Doses Of Acrolein Research Articles

Combined effect of chronic hypoxia and in vitro exposure to gas pollutants on airway reactivity.

This study investigated the interaction between exposure to air pollutants and chronic hypoxia (CH). We used a hypobaric chamber (14 days at barometric pressure 380 mmHg) to produce CH in rats. Exposure to various doses of acrolein or ozone did not modify the mechanical response to cholinergic agonists. Exposure to 3 microM/min acrolein did not alter epithelium-free trachea responsiveness. In contrast, direct exposure of freshly isolated myocytes to 2 and 3 microM/min acrolein enhanced the amplitude of the first intracellular [Ca(2+)] rise in response to 0.1 microM ACh and the calcium oscillation frequency in response to 10 microM ACh. CH alone did not alter smooth muscle cross-sectional area (SMA) or epithelium-plus-submucosa thickness. CH decreased maximal contractile response (maximal force normalized to SMA) but increased sensitivity (pEC(50)) to cholinergic agonists. We conclude that unlike in normoxic rats, exposure to air pollutants does not induce airway hyperresponsiveness in CH rats, although it increased calcium signaling. These results cannot be explained by change in smooth muscle accessibility, but may be linked to the effect of CH on calcium-contraction coupling.

Acrolein causes transcriptional induction of phase II genes by activation of Nrf2 in human lung type II epithelial (A549) cells

Acrolein, an α,β-unsaturated aldehyde, is by far the strongest electrophile present in cigarette smoke which is involved in several lung pathophysiological conditions. Acrolein depletes glutathione and creates thiol imbalance. Acrolein due to thiol imbalance as well as covalent modification of cysteine is known to inhibit the activity of redox sensitive transcription factors such as NF-κB and AP-1. Exposure of human type II lung epithelial (A549) cells to non-lethal dose of acrolein (150 fmol/cell for 1 h) depletes 80% of intracellular glutathione and increases the transcription of γ-glutamylcysteine synthetase (γ-GCS) at 6–12 h post-treatment, which helps in replenishing the glutathione to normal level. Acrolein treatment activates transcription of phase II genes in general, as indicated by an increase in mRNA for NAD (P) H:quinone oxidoreductase (NQO1). Western blot analysis revealed the increased level of the transcription factor, Nrf2 in the nuclear extract from acrolein treated cells. Electrophoretic mobility shift assay shows increased binding of nuclear proteins to human antioxidant response element (ARE) consensus sequence after treatment with acrolein. The involvement of Nrf2 in ARE mediated transcriptional activation in response to acrolein exposure has been confirmed by human NQO1-ARE reporter assay. The ability of acrolein to transcriptionaly activate genes responsible for phase II enzymes may form the basis of resistance against cell death and can have implications in cigarette smoke related lung carcinogenesis.

Acrolein activates mitogen-activated protein kinase signal transduction pathways in rat vascular smooth muscle cells.

Acrolein, a major component of cigarette smoke, an environmental pollutant and an endogenous lipid peroxidation product, has been implicated in the development of atherosclerosis. Although a link between vascular injury and acrolein has been indicated, the exact molecular mechanism of acrolein-induced toxicity to vasculature is unknown. In an effort to elucidate the molecular basis of acrolein-induced vascular toxicity, the possibility of the intracellular signaling system as one of the targets of acrolein-induced toxicity is investigated in the present study. Exposure of cultured rat vascular smooth muscle cells (VSMCs) to different doses of acrolein not only causes cytotoxicity but also alters cellular morphology in a concentration and time-dependent manner. VSMCs exhibit cytotoxicity to a narrow concentration range of 5-10 microg/ml and display no toxicity to 2 microg/ml acrolein even after 24 h of exposure. Furthermore, exposure to acrolein results in activation of members of the mitogen-activated protein kinase (MAPK) family and protein tyrosine kinases. The extracellular signal-regulated kinases 1 and 2 (ERK1/2), stress-activated protein kinases/c-jun NH2-terminal kinases (SAPK/JNK) and p38MAPK are effectively and transiently activated by acrolein in a concentration and time-dependent fashion. While all three MAPKs exhibit significant activation within 5 min of exposure to acrolein, maximum activation (ERK1/2 and p38MAPK) or close to maximum activation (SAPK/JNK) occurs on exposure to 5 microg/ml acrolein for 2 h. Acrolein-induced activation of MAPKs is further substantiated by the activation of transcription factors, c-jun and activator transcription factor-2 (ATF-2), by acrolein-activated SAPK/JNK and p38MAPK, respectively. Additionally several cellular proteins exhibit spectacular protein tyrosine phosphorylation, particularly in response to 2 and 5 microg/ml of acrolein. Interestingly, the acrolein-induced activation of MAPKs precedes acrolein-stimulated protein tyrosine phosphorylation, which occurs after 2 h of exposure to acrolein. However, the time course of maximum protein tyrosine phosphorylation profile corresponds to the peak activation profile of MAPKs. The activation of MAPKs and protein tyrosine phosphorylation by acrolein appears to be independent of acrolein-induced toxicity. VSMCs exposed to 2 microg/ml acrolein exhibit no toxicity but stimulates significant activation of MAPKs and protein tyrosine phosphorylation. Although acrolein-induced VSMC toxicity is not blocked by MAPK inhibitors, PD98059, an inhibitor of MAPK kinase and SB203580, an inhibitor of p38MAPK, eitheralone or in combination, each MAPK responds differently to the inhibitors. Most prominently, although SB203580, an inhibitor of both SAPK/JNK and p38MAPK, significantly inhibited acrolein-induced activation of p38MAPK, it also stimulated SAPK/JNK activation by acrolein alone and in combination with PD98059. These results provide the first evidence that the activation of both growth-regulated (ERK1/2) and stress-regulated (SAPK/JNK and p38MAPK) MAPKs as well as tyrosine kinases are involved in the mediation of acrolein-induced effects on VSMC, which may play a crucial role in vascular pathogenesis due to environmentally and endogenously produced acrolein.

