Non-selective COX inhibitors impair memory formation and short-term but not long-term synaptic plasticity.

Cyclooxygenase (COX) plays a critical role in synaptic plasticity. Therefore, long-term administration of acetylsalicylic acid (ASA) and its main metabolite, salicylate, as a COX inhibitor may impair synaptic plasticity and subsequently memory formation. Although different studies have tried to explain the effects of ASA and sodium salicylate (SS) on learning and memory, the results are contradictory and the mechanisms are not exactly known. The present study was designed to investigate the effects of long-term low-dose (equivalent to prophylactic dose) and short-term high-dose (equivalent to analgesic dose) administration of ASA and SS respectively, on spatial learning and memory and hippocampal synaptic plasticity. Animals were treated with a low dose of ASA (2 mg/ml solvated in drinking water, 6 weeks) or a high dose of SS, a metabolite of ASA, (300 mg/kg, 3 days, twice-daily, i.p). Spatial memory and synaptic plasticity were assessed by water maze performance and in vivo field potential recording from CA1, respectively. Animals treated with ASA but not SS showed a significant increase in escape latency and distance moved. Furthermore, in the probe test, animals treated with both drugs spent less time in the target quadrant zone. The paired-pulse ratio (PPR) at 20-ms inter-pulse intervals (IPI) as an index of short-term plasticity in both treated groups was significantly higher than of the control group. Interestingly, none of the administered drugs affected long-term potentiation (LTP). These data suggested that long-term inhibition of COX disrupted memory acquisition and retrieval. Interestingly, cognitive impairments happened along with short-term but not long-term synaptic plasticity disturbance.

Uncovering the contribution of enhanced central gain and altered cortical oscillations to tinnitus generation.

Various theories and their associated mechanisms have been proposed as the neural basis of phantom sound perception (tinnitus), including central gain enhancement and altered cortical oscillations. However, it remains unknown whether these cortical changes directly cause tinnitus, or simply coexist with the phantom percept. Using chronically-implanted electrodes and drug delivery cannulae in rats, we examined whether enhanced central gain and cortical oscillations are consistent across different tinnitus induction methods (noise exposure; salicylate), and if directly-inducing enhanced central gain or altered cortical oscillations via pharmacologic manipulation of inhibition along the auditory pathway would cause behavioral evidence of tinnitus. We show that, while there appeared to be no clear link between tinnitus and the presence of enhanced sound-evoked cortical activity or altered spontaneous cortical oscillations, pharmacologic impairment of GABAergic neurotransmission in the auditory cortex was sufficient to cause tinnitus; collective findings which further advance our understanding of the neural basis of tinnitus.

Loss of Cochlear Ribbon Synapse Is a Critical Contributor to Chronic Salicylate Sodium Treatment-Induced Tinnitus without Change Hearing Threshold.

Tinnitus is a common auditory disease worldwide; it is estimated that more than 10% of all individuals experience this hearing disorder during their lifetime. Tinnitus is sometimes accompanied by hearing loss. However, hearing loss is not acquired in some other tinnitus generations. In this study, we injected adult rats with salicylate sodium (SS) (200 mg/kg/day for 10 days) and found no significant hearing threshold changes at 2, 4, 8, 12, 14, 16, 20, or 24 kHz (all p > 0.05). Tinnitus was confirmed in the treated rats via Behaviour Testing of Acoustic Startle Response (ASR) and Gap Prepulse Inhibition Test of Acoustic Startle Reflex (GPIAS). A immunostaining study showed that there is significant loss of anti-CtBP2 puncta (a marker of cochlear inner hair cell (HC) ribbon synapses) in treated animals in apical, middle, and basal turns (all p < 0.05). The ABR wave I amplitudes were significantly reduced at 4, 8, 12, 14, 16, and 20 kHz (all p < 0.05). No significant losses of outer HCs, inner HCs, or HC cilia were observed (all p > 0.05). Thus, our study suggests that loss of cochlear inner HC ribbon synapse after SS exposure is a contributor to the development of tinnitus without changing hearing threshold.

Interaction between elevated temperature and different types of Na-salicylate treatment in Brachypodium dystachion.

