allocated them into 6 groups to evaluate whether treatment with zileuton and zafirlukast, 2 agents which decrease the effects of leukotrienes, lessened the pulmonary effects of short-term hyperoxia. After 7 d, lung tissue was collected for light and electron microscopy. Pulmonary changes including edema, hemorrhage, alveolar macrophage influx, and Type II pneumocyte proliferation were graded on a numerical scoring system. Compared with controls exposed to hyperoxia [corrected] and saline, rats exposed to hyperoxia and treated with zileuton had significantly reduced levels of alveolar macrophage influx and Type II pneumocyte proliferation, but those exposed to hyperoxia [corrected] and treated with zafirlukast showed no significant reduction in any pulmonary changes. This study helps define pulmonary changes induced secondary to hyperoxia in rat pups and presents new information on the mechanisms of leukotriene inhibition in decreasing the severity of hyperoxic lung injury.     

Effect of age and sex on copper-induced toxicity in theMacular mutant mouse

It was determined if the sensitivity inmacular mutant mouse to copper-induced toxicity was affected by sex or age. The sensitivity in 6–8-d-old or 3–4-wk-oldmacular mutant mouse to copper-induced toxicity was not affected by sex. However, 8–9-wk-old mutant females were more sensitive to copper-induced toxicity than mutant males. Furthermore, 6–8-d-old or 3–4-wk-old mutant males were more sensitive to copper-induced toxicity than 8–9-wk-old mutant males. However, age-related differences in sensitivity to copper-induced toxicity did not occur significantly in mutant females. On the other hand, in the case of normal mice, the sensitivity in 6–8-d-old or 3–4-wk-old mice to copper-induced toxicity was not also affected by sex. In contrast to mutant, however, 8–9-wk-old normal males were more sensitive to copper-induced toxicity than 8–9-wk-old normal females. Adult males were also more sensitive to copper-induced toxicity than 6–8-d-old or 3–4-wk-old males. However, age-related differences in sensitivity to copper-induced toxicity did not occur significantly in normal females. These results indicate that sex- and age-related differences in the copper-induced toxicity exist inmacular mutant mice.     

Characterization of fumonisin toxicity in orally and intravenously dosed swine

Fumonisin B₁ (FB₁), a recently identified mycotoxin produced by Fusarium moniliforme in corn, has been shown to cause death in swine due to pulmonary edema, an apparently species specific effect, and to interfere with sphingolipid metabolism in vitro. Here we characterize the toxicity of fumonisins, using female cross-bred swine weighing 6 to 13 kg, and present a hypothesis regarding the mechanism of fumonisin-induced pulmonary edema in swine. FB₁ was given daily intravenously (IV) to pig 1 for 9 days for a total of 72 mg (7.9 mg/kg) and to pig 2 for 4 days for a total of 67 mg (4.6 mg/kg). Pig 3 (control) was given saline IV for 9 days. Corn screenings naturally contaminated with FB₁ (166 ppm) and FB₂ (48 ppm) were fed to pigs 4, 5, and 6, and ground corn was fed to pigs 7 and 8 (controls). Pigs 4 and 7 were killed on day 5; pig 5 was found dead on day 6; and pigs 6 and 8 were killed on day 15. Pigs 4 and 5 had ingested 187 and 176 mg total fumonisins, respectively, while pig 6 had ingested 645 mg. Feed consumption had decreased in pigs fed corn screenings, with an additional sharp decrease prior to onset of clinical signs. Increases in serum liver enzymes, total bilirubin, and cholesterol were present, but electrocardiograms, heart rate, and body temperature were unaffected. Pigs dosed IV with FB₁, developed mild intermittent respiratory abnormalities, while those fed screenings developed respiratory distress within 5 days. Mild interstitial pulmonary edema was observed in pig 1. Severe interstitial pulmonary edema, pleural effusion, and increased lung wet/dry weight ratio were observed in pigs 4 and 5. All pigs given fumonisin (either IV or orally) had hepatic changes characterized by hepatocyte disorganization and necrosis; pancreatic acinar cell degeneration was also observed. Ultrastructural changes in orally dosed swine included loss of sinusoidal hepatocyte microvilli; membranous material in hepatic sinusoids; and multilamellar bodies in hepatocytes, Kupffer cells, pancreatic acinar cells and pulmonary macrophages. Pulmonary intravascular macrophages (PIMs) contained large amounts of membranous material. Thus, the target organs of fumonisin in the pig are the lung, liver, and pancreas. At lower doses, slowly progressive hepatic disease is the most prominent feature, while at higher doses, acute pulmonary edema is superimposed on hepatic injury and may cause death. We hypothesize that altered sphingolipid metabolism causes hepatocellular damage resulting in release of membranous material into the circulation. This material is phagocytosed by the PIMs thus triggering the release of mediators which ultimately results in pulmonary edema.Presented in part at the 1991 Annual Meeting of the Society of Toxicology. The Toxicologist 11: 143 (A499).     

