The effects of exercise following exposure to bis(trifluoromethyl) disulfide.

Bis(trifluoromethyl) disulfide (TFD) was originally designed for use as an agricultural fumigant. Inhalation of toxic doses of TFD results in varying degrees of pulmonary edema. The purpose of this study was to determine if exhaustive exercise would potentiate the toxic effects of TFD. One group of treadmill-acclimated rats was exercised to exhaustion following a 10-minute whole-body exposure to TFD. A second group was similarly exposed but not exercised. Two other groups of rats were sham exposed; one was exercised while one remained sedentary following the sham exposure. Twenty-four hours after exposure, the animals were sacrificed; the lungs were removed and weighed, and a portion was collected for histopathologic examination. The remaining lung tissue was allowed to dry to constant weight. There was no difference in endurance times between exposed and sham-exposed rats. There was a significant increase in the amount of pulmonary edema and associated pulmonary pathology in rats exercised following exposure to TFD. Eleven of twelve animals exercised following exposure to TFD and three of twelve animals which remained sedentary following exposure died by 24 hours. The degree of pulmonary pathology in all rats exposed to TFD was profound.     

Progressive Pulmonary Pathology of Two Organofluorine Compounds in Rats

Abstract

Rat lungs were studied by light and electron microscopy to morphologically characterize the development of lung injury associated with the inhalation of two organo-fluorine compounds, perfluoroisobutylene (PFIB) and bis(trifluoromethyl) disulfide (TFD). Rats were exposed to test compounds in an inhalation chamber and euthanatized at 5 min, 30 min, 90 min, 4 h, 12 h, 24 h, and 72 h postexposure. Inhalation of the compounds resulted in a progressive pulmonary pathology dominated by pulmonary edema and fibrin deposition, which peaked at 12 to 24 h but which resolved to a large extent by 72 h postexposure. The edema was microscopically evident as early as 5–30 min after exposure. Endothelial change was the earliest recognized lesion by electron microscopy and was produced by both compounds. This was characterized by increased pinocytotic-vesicular activity and increased electron density of endothelial cells. Injury to type I and II pneumocytes was also evident, but appeared more severe in the lungs of TFD-exposed rats. The morphologic pathogenesis of the edema appears related to the primary endothelial changes and Concomitant pneumocyte damage.     

Breathing Patterns of Awake Rats Exposed to Acrolein and Perfluorisobutylene Determined with an Integrated System of Nose-Only Exposure and Online Analyzed Multiple Monitoring of Breathing

Abstract

Studies on changes in breathing patterns of rats due to exposure to acrolein and the Teflon pyrolysis product perfluorisobutylene (PFIB) were performed to evaluate a newly developed integrated system of nose-only exposure and multiple monitoring of breathing of up to eight rats. Measurement of breathing was based on nose flow pneumotachography using differential pressure transducers and monitoring on the videoscreen the 12-s breathing records of 4 rats, including online analysis of respiration frequency (f) and respiratory minute volume (V?_I) simultaneously. Acrolein concentrations (7-54 ppm) caused an immediate change of the breathing pattern in exposed rats characterized by a concentration-dependent decrease of f and a similar change of V?_I. Analysis of the breathing records showed increasing postinspiratory apneic periods as major cause of the decreased f. An RD50 of 4.6 ppm for acrolein was calculated (95% confidence limits 2.4 and 7.2 ppm). Acute nose-only exposure of rats to 100 ppm PFIB during 6-18 min did not change the breathing pattern immediately. However, 24 h after exposure a changed breathing pattern was monitored, characterized by small preinspiratory apneic pauses. Lung edema was confirmed at histopathological examination. Continued monitoring of breathing patterns after the acute exposure of PFIB showed normal breathing patterns in recovering rats.     

全氟异丁烯单次暴露诱发小鼠急性肺损伤的长期效应

目的 探讨全氟异丁烯( PFIB)单次暴露诱发急性肺损伤的长期效应.方法 70只雄性小鼠暴露于全氟异丁烯130 mg·m-3 5 min.10只小鼠于暴露后24 h评价肺水肿程度.其余小鼠分别在PFIB暴露后2,4,6,8,12和16周,应用HE染色和天狼星红染色分别观察肺组织的病理变化和胶原沉积,测定肺及血浆中羟脯氨...     