Salicylic acid (SA) plays a role in several physiological processes in plants. Exogenously applied SA is a promising tool to reduce stress sensitivity. However, the mode of action may depend on how the treatment was performed and environmental conditions may alter the effects of SA. In the present study the physiological and biochemical effects of different modes of application (soaking seeds prior sowing; spraying leaves with 0.5 mM NaSA) were compared at normal and moderately elevated temperatures (4 h; 35°C) in Brachypodium distachyon (L.) P. Beauv. plants. While soaking the seeds stimulated plant growth, spraying caused mild stress, as indicated by the chlorophyll-a fluorescence induction parameters and changes in certain protective compounds, such as glutathione, flavonoids or antioxidant enzymes. Elevated temperature also caused an increase in the glutathione-S-transferase activity, and this increase was more pronounced in plants pre-treated with NaSA. Both seed soaking or spraying with NaSA and exposure to heat treatment at 35°C reduced the abscisic acid levels in the leaves. In contrast to abscisic acid, the jasmonic acid level in the leaves were increased by both spraying and heat treatment. The present results suggest that different modes of application may induce different physiological processes, after which plants respond differently to heat treatment. Since these results were obtained with a model plants, further experiments are required to clarify how these changes occur in crop plants, especially in cereals.

The effect of uncouplers of oxidative phosphorylation on the feeding behavior of lactating dairy cows.

Our objective was to determine the effects of uncouplers of oxidative phosphorylation on feeding behavior of lactating dairy cows. We hypothesized that uncouplers of oxidative phosphorylation would increase meal size and meal length and performed 2 experiments to test our hypothesis. In experiment 1, 4 late-lactation cows (345 ± 48.4 d in milk; mean ± SD) were administered a daily intrajugular injection of either 10 mg/kg of BW0.75 of 2,4-dinitrophenol methyl ether (DNPME) and propylene carbonate or propylene carbonate (control; CON) in a crossover design with 2-d periods. In experiment 2, 8 early-lactation cows (11.3 ± 0.89 d in milk) were administered a daily intrajugular injection via jugular catheter of either 50 mg/kg of BW of sodium salicylate (SAL) and saline or saline (control; CON) in a crossover design with 1-d periods. Feeding behavior was recorded by a computerized data acquisition system and analyzed for the first 4 h after access to feed within 15 min of treatment for both experiments. Neither DNPME nor SAL affected meal size over the first 4 h after access to feed. However, DNPME increased meal length by 6.4 min (26.3 vs. 19.9 min) and tended to decrease the number of meals (2.55 vs. 2.78 meals/4 h) over the first 4 h after access to feed compared with CON. Both DNPME and SAL decreased eating rate over the first 4 h after access to feed compared with their respective controls (0.10 vs. 0.12 kg/min for DNPME vs. CON; 0.06 vs. 0.07 kg/min for SAL vs. CON). Lack of treatment effects on meal size may have been caused by increased rate of oxidation of fuels compensating for the disruption of oxidative phosphorylation.

A nanoliter resolution implantable micropump for murine inner ear drug delivery.

Advances in protective and restorative biotherapies have created new opportunities to use site-directed, programmable drug delivery systems to treat auditory and vestibular disorders. Successful therapy development that leverages the transgenic, knock-in, and knock-out variants of mouse models of human disease requires advanced microsystems specifically designed to function with nanoliter precision and with system volumes suitable for implantation. Here we present results for a novel biocompatible, implantable, scalable, and wirelessly controlled peristaltic micropump. The micropump configuration included commercially available catheter microtubing (250 µm OD, 125 µm ID) that provided a biocompatible leak-free flow path while avoiding complicated microfluidic interconnects. Peristaltic pumping was achieved by sequentially compressing the microtubing via expansion and contraction of a thermal phase-change material located in three chambers integrated adjacent to the microtubing. Direct-write micro-scale printing technology was used to build the mechanical components of the micropump around the microtubing directly on the back of a printed circuit board assembly (PCBA). The custom PCBA was fabricated using standard commercial processes providing microprocessor control of actuation and Bluetooth wireless communication through an Android application. The results of in vitro characterization indicated that nanoliter resolution control over the desired flow rates of 10-100 nL/min was obtained by changing the actuation frequency. Applying 10× greater than physiological backpressures and ±â€¯3 °C ambient temperature variation did not significantly affect flow rates. Three different micropumps were tested on six mice for in vivo implantation of the catheter microtubing into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion. There were systematic increases in distortion product threshold shifts during the 20-min perfusions; the mean shift was 15 dB for the most basal region. A biocompatibility study was performed to evaluate material suitability for chronic subcutaneous implantation and clinical translational development. The results indicated that the micropump components successfully passed key biocompatibility tests. A micropump prototype was implanted for one month without development of inflammation or infection. Although tested here on the small murine cochlea, this low-cost design and fabrication methodology is scalable for use in larger animals and for clinical applications in children and adults by appropriate scaling of the microtubing diameter and actuator volume.