Effect of LY171883 on endotoxin-induced lung injury in pigs

We evaluated the role of sulfidopeptide leukotrienes as mediators of endotoxin-induced respiratory failure in pigs. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized 10- to 14-wk-old pigs at 5 micrograms/kg the 1st h followed by 2 micrograms.kg-1.h-1 for 3 h in the presence and absence of LY171883, a specific leukotriene D4 (LTD4)/LTE4 receptor antagonist. Endotoxin caused hemoconcentration, granulocytopenia, decreased cardiac index, systemic hypotension, pulmonary hypertension, increased pulmonary vascular resistance, bronchoconstriction, hypoxemia, increased permeability of the alveolar-capillary membrane, pulmonary edema, and increased plasma concentrations of thromboxane B2 (TxB2), prostaglandin F2 alpha (PGF2 alpha), and 6-keto-PGF1 alpha. LY171883 did not modify endotoxin-induced cardiopulmonary and hematologic abnormalities, except for a modest attenuation of pulmonary hypertension (at 1 h) and increased pulmonary vascular resistance (at 1-2 h). Ex vivo stimulation of whole blood with calcium ionophore caused large increases in plasma concentrations of TxB2, PGF2 alpha, and LTB4. These increases were not significantly modified in blood derived from pigs treated with LY171883, indicating no inhibition of cyclooxygenase or 5-lipoxygenase. We conclude that LTD4 and LTE4 are not important mediators of endotoxin-induced lung injury in anesthetized pigs, although they may contribute modestly to pulmonary vasoconstriction.     

Temporal and dose-response features in swine fed corn screenings contaminated with fumonisin mycotoxins

Fumonisin B₁ (FB₁), a mycotoxin produced byFusarium moniliforme andF. proliferatum, induces liver damage and pulmonary edema in swine. We examined the temporal and dose-response features of FB₁ toxicosis in male weanling crossbred pigs fed nutritionally balanced diets, containing corn screenings naturally contaminated with fumonisins, for 14 days. Total fumonisins (FB₁ and FB₂) in diets 1 through 6 were assayed at 175, 101, 39, 23, 5, and <1 ppm (below detectable concentrations), respectively. Clinical signs, serum biochemical alterations, and morphologic changes were evaluated. Pigs were weighed, and bled for hematologic and clinical chemistry evaluation on days 5 and 14. They were euthanized on day 14, or earlier if respiratory distress was observed. Respiratory distress developed in 3/5 pigs fed diet 1 between days 4 and 6 due to severe pulmonary edema and pleural effusion. Histologic evidence of hepatic injury was present in all pigs fed diets 1 and 2, 3/5 on diet 3, and 1/5 on diet 4. Serum bilirubin and cholesterol concentrations, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and arginase (ARG) activities were elevated in pigs fed diets 1 and 2. Based on liver histopathology, the no observed adverse effect level (NOAEL) for fumonisin toxicity in swine was <23 ppm total fumosins for the 14-day period. Based on regression analyses of the clinical chemistry profiles at 14 days, the NOAEL was <12 ppm, with ALP being the most sensitive parameter. In conclusion, pulmonary edema occurred only at the highest fumonisin concentration (175 ppm), while liver damage occurred at much lower concentrations with a NOAEL of <12 ppm.Abbreviations ALP alkaline phosphatase - ALT alanine aminotransferase - ARG arginase - AST aspartate aminotransferase - ELEM equine leukoencephalomalacia - FB₁ fumonisin B₁ - GGT gamma-glutamyl transferase - NOAEL no observed adverse effect level     