Acrolein Causes Inhibitor κB-independent Decreases in Nuclear Factor κB Activation in Human Lung Adenocarcinoma (A549) Cells

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde to which humans are exposed in various situations. In the present study, the effects of sublethal doses of acrolein on nuclear factor kappaB (NF-kappaB) activation in A549 human lung adenocarcinoma cells were investigated. Immediately following a 30-min exposure to 45 fmol of acrolein/cell, glutathione (GSH) and DNA synthesis and NF-kappaB binding were reduced by more than 80%. All parameters returned to normal or supranormal levels by 8 h post-treatment. Pretreatment with acrolein completely blocked 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced activation of NF-kappaB. Cells treated for 1 h with 1 mM diethyl maleate (DEM) showed a 34 and 53% decrease in GSH and DNA synthesis, respectively. DEM also reduced NF-kappaB activation by 64% at 2 h post-treatment, with recovery to within 22% of control at 8 h. Both acrolein and DEM decreased NF-kappaB function approximately 50% at 2 h after treatment with TPA, as shown by a secreted alkaline phosphatase reporter assay. GSH returned to control levels by 8 h after DEM treatment, but proliferation remained significantly depressed for 24 h. Interestingly, DEM caused a profound decrease in NF-kappaB binding, even at doses as low as 0.125 mM that had little effect on GSH. Neither acrolein nor DEM had any effect on the levels of phosphorylated or nonphosphorylated inhibitor kappaB-alpha (IkappaB-alpha). Furthermore, acrolein decreased NF-kappaB activation in cells depleted of IkappaB-alpha by TPA stimulation in the presence of cycloheximide, demonstrating that the decrease in NF-kappaB activation was not the result of increased binding by the inhibitory protein. This conclusion was further supported by the finding that acrolein modified NF-kappaB in the cytosol prior to chemical dissociation from IkappaB with detergent. Together, these data support the conclusion that the inhibition of NF-kappaB activation by acrolein and DEM is IkappaB-independent. The mechanism appears to be related to direct modification of thiol groups in the NF-kappaB subunits.

Fumigant Action of Acrolein on Stored-Product Insects

Acrolein was investigated as a fumigant for the control of stored-product insects. When exposed in space, confused flour beetle adults, Tribolium confusum Jacqueline duVal, cigarette beetle adults, Lasioderma serricorne (F.), and black carpet beetle larvae, Attagenus unicolor (Brahm), were killed by doses of acrolein that were lower than corresponding doses of methyl bromide. However, experiments done in grain showed that when acrolein was applied in the headspace, high doses were required to kill insects in the geometric canter of the mass. In contrast, when acrolein was applied to the surface and the grain was mixed to distribute the compound, insects exposed in the grain were killed by much lower doses than when the grain was not mixed. Sorption of the acrolein on wheat was also investigated to determine the amount of compound available to insects in the interstitial spaces of the grain during a 24-h treatment. Because of the sorption characteristics of acrolein, it may have only limited use as a fumigant