Effects of sodium salicylate on glucose kinetics and insulin signaling in postpartum dairy cows.

Low-grade inflammation has been implicated as a contributor to metabolic disease during the transition to lactation. In previous work, administration of sodium salicylate (SS) for 7 d led to hypoglycemia in mature dairy cows in early lactation. The purpose of this study was to identify the mode of action underlying this response to SS. Twenty mature (parity 3) cows were assigned alternately at time of calving to either control or SS treatments; the control received a molasses placebo in drinking water, whereas SS received 2.3 g/L of SS with the molasses carrier in drinking water for 7 d after parturition. Blood samples were collected daily. A glucose turnover assay was performed on d 7, followed by liver, muscle, and adipose tissue biopsies. There were no treatment effects on intake of dry matter or water. Tumor necrosis factor α mRNA abundance tended to be decreased by SS in adipose tissue but not in muscle or liver, and plasma haptoglobin and adiponectin concentrations were not altered by treatment. Treatment did not significantly alter plasma glucose or insulin concentrations, but plasma glucagon concentration tended to be increased by SS and the insulin:glucagon molar ratio was significantly decreased. Cows on SS had a tendency for a 25% decrease in glucose turnover rate compared with control cows. However, there were no differences in transcript abundance of pyruvate carboxylase (PC) or glucose-6-phosphatase (G6PC) in liver or of glucose transporter 4 (GLUT4) in any of the tissues. Finally, SS did not alter insulin receptor substrate-1 phosphorylation in muscle or adipose, but tended to increase phosphorylation of AMP-activated protein kinase and decrease protein kinase B phosphorylation in adipose tissue. These findings may be explained by enhanced hepatic insulin sensitivity leading to posttranscriptional suppression of gluconeogenesis and adaptive responses to decreased glucose supply in the pancreas and adipose tissue.

Sustained-Release Injectable Hydrogel Formulations for Administration of Sodium Salicylate in Broiler Chickens.

We developed injectable hydrogels for the slow release of analgesic drugs in birds as an in vivo model of pharmacokinetics in wild avian species. Hydrogels loaded with sodium salicylate (NaSA) were injected subcutaneously in Ross broiler chickens. The hydrogels were made by dissolving sodium alginate and NaSA in water at 2 different concentrations (low, LALG; high, HALG) and then adding calcium chloride. In vitro drug release studies were performed by swelling the hydrogels in water and analyzing serial samples by ultraviolet-visible (UV-Vis) spectroscopy. Dried hydrogel films of the same formulations of the two alginate concentrations then were dissolved in sterile water for the in vivo pharmacokinetic study conducted in 18 chickens divided into 3 groups of 6 birds. Each of the 2 resultant NaSA hydrogel solutions were filtered with 0.2-µm syringe filters before injecting at a NaSA dose of 150 mg/kg SC in the respective LALG or HALG groups. The control group was injected SC with the same dose of NaSA dissolved in water. Pharmacokinetics parameters calculated by the compartmental and noncompartmental approaches were compared among the 3 groups by the Kruskal-Wallis test. Results of in vitro studies showed that both hydrogels released 80% of the drug during the first 3.5 hours. Results of the pharmacokinetic study indicated that NaSA concentrations remained above the minimum effective concentration (MEC) for analgesia in humans for 24 ± 8.9 (LALG) to 26 ± 4 (HALG) hours for the hydrogel formulations compared to 10 ± 5.6 hours for the aqueous formulation. These hydrogel formulations may have potential in providing long-term analgesia in avian species, but need further evaluation with pharmacodynamic or pharmacokinetic/pharmacodynamic modeling studies.

Gelatinized-core liposomes: Toward a more robust carrier for hydrophilic molecules.