Protection of Rats Against Perfluoroisobutene (PFIB)-Induced Pulmonary Edema by Curosurf and N-Acetylcysteine

Airborne exposure to lung-toxic agents may damage the lung surfactant system and epithelial and endothelial cells, resulting in a life-threatening pulmonary edema that is known to be refractory to treatment. The aim of this study was to investigate in rats (1) the respiratory injury caused by nose-only exposure to perfluoroisobutene (PFIB), and (2) the therapeutic efficacy of a treatment at 4 and/or 8 h after exposure consisting of the natural surfactant Curosurf and/or the anti-inflammatory drug N-acetylcysteine (NAC). For that purpose, the following parameters were examined: respiratory frequency (RF), lung compliance (Cdyn), airway resistance (Raw), lung wet weight (LWW), airway histopathology; and in brochoalveolar lavage (BAL) fluid, total protein, total phospholipid, cell count and differentiation, and changes in the surface tension of the BAL fluid. The mean (± SEM) surface tension of BAL fluid derived from PFIB-exposed (C · t = 1100–1200 mg min^?1 m^?3, ～1LCt50; t = 20 min) animals at 24 h following exposure (11 ± 3 mN/m) was higher than that of unexposed rats (0.8 ± 0.4 mN/m), reflecting damage to the surfactant system and justifying treatment with exogenous surfactant. Curosurf treatment (62.5 mg/kg i.t.) decreased pulmonary edema caused by PFIB, reflected by a decreased LWW, and decreased the amount of protein in BAL fluid. NAC treatment (1000 mmol/kg ip) inhibited the interstitial pneumonia reflected by a decreased percentage of neutrophils in the alveolar space. It was concluded that a combined treatment of Curosurf + NAC improved respiration, that is, RF and Cdyn, whereby Curosurf predominantly decreased pulmonary edema and NAC predominantly reduced the inflammatory process. A combined treatment may therefore be considered a promising therapeutic approach in early-stage acute respiratory distress caused by PFIB, although the treatment regimes need further investigation.     

Protection of rats against perfluoroisobutene (PFIB)-induced pulmonary edema by curosurf and N-acetylcysteine

Airborne exposure to lung-toxic agents may damage the lung surfactant system and epithelial and endothelial cells, resulting in a life-threatening pulmonary edema that is known to be refractory to treatment. The aim of this study was to investigate in rats (1) the respiratory injury caused by nose-only exposure to perfluoroisobutene (PFIB), and (2) the therapeutic efficacy of a treatment at 4 and/or 8 h after exposure consisting of the natural surfactant Curosurf and/or the anti-inflammatory drug N-acetylcysteine (NAC). For that purpose, the following parameters were examined: respiratory frequency (RF), lung compliance (Cdyn), airway resistance (Raw), lung wet weight (LWW), airway histopathology; and in brochoalveolar lavage (BAL) fluid, total protein, total phospholipid, cell count and differentiation, and changes in the surface tension of the BAL fluid. The mean (+/- SEM) surface tension of BAL fluid derived from PFIB-exposed (C . t = 1100-1200 mg min(-1) m(-3), approximately 1LCt50; t = 20 min) animals at 24 h following exposure (11 +/- 3 mN/m) was higher than that of unexposed rats (0.8 +/- 0.4 mN/m), reflecting damage to the surfactant system and justifying treatment with exogenous surfactant. Curosurf treatment (62.5 mg/kg i.t.) decreased pulmonary edema caused by PFIB, reflected by a decreased LWW, and decreased the amount of protein in BAL fluid. NAC treatment (1000 mmol/kg ip) inhibited the interstitial pneumonia reflected by a decreased percentage of neutrophils in the alveolar space. It was concluded that a combined treatment of Curosurf + NAC improved respiration, that is, RF and Cdyn, whereby Curosurf predominantly decreased pulmonary edema and NAC predominantly reduced the inflammatory process. A combined treatment may therefore be considered a promising therapeutic approach in early-stage acute respiratory distress caused by PFIB, although the treatment regimes need further investigation.     