Respiratory disease and wasting in athymic mice infected with pneumonia virus of mice

Although pneumonia virus of mice (PVM) is ubiquitous among rodent colonies in the United States, it has not been reported to cause clinically apparent disease in euthymic mice. However, PVM has been reported to cause respiratory disease and death in experimentally infected euthymic and athymic mice. A group of nu/nu mice, housed in quarantine in a Trexler-type isolator, had weight loss and dyspnea. Gross necropsy findings included cachexia and diffuse pulmonary edema or lobar consolidation. Histologically there was diffuse interstitial pneumonia. Electron microscopy revealed filamentous virions budding from plasma membranes, and immunohistochemical staining of lung tissue was positive for PVM antigen. PVM was isolated from affected lung tissue in BHK 21 cells and mouse antibody production tests resulted in seroconversion to PVM. Experimental inoculation of athymic mice with lung homogenate from spontaneously infected mice resulted in clinically apparent respiratory disease and histologic lung changes similar to those in naturally infected mice. Inoculation of athymic mice with infected BHK 21 cell culture fluid resulted in pneumonia which was qualitatively similar to, but less severe than, that observed in mice with spontaneous disease. These findings indicate that naturally occurring PVM infection in athymic mice may cause respiratory disease and wasting.     

Fatal pulmonary acariasis in an aged indoor rhesus macaque (Macaca mulatta)

Pulmonary acariasis is a sporadic, incidental finding in colony‐raised rhesus macaques (Macaca mulatta). Prophylactic treatment in indoor‐raised and indoor‐housed macaques is not routine due to low prevalence, lack of clinical significance, and potential risk of toxicosis. This case is an unusually severe infestation of Pneumonyssus simicola in an indoor‐housed rhesus macaque, which ultimately resulted in this animal's death.     

Methylmercury accumulation in tissues and its effects on growth and appetite in captive great egrets

To test the hypothesis that fledging wading birds would be more at risk from mercury toxicosis than younger nestlings, captive great egret nestlings were maintained as controls or were dosed from 1- to 14-wk-old with 0.5 or 5 mg methylmercury chloride/kg wet weight in fish. Birds dosed with 5 mg/kg suffered from subacute toxicosis at wk 10-12. Growing feather concentrations were the most closely correlated with cumulative mercury consumed per weight. Blood concentrations of mercury increased more rapidly after 9 wk in all groups when feathers stopped growing. Total mercury accumulated in tissues in concentrations in the following order: growing scapular feathers > powderdown > mature scapular feathers > liver > kidney > blood > muscle > pancreas > brain > bile > fat > eye. The proportion of total mercury that was methylated depended upon tissue type and dose group. Selenium accumulated in liver in direct proportion to liver mercury concentrations. After wk 9, appetite and weight index (weight/bill length) declined significantly in both dosed groups. At current exposure levels in the Everglades (Florida, USA) mercury deposited in rapidly growing feathers may protect nestlings from adverse effects on growth until feathers cease growing.     