Reproductive study of acrolein on two generations of rats

Four groups of 30 male and 30 female rats were intubated with 70 daily doses of acrolein at levels of 0, 1, 3, or 6 mg/kg in a dosing volume of 5 ml/kg. Rats within each dosing group ( F 0 generation) were then assigned to a 21-day period of cohabitation and dosing for females continued through cohabitation gestation and lactation. Males were euthanized after cohabitation. F 1 generation rats were chosen from pups, and a similar pretreatment, cohabitation, gestation, and lactation regimen was accomplished resulting in F 2 generation pups. Reproductive parameters, body weights, food consumption, and clinical signs were recorded and necropsies were carried out on all treated animals. Histopathologic exams were accomplished on selected reproductive tissues. In addition, gross lesions, target tissues, stomachs, and lungs were examined. For the most part, reproductive parameters were unaffected by acrolein treatment with the exception of reduced pup weights in the F 1 generation pups at the high-dose level (6 mg/kg/day). Gastric lesions were noted consistently in high-dose animals and some mid-dose (3 mg/kg/day) rats. Erosions of glandular mucosa and hyperplasia/hyperkeratosis of the forestomach were the most frequent stomach lesions observed. Effects on body weight gains were noted frequently for the high-dose animals and achieved statistical significance in the mid-dose animals on several occasions. Mortality in all high-dose animals was elevated relative to control animals. Acrolein, therefore, cannot be considered a selective reproductive toxin in the rat, but does produce toxicological effects down to a dosing level of 3 mg/kg/day.

The effects of acrolein exposure on pulmonary antibacterial defenses

Inhalation exposure to acrolein induced a dose-dependent impairment of pulmonary antibacterial defenses in mice. Animals exposed to 3 or 6 ppm of acrolein were increasinglless effective in inactivation of aerogenic challenges of 32P-labeled Staphylococcus aureus. Acrolein concentrations greater than 6 ppm caused increased sensory irritations, but no additional impairment of lung antibacterial resistance. Influenza A viral pneumonia in mice also suppressed pulmonary bactericidal activity. Mice convalescing from moderate viral pneumonia became severely deficient in antibacterial defenses when exposed to acrolein. Whether the viral-induced impairment in pulmonary defense delayed the inactivation or allowed the proliferation of bacteria was dependent upon the dose of acrolein. The present study demonstrated that an underlying infectious disease process compounded the pulmonary toxicity of acrolein such that normally moderate toxicity was elevated to a virtual abolition of antibacterial defense mechanisms.

Acrolein: A potent modulator of lung macrophage arachidonic acid metabolism

Resting rat pulmonary alveolar macrophages exposed to acrolein were stimulated to synthesize and release thromboxane B 2 and prostaglandin E 2 in a dose-dependent manner. Zymosan-activated pulmonary alveolar macrophages released approximately twice as much prostaglandin E 2 as thromboxane B 2, whereas acroleinactivated pulmonary alveolar macrophages released 4–5 times less prostaglandin E 2 than thromboxane B 2. In the zymosan-stimulated pulmonary alveolar macrophages, acrolein also induced a reversal in the relative amounts of prostaglandin E 2 and thromboxane B 2 synthesized and released into the culture medium. This reversal was achieved by a dose-dependent reduction in prostaglandin E 2 synthesis. Although phagocytosis was also inhibited in a dose-dependent manner, the reduction in prostaglandin E 2 appeared to be partially independent of particle ingestion since thromboxane B 2 synthesis was not affected by low doses of acrolein. In fact, high doses induced a slight enhancement in thromboxane B 2 synthesis. These results suggest that acrolein selectively inhibited the enzyme, prostaglandin endoperoxide E isomerase, necessary for the conversion of the endoperoxide to prostaglandin E 2. Sulfhydryl reagents such as N-ethylmaleimide and 5,5'-dithiobis ( 2-nitrobenzoic acid) mimicked acrolein's effects, and reduced glutathione afforded protection against the effects of acrolein. These results indicated the possible involvement of acrolein's sulfhydryl reactivity in the inhibition of the isomerase enzyme. Propionaldehyde had no effect on macrophage arachidonic acid metabolism whereas crotonaldehyde mimicked the effects of acrolein. Pulmonary macrophages were unable to reverse the acrolein effects on arachidonate metabolite synthesis after 6 h in an acrolein-free environment. These data indicated the necessity of the unsaturated carbon bond for the acrolein effects on arachidonic acid metabolism and the relative irreversibility of acrolein's reaction with the macrophage.

Action de l'acroléine sur les synthèses d'acides nucléiques in vivo

Summary The present work intends to study the action of acrolein on hepatic and pulmonary nucleic acid metabolism of partly hepatectomized rats. Quantity and action time of acrolein on nuclear and nucleolar nucleic acids turnover have been successively considered. At the hepatic level, the variations of DNA and RNA synthesis are parallel and are proportional to the quantity of acrolein injected. In the lung, the inhibition of DNA synthesis is proportional to the dose of acrolein injected, (between 50 an 270 μg for 100 g of rat). When acrolein acts during variable periods of time (30 mn to 6 hours), the inhibition of hepatic nuclear DNA synthesis occurs very early (30 mn), and increases with time. The inhibition of RNA synthesis occurs after a longer time (2 hours). In the lungs, the results are similar though acrolein has no effect on DNA synthesis during one hour following its injection. Acrolein does not seem to have a specific action on the system of ribosomal RNA precursors as inhibition of synthesis is similar if we study either nuclear or nucleolar hepatic nucleic acid turnover.