The effect of perfluoroisobutene and phosgene on rat lavage fluid surfactant phospholipids

1. This study investigated whether the reactive organohalogen gases perfluoroisobutene (PFIB) and phosgene, which cause death by overwhelming pulmonary oedema, affect the surfactant system or type II pneumocytes of rat lung. 2. The progression and type of pulmonary injury in Porton Wistar-derived rats was monitored over a 48 h period following exposure to either PFIB or phosgene (LCt30) by analyzing the inflammatory cells and protein in bronchoalveolar lavage fluid. Six rat lung phospholipids were measured by high-performance liquid chromatography, following solid phase extraction from lavage fluid. 3. Alterations in the cell population and lung permeability occurred following both gases, indicating that the injury was a permeability-type pulmonary oedema. Changes in the total amount of phospholipid and in the percentage composition of the surfactant were different for the two gases. PFIB produced increases in phosphatidylglycerol and phosphatidylcholine over the first hour, similar to that seen following air exposure, followed by substantial decreases in these phospholipids. Phosgene caused late increases in all phospholipids from 6 h post-exposure. 4. Differences in the response of the surfactant system to exposure to PFIB and phosgene suggest different mechanisms of action at the alveolar surface although the final injurious response is pulmonary oedema for both gases.     

Inhalation Toxicity of Cyclododecatriene in Rats

ABSTRACT

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was tested for its inhalation toxicity in rats following repeated exposures. Male rats were exposed nose-only to CDDT for 6 hr/day, 5 days/wk for a total of 9 exposures over 2 weeks. Particular attention was paid to neurotoxicologic endpoints. Concentrations of 0 (control), 5, 50, and 260 ppm were studied. The 260 ppm chamber contained both vapor and aerosol while the 5 and 50 ppm chambers were vapor only. Four groups of 10 rats each were used to measure standard clinical signs and growth, clinical pathology (including hematology, biochemistries, and urine analysis), and tissue pathology. Another 4 groups of similar size were used for neurotoxicity testing. In the standard toxicity groups, 1/2 of the rats were sacrificed 1 day following the 9th exposure; the other half underwent a 2-week recovery period prior to being sacrificed (recovery group). During the exposures rats inhaling 260 ppm had a diminished or absent response to an alerting stimulus. Irregular respiration and lethargy were observed in these rats immediately following exposure. These signs were rapidly reversible and were not seen prior to the subsequent exposure. Body weights in rats exposed to either 50 or 260 ppm were significantly lower than the corresponding controls. No compound-related clinical pathology changes were seen in any of the test groups and tissue pathology effects only occurred in the nasal tissue. In rats exposed to 260 ppm, minimal degeneration/necrosis of nasal olfactory epithelium was observed in rats examined immediately following the exposure period. This change was not seen in the recovery rats. Functional observational battery (FOB) assessments and motor activity (MA) evaluations conducted after the 4th and 9th exposures on rats from all test groups, and specific neuropathologic evaluation on perfused brain, spinal cord, and skeletal muscle from rats exposed to 260 ppm failed to demonstrate any specific neurotoxicity. Outward signs of sedation were seen at the top level tested. Under the conditions of this test, the no-observed-adverse-effect level (NOAEL) was determined to be 5 ppm based upon a reduced rate of body weight gain in the 50 ppm group. No specific neurotoxicity was detected and the histopathologic response was limited to reversible changes in the nasal epithelia in rats exposed to 260 ppm.     

Epithelial sodium channel is involved in H2S-induced acute pulmonary edema

Abstract

Acute pulmonary edema is one of the major outcomes of exposure to high levels of hydrogen sulfide (H₂S). However, the mechanisms involved in H₂S-induced acute pulmonary edema are still poorly understood. Therefore, the present study is designed to evaluate the role of epithelial sodium channel (ENaC) in H₂S-induced acute pulmonary edema. The Sprague–Dawley rats were exposed to sublethal concentrations of inhaled H₂S, then the pulmonary histological and lung epithelial cell injury were evaluated by hematoxylin–eosin staining and electron microscopy, respectively. In addition to morphological investigation, our results also revealed that H₂S exposure significantly decreased the alveolar fluid clearance and increased the lung tissue wet–dry ratio. These changes were demonstrated to be associated with decreased ENaC expression. Furthermore, the extracellular-regulated protein kinases 1/2 pathway was demonstrated to be implicated in H₂S-mediated ENaC expression, because PD98059, an ERK1/2 antagonist, significantly mitigated H₂S-mediated ENaC down-regulation. Therefore, our results show that ENaC might represent a novel pharmacological target for the treatment of acute pulmonary edema induced by H₂S and other hazardous gases.     