Respiratory failure after endotoxin infusion in sheep: lung mechanics and lung fluid balance

Infusion of Escherichia coli endotoxin (0.12-1.5 micrograms/kg) into unanesthetized sheep causes transient pulmonary hypertension and several hours of increased lung vascular permeability, after which sheep recover. To produce enough lung injury to result in pulmonary edema with respiratory failure, we infused larger doses of E. coli endotoxin (2.0-5.0 micrograms/kg) into 11 chronically instrumented unanesthetized sheep and continuously measured pulmonary arterial, left atrial and aortic pressures, dynamic lung compliance, lung resistance, and lung lymph flow. We intermittently measured arterial blood gas tensions and pH, made interval chest radiographs, and calculated postmortem extravascular bloodless lung water-to-dry lung weight ratio (EVLW/DLW). Of 11 sheep 8 developed respiratory failure; 7 died spontaneously 6.3 +/- 1.1 h, and one was killed 10 h after endotoxin infusion. All sheep that had a premortem room air alveolar-arterial gradient in partial pressure of O2 (PAo2-Pao2) greater than 42 Torr (58 +/- 5 (SE) Torr) died. Of eight sheep that had radiographs made, six developed radiographically evident interstitial or interstitial and alveolar edema. Pulmonary artery pressure rose from base line 22 +/- 2 to 73 +/- 3 cmH2O and remained elevated above baseline levels until death. There was an initial fourfold decrease in dynamic compliance and sixfold increase in pulmonary resistance; both variables remained abnormal until death. EVLW/DLW increased with increasing survival time after endotoxin infusion, suggesting that pulmonary edema accumulated at the same rate in all fatally injured sheep, regardless of other variables. The best predictor of death was a high PAo2-Pao2. The marked increase in pulmonary resistance and decrease in dynamic compliance occurred too early after endotoxin infusion (15-30 min) to be due to pulmonary edema. The response to high-dose endotoxin in sheep closely resembles acute respiratory failure in humans following gram-negative septicemia. Respiratory failure and death in this model were not due to pulmonary edema alone.     

The large spectrum of pulmonary complications following illicit drug use: Features and mechanisms

Damage to lungs may occur from systemic as well as inhalational exposure to various illegal drugs of abuse. Aspiration pneumonia probably represents the most common pulmonary complication in relation to consciousness impairment. Some pulmonary consequences may be specifically related to one given drug. Prolonged smoking of marijuana may result in respiratory symptoms suggestive of obstructive lung disease. Non-cardiogenic pulmonary edema has been attributed to heroin, despite debated mechanisms including attempted inspiration against a closed glottis, hypoxic damage to alveolar integrity, neurogenic vasoactive response to stress, and opiate-induced anaphylactoid reaction. Naloxone-related precipitated withdrawal resulting in massive sympathetic response with heart stunning has been mistakenly implicated. In crack users, acute respiratory syndromes called “crack-lung” with fever, hemoptysis, dyspnea, and pulmonary infiltration on chest X-rays have been reported up-to 48 h after free-base cocaine inhalation, with features of pulmonary edema, interstitial pneumonia, diffuse alveolar hemorrhage, and eosinophil infiltration. The high-temperature of volatilized cocaine and the presence of impurities, as well as cocaine-induced local vasoconstriction have been suggested to explain alveolar damage. Some other drug-related pulmonary insults result from the route of drug self-administration. In intravenous drug users, granulomatous pneumonia with multinodular patterns on thoracic imaging is due to drug contaminants like talcum. Septic embolism from right-sided endocarditis represents an alternative diagnosis in case of sepsis from pulmonary origin. Following inhalation, pneumothorax, and pneumomediastinum have been attributed to increased intrathoracic pressure in relation to vigorous coughing or repeated Valsalva maneuvers, in an attempt to absorb the maximal possible drug amount. In conclusion, pulmonary consequences of illicit drugs are various, resulting in both acute life-threatening conditions and long-term functional respiratory sequelae. A better understanding of their spectrum and the implicated mechanisms of injury should help to improve patient management.     