The use of liposomes as a delivery system for hydrophobic and hydrophilic drugs is well recognized. However, they possess several limitations that remained unresolved, including stability problems, low entrapment of the hydrophilic drugs, and the subsequent rapid release. This study introduces a novel approach to incorporate gelatin in the liposomal core to overcome these limitations. A rheological study was conducted to select suitable masses of the gelatin used in the liposomal formulations. Moreover, a full-factorial experimental design was utilized to compare the newly produced gel-core liposomes to the conventional liposomes with respect to the amount of a model hydrophilic molecule loading. An advanced machine learning method, namely, artificial neural networks was utilized to capture the effects of gelatin and cholesterol incorporation in the liposomes on the entrapment efficiency. The results revealed the successful preparation of the novel vesicles and their superiority over the conventional liposomes in drug loading, sustaining the drug release and stability which pose the newly introduced liposomal system as a successful delivery carrier for hydrophilic molecules and drugs. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3086-3092, 2017.

Salicylic acid analogues as chemical exchange saturation transfer MRI contrast agents for the assessment of brain perfusion territory and blood-brain barrier opening after intra-arterial infusion.

The blood-brain barrier (BBB) is a major obstacle for drug delivery to the brain. Predicted, focal opening of the BBB through intra-arterial infusion of hyperosmolar mannitol is feasible, but there is a need to facilitate imaging techniques (e.g. MRI) to guide interventional procedures and assess the outcomes. Here, we show that salicylic acid analogues (SAA) can depict the brain territory supplied by the catheter and detect the BBB opening, through chemical exchange saturation transfer (CEST) MRI. Hyperosmolar SAA solutions themselves are also capable of opening the BBB, and, when multiple SAA agents were co-injected, their locoregional perfusion could be differentiated.

Neutrophils influx and proinflammatory cytokines inhibition by sodium salicylate, unlike aspirin, in Candida albicans-induced peritonitis model.

Sodium salicylate (NaS) and aspirin (ASA) are known to have a variety of effects on microorganisms, such as fungus (C. albicans and C. neoformans), moreover, it have effects in leukocyte adhesion and migration in vitro. In this report, we investigated the effect of ASA and NaS in neutrophil migration and cytokine production in C. albicans-induced peritonitis murine model. For this, mice were treated intraperitoneally (i.p) or orally (po) with NaS or ASA; after they were stimulated i.p. with C. albicans, the cellular migration was evaluated 24 h after stimulation. NaS, in mice treated i.p., unlike ASA, was able to inhibit the neutrophil migration and proinflammatory cytokine production induced by C. albicans, such as TNF-α, IL-1, IFN-γ, IL-12, and IL-10, but did not alter the IL-4 levels in these animals. However, the po treatment with same the dose of NaS or ASA did not affect the influx of this cell for inflammatory site. These results suggest that the NaS inhibits cellular migration and proinflammatory cytokine by different anti-inflammatory mechanism compared to ASA.

Salicylic acid derivatives as potential anti asthmatic agents using disease responsive drug delivery system for prophylactic therapy of allergic asthma.

Asthma is a multi-factorial and complicated lung disorder of the immune system which has expanded to a wider ambit unveiling its etiology to be omnipresent at both ends of the spectrum involving basic pharmacology and in-depth immunology. As asthma occurs through triggered activation of various immune cells due to different stimuli, it poses a great challenge to uncover specific targets for therapeutic interventions. Recent pharmacotherapeutic approaches for asthma have been focused on molecular targeting of transcription factors and their signaling pathways; mainly nucleus factor kappa B (NFκB) and its associated pathways which orchestrate the synthesis of pro-inflammatory cytokines (IL-1ß, TNF-α, GM-CSF), chemokines (RANTES, MIP-1a, eotaxin), adhesion molecules (ICAM-1, VCAM-1) and inflammatory enzymes (cyclooxygenase-2 and iNOS). 5-aminosalicylic acid (5-ASA) and sodium salicylate are known to suppress NFκB activation by inhibiting inhibitor of kappa B kinase (IKκB). In order to target the transcription factor, a suitable carrier system for delivering the drug to the intracellular space is essential. 5-ASA and sodium salicylate loaded liposomes incorporated into PEG-4-acrylate and CCRGGC microgels (a polymer formed by crosslinking of trypsin sensitive peptide and PEG-4-acrylate) could probably suit the needs for developing a disease responsive drug delivery system which will serve as a prophylactic therapy for asthmatic patients.

Chronic sodium salicylate administration enhances population spike long-term potentiation following a combination of theta frequency primed-burst stimulation and the transient application of pentylenetetrazol in rat CA1 hippocampal neurons.