Inhalation Toxicology and Histopathology of Ricin and Abrin Toxins

Abstract

The inhalation toxicology of ricin (supplied by Sigma) from the seed variety “Hale Queen” and abrin was examined following head-only exposure of rats to a range of concentrations of each toxin generated as an aerosol from solution using a constant-output nebulizer. The inhalation toxicity of an in-house preparation of ricin from a different seed type, Ricinus communis var. zanzibariensis (R. zanzibariensis), was also assessed for comparison. The approximate LCt50 values determined were very similar for the Sigma ricin and abrin (4.54–5.96 and 4.54 mg min m^-3, respectively). However, the LCt50 of ricin toxin prepared in-house from seeds of the R. zanzibariensis variety was assessed to be 12.7 mg min m^-3. Ricin prepared from this seed variety was therefore less toxic than Sigma ricin by a factor of almost threefold. Given that both ricin preparations were pure by silver-stained, sodium dodecyl sulfate polyacrylamide electrophoresis gels, the data must reflect differences in specific toxicity between seed varieties. The histopathology was studied in a separate group of experimental animals exposed to approximate LCt30 levels of each in-house toxin preparation and was found to be entirely restricted to the lung. The overall pattern and time course of damage observed were similar for ricin and abrin and were characterized by rapidly progressive and overwhelming pulmonary edema accompanied by acute destructive alveolitis and necrosis/apoptosis of the lower respiratory tract epithelium; severe intraalveolar edema and resulting hypoxia accounted for the majority of deaths in the decedent population. The resolution phase of the pulmonary damage in those animals destined to survive was heralded by a gradual disappearance of edema fluid accompanied by generalized, focally florid, hyperplasia of type II pneumocytes and striking transitory consolidation of the lung parenchyma by chronic inflammatory cells. Despite many similarities in histopathology between abrin and ricin there were some differences. Although by systemic administration abrin is several times more toxic than ricin, when delivered by inhalation there was no significant difference in potency between abrin and the commercial preparation of ricin (Sigma).     

Pulmonary Host Defenses and Resistance to Infection Following Subchronic Exposure to Phosgene

Abstract

Acute exposure to phosgene, a toxic gas widely used in industrial processes, decreases resistance to bacteria in mice and rats and enhances susceptibility to B16 tumor cell challenge in mice. These effects appear to be due to impaired alveolar macrophage and natural killer (NK) cell activity, respectively. In this study effects of repeated phosgene exposures on bacterial infection and NK activity were determined. Rats were exposed for 4 or 12 wk, 6 h/day, 5 days/wk, to 0.1 or 0.2 ppm phosgene or 2 days/wk to 0.5 ppm and infected by aerosol with Streptococcus zooepidemicus immediately after the last exposure. An additional group was also infected after 4 wk of recovery following the 12-wk exposure regimens. Bronchoalveolar lavage (BAL) fluid was assessed 0, 6, and 24 h postinfection for bacteria and inflammatory cells. Differential cell counts in BAL and pulmonary NK activity were also determined in uninfected rats 18 Is after the last exposure. All phosgene exposures impaired clearance of bacteria from the lungs and caused an increase in polymorphonuclear leukocytes (PMNs) in BAL of infected rats. Effects in the 0.5 ppm exposure group were greatest, and were significantly different from those in the 0.2 ppm exposure group, although the product of concentration × time was the same. BAL cell counts and bacterial clearance were normal in rats assessed 4 wk after the 12-wk phosgene exposures. Bacterial clearance and the PMN response to infection following repeated exposure were similar to those observed after a single exposure; that is, for these endpoints, effects due to repetitive exposure were neither additive nor attenuated. In contrast, NK activity was suppressed only at the 0.5 ppm level, and the magnitude of suppression was much less than that following acute exposure, suggesting that attenuation of this effect did occur with repeated exposure. The data indicate that susceptibility to streptococcal infection is a sensitive endpoint for phosgene toxicity following subchronic exposure.     