Ascorbic acid synthesis and concentrations in organs of copper-deficient and brindled mice

Copper deficiency was studied in mice to investigate an interaction between copper and ascorbic acid. Twelve-day-old mutant brindled mice that exhibited signs of copper deficiency were compared to their normal brothers as well as to age-matched suckling mice that were copper deficient (-Cu) because their dams were consuming a copper-deficient diet throughout gestation and lactation, and a fourth group of copper-supplemented ( + Cu) suckling mice that served as dietary controls. Dietary copper deficiency was also produced in older mice by beginning the treatment at birth and continuing for 7 wk. Organ ascorbate levels were determined by high performance liquid chromatography with electrochemical detection. Differences caused by diet and genetics were evident but age-dependent. Compared to controls, liver and kidney ascorbate levels did not change remarkably in young or old copper-deficient mice. Cardiac ascorbate levels were higher in 7-wk-old - Cu mice and lower in 12-d-old - Cu mice, despite hypertrophy in both cases. Spleen ascorbate levels were lower in older -Cu mice and higher in 12-d-old mice, but total spleen ascorbate reflected the hypertrophic and atrophic size in the older and younger -Cu mice, respectively. Brindled mutants had an extremely low level of ascorbate in spleen. Plasma ascorbate was lower in 7-wk-old - Cu mice. Reasons for the alterations in ascorbate levels are not known. Synthesis in liver from D-glucuronate was not altered by dietary copper deficiency in 7-wk-old mice. Synthesis was lower in livers from 12-d-old - Cu and brindled mice compared to control values. However, the difference correlated better with body weight of the mice rather than with degree of copper deficiency. Consequences of the altered organ levels of ascorbate in copper-deficient mice are not completely known.     

Effects of hyperoxia on vasoconstriction and VA/Q matching in the neonatal lung

Exposure of adult animals to 48-72 h of 100% O2 breathing is associated with a blunting of hypoxic pulmonary vasoconstriction (HPV) (Newman et al. J. Appl. Physiol. 54: 1379-1386, 1983). It is unknown whether HPV is also diminished in neonates after hyperoxic exposure and if so to what extent such suppression might interfere with pulmonary gas exchange during hypoxic gas breathing. We tested the possibility that hyperoxia would suppress HPV and interfere with ventilation-perfusion (VA/Q) matching and therefore gas exchange in neonatal piglets. Twelve 2- to 4-wk-old piglets were exposed for an average of 68 h to greater than 90% inspired O2. A control group of eight piglets was exposed to room air for a similar period of time. Immediately after exposure the animals were anesthetized and instrumented. Pulmonary hemodynamics and respiratory and inert gas exchange were assessed while the animals inspired an O2 fraction of 1.0, 0.21, and 0.12. After 20 min of hypoxic gas breathing, pulmonary arterial pressure rose to a lesser degree in the hyperoxia (H)-exposed animals than in the control (C) animals (P less than 0.02). The increase in pulmonary vascular resistance was similarly blunted. Venous admixture of the insoluble inert gas, sulfur hexafluoride, an index of extremely low VA/Q areas, was increased during hypoxic gas breathing compared with room air breathing in the H-preexposed animals (P less than 0.02). Standard deviation of pulmonary blood flow was increased (P less than 0.02), indicating an increase in mismatching of VA/Q during hypoxic breathing in the H-preexposed animals compared with the C animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

The three syndromes of fat embolism: pulmonary manifestations.

The clinical course and radiographs of 30 patients with fat embolism syndrome were reviewed. In all cases the classic triad of neurologic dysfunction, respiratory insufficiency, and petechiae were present. Three responses to embolized fat were noted. The hyperacute response was seen in two patients with paradoxical embolization of fat to the systemic circulation. A "classic response" was noted in 18 patients with transient respiratory compromise and variable radiographic findings. The two deaths in the group responding in the classical manner were attributed to massive pulmonary emboli. The third response, noted in ten patients, consisted of a chest radiograph compatible with pulmonary edema in the clinical setting of the adult respiratory distress syndrome. In this group the degree of respiratory dysfunction and pulmonary damage correlated with the development of disseminated intravascular coagulation. Pathologic correlations are presented and the mechanisms by which embolic fat produces tissue damage are discussed.     