The effect of chronic administration of sodium salicylate (NaSal) on the excitability and synaptic plasticity of the rodent hippocampus was investigated. Repeated systemic treatment with NaSal reliably induced tolerance to the anti-nociceptive effect of NaSal (one i.p. injection per day for 6 consecutive days). Following chronic NaSal or vehicle treatment, a series of electrophysiological experiments on acute hippocampal slices (focusing on the CA1 circuitry) were tested whether tolerance to NaSal would augment pentylenetetrazol (PTZ)-induced long-term potentiation (LTP) and /or epileptic activity, and whether the augmentation was the same after priming activity with a natural stimulus pattern prior to PTZ. We noted an altered synaptic input-to-spike transformation, such that neuronal firing increased after a given synaptic drive. Population spike-LTP (PS-LTP) was increased in the NaSal-tolerant animals, but only when it was induced via a combination of electrical stimulation (theta pattern primed-burst stimulation) and the transient application of PTZ. Identifying and understanding these changes in neuronal excitability and synaptic plasticity following chronic salicylate treatment could prove useful in the clinical diagnosis or treatment of chronic aspirin-induced, or even idiopathic, seizure activity.

[Investigations on the acute, carrageenan-induced inflammatory reaction and pharmacology of orally administered sodium salicylate in turkeys]. / Untersuchungen zur akuten, Karrageen-induzierten Entzündungsreaktion sowie der Pharmakologie oral applizierten Natriumsalicylats bei Puten.

The complex mechanisms of acute inflammation have been subject to veterinary investigations since a long time. However, knowledge on the role of specific inflammatory mediators, as well as pharmacokinetics (PK) and -dynamics (PD) of non-steroidal anti-inflammatory drugs (NSAID) in birds is limited. The objective of this work therefore was to establish a modified tissue cage-model to investigate the acute, carrageenan-mediated inflammatory response, as well as plasma and exudate-kinetics and the antiphlogistic effect of orally administered sodium salicylate on the elicited inflammatory reaction in turkeys. Within the class Aves, comparable studies have so far only been published in chicken. Following bilateral subcutaneous implantation of carrageenan-treated synthetic sponges in the lateral thoracic region, sodium salicylate was administered orally at a dose of 50 mg/kg body weight (BW; therapy group) twice daily on three consecutive days, while a control group received drinking water as a placebo (n = 24 per group). Combined PK and PD of sodium salicylate were evaluated on the basis of salicylate- and prostaglandin (PG) E2-plasma- and -exudate-concentrations, exudate volumes, as well as leukocyte exudate counts. Sodium salicylate was readily absorbed from the gastrointestinal tract and accumulated in the inflammatory exudate. At 4, 6, and 10 h after first application, sodium salicylate significantly reduced PG E2-concentrations in the inflammatory exudate when compared to the control group, whereas leukocyte exudate counts increased over time in both study groups, unaffected by sodium salicylate The described modified tissue cage-model can be beneficial for further research on the pathophysiology of avian inflammatory processes and the investigation of the combined pharmacodynamics and -kinetics of drugs in birds of adequate size.

Pharmacokinetics of repeated sodium salicylate administration to laying hens: evidence for time dependent increase in drug elimination from plasma and eggs.

Salicylates were the first non-steroid anti-inflammatory drugs (NSAIDs) to be used in any species and are still widely used in humans and livestock. However, the data on their pharmacokinetics in animals is limited, especially after repeated administration. Evidence exist that in chickens (Gallus gallus) salicylate (SA) may induce its own elimination. The aim of this study was to investigate salicylate pharmacokinetics and egg residues during repeated administration of sodium salicylate (SS) to laying hens. Pharmacokinetics of SA was assessed during 14 d oral administration of SS at daily doses of 50 mg/kg and 200 mg/kg body weight to laying hens. On the 1st, 7th and 14th d a 24 h-long pharmacokinetic study was carried out, whereas eggs were collected daily. Salicylate concentrations in plasma and eggs were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model. Mean residence time (MRT), minimal plasma concentration (Cmin, C16h) and elimination half-life (T1/2el) of SA showed gradual decrease in layers administered with a lower dose. Total body clearance (ClB) increased. Layers administered with the higher dose showed a decrease only in the T1/2el. In the low dose group, SA was found only in the egg white and was low throughout the experiment. Egg whites from the higher dose group showed initially high SA levels which significantly decreased during the experiment. Yolk SA levels were lower and showed longer periods of accumulation and elimination. Repeated administration of SS induces SA elimination, although this effect may differ depending on the dose and production type of a chicken. Decreased plasma drug concentration may have clinical implications during prolonged SS treatment.