Selected responses of hypertension-sensitive and resistant rats to inhaled acrolein

The Dahl selected rat lines, one susceptible to salt-induced hypertension (DS) and the other resistant to salt-induced hypertension (DR), were exposed to filtered air, 0.4, 1.4, or 4.0 ppm acrolein for 6 h/day, 5 days/week for 62 days. All of the DS rats exposed to 4.0 ppm acrolein died within the first 11 days, while 60% of the DR animals survived the duration of the study. Neither dose dependent blood pressure changes nor altered behavioral characteristics were evident in either rat strain following acrolein exposure. Exposure to 4.0 ppm acrolein increased the level of several serum enzymes in the DR rats which survived. This concentration of acrolein also led to pulmonary edema and a significant increase in lung connective tissue in these animals. There was a marked difference in the pulmonary pathology observed in DS and DR rats exposed to 4.0 ppm acrolein. The lungs of moribund DS rats exhibited severe airway epithelial necrosis with edema and hemorrhage, while surviving DR rats primarily showed a proliferative change. Following exposure to 0.4 and 1.4 ppm acrolein, both rat lines displayed similar pathologic changes. Epithelial hyperplasia and/or clusters of macrophages were usually found near terminal bronchiolar areas. These findings suggest that further investigation of the physiopathologic sensitivity of the DS rat line may elucidate a model for investigating the underlying characteristics of stress susceptible populations.     

Are Changes in Breathing Pattern on Exposure to Ozone Related to Changes in Pulmonary Surfactant?

Abstract

Rats respond to the inhalation of ozone with changes in breathing pattern during the exposure and the development of a pulmonary inflammatory response 24–48 h postexposure. We report experiments designed to investigate the relationships between changes in breathing pattern and the composition and surface tension-reducing properties of pulmonary surfactant immediately after the exposure. A total of 64 male Fischer 344 rats were exposed to 0.8 ppm O₃ for 4 h in 4 replicate exposures with matched purified air control exposures and 8 rats per exposure group. Those exposed to O₃ developed the rapid-shallow breathing pattern characteristic of oxidant pulmonary irritation during exposure. The rats were sacrificed immediately following the exposure, and pulmonary surfactant was isolated from samples of bronchoalveolar lavage fluid pooled from groups of eight rats. After esterification, the fatty acid methyl ester composition was measured using GC-MS. in the ozone-exposed animals, the decreases in unsaturated species (linoleic, oleic, palmitoleic, and an unidentified fatty acid) relative to the major saturated component, palmitic acid, were highly statistically significant, while stearic acid showed no significant change. Total protein in the lavage fluids of the exposed animals was not elevated, indicating that sacrifice and analysis were performed early in the O₃ injury-inflammation response sequence, and suggesting that the fatty acid changes in the pulmonary surfactant may be due in part to a direct reaction with inhaled O₃. The group mean change in breath frequency (as percent of matched purified air control values) was significantly correlated with the percent change in lnoleic acid fraction among replicate exposures, suggestive of a possible relationship between ozone-induced changes in pulmonary surfactant and changes in breathing patterns. There was no significant change in the surface pressure-area isotherms of monolayers of pulmonary surfactant upon ozone exposure. However, comparison to isotherms from an in vitro exposure of a synthetic mixture of saturated and unsaturated phospholipids suggests that changes due to the observed change in the fatty acid composition in the in vivo experiments may be too small to be observed. Furthermore, the pulmonary surfactant isolation procedure was specifically designed to recover the undamaged surfactant and may discriminate against products of reaction with ozone; hence the isotherms may not necessarily reflect the actual changes during the exposure. Further experiments to elucidate the interaction of inhaled O₃ with pulmonary surfactant and its relationship to changes in breathing pattern are discussed.     

Lung damage following whole body,but not intramuscular,exposure to median lethality dose of sarin: findings in rats and guinea pigs

Objective: Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic, volatile warfare agent. Rats and guinea pigs exposed to sarin display cholinergic excitotoxicity which includes hyper-salivation, respiratory distress, tremors, seizures, and death. Here we focused on the characterization of the airways injury induced by direct exposure of the lungs to sarin vapor and compared it to that induced by the intramuscularly route.

Materials and methods: Rats were exposed to sarin either in vapor (～1LCT50, 34.2?±?0.8?µg/l/min, 10?min) or by i.m. (～1LD50, 80?µg/kg), and lung injury was evaluated by broncho-alveolar lavage (BAL).