Open-field behaviour in chickens: A replication revisited

In an attempt to show that the open field can still be used as a valid measure of fear, Jones (1983) has reported a failure to replicate some of our findings. The present studies show that this was due to procedural and methodological differences. For instance, we found that birds tested in a novel environment behaved quite differently from those, as in Jones' case, which were placed in one resembling the home cage. Moreover, birds housed in isolation for two days prior to testing reacted differently than those, as again in Jones' case, which were reared in isolation from hatching to the time of testing. The results were interpreted as being consistent with our view that open-field behaviour reflects a conflict between the need to reinstate contact with conspecifics on the one hand, and evade predation on the other.     

Pathogenesis of pulmonary edema associated with the adult respiratory distress syndrome.

Pulmonary edema is common cause of acute respiratory failure and can be seen in not only cardiac but also noncardiac diseases. The pathophysiologic mechanism for the development of acute pulmonary edema in any clinical situation can usually be explained alterations in the forces governing the transvascular flux of fluid in the pulmonary microvasculature, according to the Starling equation. "Cardiac" pulmonary edema is primarily due to an increase in the capillary hydrostatic pressure of sufficient magnitude to overcome the forces maintaining fluid within the vessel and the ability of the lymphatics to drain the transudated fluid. On the other hand, pulmonary edema occurring in association with noncardiac disease (e.g., sepsis, aspiration or shock) is secondary to an increase in the permeability of the pulmonary microvasculature and is referred to as noncardiogenic pulmonary edema or the adult respiratory distress syndrome. This article examines the mechanisms for the development of pulmonary edema and discusses the differences between the cardiac and noncardiac types.     

Baseline Knowledge of Potential Pet Toxins among the US General Public

In 2014, the American Society for the Prevention of Cruelty toAnimals Animal Poison Control Center fielded more than 167,000cases of potential nonhuman animal toxicosis. Concomitantly, thereremain limited free and reputable veterinary toxicology resourcesavailable for companion-animal (pet) caregivers (owners) seekingassistance and advice about potentially harmful exposures inanimals. The objective of this study was to assess pet toxicantknowledge among a representative sample of Americans andgauge the need for additional toxicology resources. The studyinvolved a survey designed to capture participants’ ability to identifypotential animal toxicants and what resource they would use ifan accidental toxic ingestion occurred. Participants were ableto correctly identify 52% of potential pet toxins. Women, olderparticipants and participants from the South expressed moreconcern about each potential pet poison. Approximately halfof participants indicated they would consult a veterinarian andwhereas most others indicated they would search the Internet formore information about pet toxicology. The findings suggest moreveterinary poisoning education is needed for pet owners to be ableto accurately distinguish potential pet toxicants from nontoxicants.     

Effect of nickel chloride on hepatic lipid peroxidation and glutathione concentration in mice

Intraperitoneal administration of nickel chloride enhanced hepatic lipid peroxidation (HLP) in 6-wk-old and 8–12-wk-old male CBA-mice but not in 3-wk-old mice. nickel chloride administration depleted hepatic GSH in 8–12-wk-old mice but not in the younger age groups. After 300 μmol NiCl₂/kg mortality occurred among 8–12-wk-old mice but not among the younger mice. Stimulation of GSH synthesis by administration ofl-2-oxothiazolidine-4-carboxylate reduced nickel chloride induced mortality and HLP. Reduction of GSH synthesis by administration of buthionine sulfoximine (BSO) did not, however, enhance the toxicity of nickel chloride. This might be owing to chelation of the Ni(II)-ion by BSO. The results demonstrate age dependency and a protective effect of enhanced GSH synthesis in nickel chloride stimulated HLP.