Additive cytotoxic effects of dihydroartemisinin and sodium salicylate on cancer cells.

BACKGROUND/AIM: The standard methods of chemotherapy in cancer treatment are expensive and pose serious health effects. The present study investigates an alternative chemotherapy by testing the combined treatment of two drugs on leukemia cells: dihydroartemisinin (DHA) and sodium salicylate (SS). MATERIALS AND METHODS: Cells were divided into 4 treatment groups: a control, treatment with DHA-only, treatment with SS-only, and treatment with both DHA and SS. Cells were counted immediately before the addition of any reagents (0-h count), and at 24, 48, and 72 h after treatment. RESULTS AND CONCLUSION: At low concentrations, the combination of DHA and SS significantly reduced cancer cell proliferation, although no synergistic interaction between the two drugs was found. Even without a clear synergistic interaction, the combination of DHA and SS provides a safe and affordable form of cancer treatment.

Round window membrane intracochlear drug delivery enhanced by induced advection.

Delivery of therapeutic compounds to the inner ear via absorption through the round window membrane (RWM) has advantages over direct intracochlear infusions; specifically, minimizing impact upon functional hearing measures. However, previous reports show that significant basal-to-apical concentration gradients occur, with the potential to impact treatment efficacy. Here we present a new approach to inner ear drug delivery with induced advection aiding distribution of compounds throughout the inner ear in the murine cochlea. Polyimide microtubing was placed near the RWM niche through a bullaostomy into the middle ear cavity allowing directed delivery of compounds to the RWM. We hypothesized that a posterior semicircular canalostomy would induce apical flow from the patent cochlear aqueduct to the canalostomy due to influx of cerebral spinal fluid. To test this hypothesis, young adult CBA/CaJ mice were divided into two groups: bullaostomy approach only (BA) and bullaostomy+canalostomy (B+C). Cochlear function was evaluated by distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) thresholds during and after middle ear infusion of salicylate in artificial perilymph (AP), applied near the RWM. The mice recovered for 1week, and were re-tested. The results demonstrate there was no significant impact on auditory function utilizing the RWM surgical procedure with or without the canalostomy, and DPOAE thresholds were elevated reversibly during the salicylate infusion. Comparing the threshold shifts for both methods, the B+C approach had more of a physiological effect than the BA approach, including at lower frequencies representing more apical cochlear locations. Unlike mouse cochleostomies, there was no deleterious auditory functional impact after 1week recovery from surgery. The B+C approach had more drug efficacy at lower frequencies, underscoring potential benefits for more precise control of delivery of inner ear therapeutic compounds.

Single high-dose dexamethasone and sodium salicylate failed to attenuate phosgene-induced acute lung injury in rats.

Life-threatening acute lung injury potentially occurs following high-level accidental exposures to phosgene gas. This situation was mirrored in rats exposed nose-only at 900-1000 mg phosgene/m(3)min. At this exposure level, previous studies on rats demonstrated sustained reflexively induced cardiopulmonary dysfunction and evidence of vascular fluid redistribution. These findings challenge the currently applied treatment strategies to mitigate the presumed non-cardiogenic lung edema by steroidal or non-steroidal anti-inflammatory drugs. This study investigates whether high doses of curatively administered dexamethasone (DX; 100 mg/kg bw, ip) and sodium salicylate (SS; 200 mg/kg bw, ip), alone or in combination, show efficacy to mitigate the phosgene-induced lung edema. Exhaled nitric oxide (eNO), animal morbidity and mortality, and increased lung weights one day postexposure served as endpoints of lung injury and drug efficacy. When applying this dosing regimen, SS showed minimal (if any) efficacy while DX, alone or in combination with SS, substantially aggravated the emerging lung edema (lung weights) with 40% mortality. The degree of acute lung injury (ALI) was mirrored by increased eNO. Its direct relationship to ALI-severity was evidenced by decreased eNO following NO-synthetase inhibitor administration (aminoguanidine-aerosol) and associated mitigation of ALI. All non-treated phosgene-exposed as well as treated but non-phosgene-exposed rats survived. This experimental evidence suggests that high-dose corticoid treatments may aggravate the pulmonary toxicity of phosgene. Similarly, this outcome supports the supposition that non-inflammatory, cardiogenic and/or neurogenic factors play a role in this type of acute lung injury.