Results and discussion: BAL analysis revealed route-dependent effects in rats: vapor exposed animals showed elevation of inflammatory cytokines, protein, and neutrophil cells. These elevations were seen at 24?h and were still significantly higher compared to control values at 1?week following vapor exposure. These elevations were not detected in rats exposed to sarin i.m. Histological evaluation of the brains revealed typical changes following sarin poisoning independent of the route of administration. The airways damage following vapor exposure in rats was also compared to that induced in guinea pigs. The latter showed increased eosinophilia and histamine levels that constitutes an anaphylactic response not seen in rats.

Conclusions: These data clearly point out the importance of using the appropriate route of administration in studying the deleterious effects of volatile nerve agents, as well as the selection of the appropriate animal species. Since airways form major target organs for the development of injury following inhalation toxicity, they should be included in any comprehensive evaluation of countermeasures efficacy.     

Histopathologic Examinations Of Rats Treated By Chronic Inhalation Exposures To Glass Fibers

Abstract

Effects on rats of a chronic inhalation exposure to glass fibers were examined histopatho-logically with special reference to pulmonary fibrosis and tumor genesis. Twenty-seven male Wistar rats of 6 wk of age were exposed to glass fibers, the exposure concentration was 2.2 ± 0.6 mg/m³, and the mass median aerodynamic diameter 2.6 mm (the geometric standard deviation 1.9), for I yr. Among them 6 and 9 rats were sacrificed just after the 1-yr exposure period and after a further l-yr clearance period, respectively. Among 25 control rats who did not undergo the exposure, 5 and 15 rats were sacrificed at the same time as each exposure group. Twelve exposure and five control rats died during the exposure and clearance period, respectively. No tumors were found in both the exposure and control rats immediately after the inhalations. There were no pneumoconiotic nodules or interstitial fibrosis in any of the rats, though a somewhat shorter survival was observed in the exposure group than in the control group. As for the group after the clearance period, increasing macrophages aggregated around the terminal bronchioles and a small number of lung tumors; (or example, two adenomas in the exposure group, and one adenoma and one squamous-cell carcinoma in the control group were noted. Sporadic tumors in other organs were also noted. However, there was no significant difference in the occurrence of these tumors between the exposure and control groups. It was concluded that the chronically inhaled glass fibers showed no apparent promoting effects of lung fibrosis or tumor genesis in this study, although a cumulative survival rate was somewhat more diminished in the exposure group than in the control.     

Long-Term Pulmonary Histopathologic Changes in Rats Following Acute Experimental Exposure to Chlorine Gas

In this study, we aimed to investigate the long-term histopathologic changes in the lungs of rats exposed to a high concentration of chlorine gas. Twenty-four Sprague-Dawley rats were divided into three groups: the control group (group I) (n = 8), early-examined group (group II) (n = 8), and late-examined group (group III) (n = 8). In group II the lungs of rats were taken out just after the exposure, whereas in group III the lungs were taken out 45 days after the exposure. Eosinophilic liquid accumulation in alveoli and bronchi, diffuse intraalveolar edema, vascular congestion, severe perivascular edema, and free bleeding in intraalveolar and interstitial area were observed in the lungs of rats in group II. Interstitial fibrosis and thickening of the alveolar septa were observed in group III. These findings suggest that the people using these cleaning agents are at risk of harming themselves, and the victims of chlorine gas injury should be reexamined at a later period since they may have pulmonary damage even after 45 days of exposure.     

Lethal concentration of perfluoroisobutylene induces acute lung injury in mice mediated via cytokine storm,oxidative stress and apoptosis

Perfluoroisobutylene (PFIB) is a highly toxic gas that targets the lungs. Low-level inhalation of the gas can lead to acute lung injury (ALI), pulmonary edema and even death. No specific anti-PFIB drugs are currently available and the pathogenesis of PFIB-induced ALI is not fully understood. Early direct oxidative injury and a secondary hyper-inflammatory response are recognized as the primary mechanisms of PFIB-induced ALI. In the present study, our data demonstrate for the first time that a cytokine storm is associated with PFIB-induced ALI. Levels of 10 pro-inflammatory cytokines and one anti-inflammatory cytokine were significantly increased in lung tissues of PFIB-exposed mice. PFIB inhalation additionally led to significant oxidative stress in lung tissue. Inflammation-associated CD11b⁺Ly6G⁺Ly6C^int neutrophils and CD11b⁺Ly6G^-Ly6C^hi monocytes were significantly increased in blood in association with PFIB-induced ALI. Bcl-2/Bax-mediated lung cell apoptosis was significantly increased at 1?h, followed by a sustained decrease after 1?h, which was significant at 4–8?h in PFIB-exposed mice. This suppression of apoptosis is possibly associated with the Akt-signaling pathway.     

Inhalation Toxicology of Trimethylamine

Abstract

Trimethylamine (TMA) is a pungent gas that occurs in nature and has many industrial applications, including use as an intermediate in the manufacture of many chemicals. The lowest lethal concentration following a single 4-h inhalation exposure was determined to be 3500 ppm. Croups of 70 male rats each were then exposed by nose-only inhalation 6 h/d, 5 d/wk for 2 wk to either 0 (control), 75, 250, or 750 ppm TMA. Rats were sacrificed either immediately following exposure or following a 14-d recovery period. Parameters investigated included in-life observations and body weights, clinical pathology, and histopathology with organ weights. Exposure to 750 ppm produced a decreased rate of weight gain in rats. Evidence of mild, reversible, polycytnemia was also seen in these rats. Effects of TMA were present in the nose, trachea, and lungs. Degenerative changes in the nose were reversible at 75 ppm, but not at 250 or 750 ppm. Mild emphysematous alveoli were seen in lungs of rats exposed to 750 ppm immediately following the exposures, but not after a recovery period. A no-observed-effect level for TMA under these test conditions was not determined, although the nasal effects seen at 75 ppm were minimal.     

Oxygen toxicity: Protection of the lung by bacterial lipopolysaccharide (endotoxin)

Adult rats were exposed to > 95% O₂ for a 72-hr period and treated with small dosages of endotoxin (250 μg/kg/day, 1/100th LD50) during the exposure or with a single dose of endotoxin (500 μg/kg) administered just prior to the hyperoxic exposure. Endotoxin treatment increased the survival rate in hyperoxia from 12/44 (27%) for untreated rats to 38/40 (95%) for the treated animals (p < 0.05). In addition, the endotoxin-treated animals had significantly decreased O₂-induced pulmonary edema and pleural fluid accumulation compared to the untreated rats (p < 0.05). Histological examination by light microscopy demonstrated marked lung damage in the untreated. hyperoxia-exposed animal lungs (perivascular, interstitial, and alveolar edema and lung hemorrhage) but only minimal changes in the lungs of the endotoxin-treated group of animals exposed to hyperoxia. Transmission electron microscopy showed a protective action of endotoxin treatment on the pulmonary capillary endothelium, compatible with the decreased exudative changes (edema) observed in the O₂-exposed endotoxin-treated lungs. Indomethacin and methylprednisolone pretreatment failed to alter the protective action of endotoxin versus pulmonary O₂ toxicity.     

Effect of ICRF-187 on the pulmonary damage induced by hyperoxia in the rat.

Histological and ultrastructural studies were made of the lungs of rats that were exposed to 100% oxygen for 60 h and were treated with either normal saline or with ICRF-187, a bis-diketopiperazine derivative of EDTA that has the capacity to chelate iron. This metal is thought to be needed to catalyze the formation of toxic oxygen free radicals. ICRF-187 (20 mg/kg) was given intraperitoneally at approximately 12 h intervals (5 doses) during the 60 h exposure. Seven of the ten saline-treated rats exposed to oxygen died prior to the end of the study whereas only one of the 10 rats in the ICRF-187-treated group died. This difference in mortality is found to be statistically significant (P less than 0.05). All saline-treated rats showed light and electron microscopic evidence of pulmonary damage. ICRF-187 attenuated the morphologic alterations observed by light microscopy (intra-alveolar edema, inflammatory exudates and bronchiolar epithelial cell swelling and hyperplasia; P less than 0.05). In addition, electron microscopic evaluation revealed that capillary thrombi, endothelial cell alterations and alveolar epithelial cell damage also were less severe in ICRF-187-treated rats. It is concluded that ICRF-187 may provide a new and useful approach for the prevention of hyperoxia-induced pulmonary damage.