Maternal alcohol consumption in pregnancy enhances arterial stiffness and alters vasodilator function that varies between vascular beds in fetal sheep.

While the impact of alcohol consumption by pregnant women on fetal neurodevelopment has received much attention, the effects on the cardiovascular system are not well understood. We hypothesised that repeated exposure to alcohol (ethanol) in utero would alter fetal arterial reactivity and wall stiffness, key mechanisms leading to cardiovascular disease in adulthood. Ethanol (0.75 g (kg body weight)(-1)) was infused intravenously into ewes over 1 h daily for 39 days in late pregnancy (days 95-133 of pregnancy, term ∼147 days). Maternal and fetal plasma ethanol concentrations at the end of the hour were ∼115 mg dl(-1), and then declined to apparent zero over 8 h. At necropsy (day 134), fetal body weight and fetal brain-body weight ratio were not affected by alcohol infusion. Small arteries (250-300 µm outside diameter) from coronary, renal, mesenteric, femoral (psoas) and cerebral beds were isolated. Endothelium-dependent vasodilatation sensitivity was reduced 10-fold in coronary resistance arteries, associated with a reduction in endothelial nitric oxide synthase mRNA (P = 0.008). Conversely, vasodilatation sensitivity was enhanced 10-fold in mesenteric and renal resistance arteries. Arterial stiffness was markedly increased (P = 0.0001) in all five vascular beds associated with an increase in elastic modulus and, in cerebral vessels, with an increase in collagen Iα mRNA. Thus, we show for the first time that fetal arteries undergo marked and regionally variable adaptations as a consequence of repeated alcohol exposure. These alcohol-induced vascular effects occurred in the apparent absence of fetal physical abnormalities or fetal growth restriction.

Berkeley Open Extended Reality Recordings 2023 (BOXRR-23): 4.7 Million Motion Capture Recordings from 105,000 XR Users.

Extended reality (XR) devices such as the Meta Quest and Apple Vision Pro have seen a recent surge in attention, with motion tracking "telemetry" data lying at the core of nearly all XR and metaverse experiences. Researchers are just beginning to understand the implications of this data for security, privacy, usability, and more, but currently lack large-scale human motion datasets to study. The BOXRR-23 dataset contains 4,717,215 motion capture recordings, voluntarily submitted by 105,852 XR device users from over 50 countries. BOXRR-23 is over 200 times larger than the largest existing motion capture research dataset and uses a new, highly efficient and purpose-built XR Open Recording (XROR) file format.

Alcohol exposure during late ovine gestation alters fetal liver iron homeostasis without apparent dysmorphology.

High levels of alcohol (ethanol) exposure during fetal life can affect liver development and can increase susceptibility to infection after birth. Our aim was to determine the effects of a moderate level of ethanol exposure in late gestation on the morphology, iron status, and inflammatory status of the ovine fetal liver. Pregnant ewes were chronically catheterized at 91 days of gestation (DG; term ~145 DG) for daily intravenous infusion of ethanol (0.75 g/kg maternal body wt; n = 8) or saline (n = 7) over 1 h from 95 to 133 DG. At necropsy (134 DG), fetal livers were collected for analysis. Liver weight, general liver morphology, hepatic cell proliferation and apoptosis, perivascular collagen deposition, and interleukin (IL)-1ß, IL-6, or IL-8 mRNA levels were not different between groups. However, ethanol exposure led to significant decreases in hepatic content of ferric iron and gene expression of the iron-regulating hormone hepcidin and tumor necrosis factor (TNF)-α (all P < 0.05). In the placenta, there was no difference in transferrin receptor, divalent metal transporter 1, and ferritin mRNA levels; however, ferroportin mRNA levels were increased in ethanol-exposed animals (P < 0.05), and ferroportin protein tended to be increased (P = 0.054). Plasma iron concentration was not different between control and ethanol-exposed groups; control fetuses had significantly higher iron concentrations than their mothers, whereas maternal and fetal iron concentrations were similar in ethanol-exposed animals. We conclude that daily ethanol exposure during the third-trimester-equivalent in sheep does not alter fetal liver morphology; however, decreased fetal liver ferric iron content and altered hepcidin and ferroportin gene expression indicate that iron homeostasis is altered.

Maternal ethanol consumption by pregnant guinea pigs causes neurobehavioral deficits and increases ethanol preference in offspring.

The objective of this study was to test the hypothesis that prenatal exposure to ethanol, through maternal consumption of an aqueous ethanol solution, induces neurobehavioral deficits and increases ethanol preference in offspring. Pregnant Dunkin-Hartley-strain guinea pigs were given 24-h access to an aqueous ethanol solution (5%, v/v) sweetened with sucralose (1 g/l), or water sweetened with sucralose (1 g/l), throughout gestation. Spontaneous locomotor activity was measured in the offspring on postnatal day (PD) 10. The offspring underwent either ethanol preference testing using a two-bottle-choice paradigm beginning on PD 40 or Morris water maze testing using a hidden moving platform design beginning on PD 60. Maternal consumption of a 5% (v/v) ethanol solution (average daily dose of 2.3±0.1 g of ethanol/kg maternal body weight; range: 1.8-2.8 g/kg) decreased offspring birth weight, increased spontaneous locomotor activity, and increased preference for an aqueous ethanol solution. In the Morris water maze test, sucralose-exposed offspring decreased escape latency on the second day of testing, whereas the ethanol-exposed offspring showed no improvement. These data demonstrate that moderate maternal consumption of ethanol produces hyperactivity, enhances ethanol preference, and impairs learning and memory in guinea pig offspring.

Mechanisms of amiodarone and desethylamiodarone cytotoxicity in nontransformed human peripheral lung epithelial cells.

Amiodarone (AM) is a potent antidysrhythmic agent that can cause potentially life-threatening pulmonary fibrosis, and N-desethylamiodarone (DEA), an AM metabolite, may contribute to AM toxicity. Apoptotic cell death in nontransformed human peripheral lung epithelial 1A (HPL1A) cells was assessed by annexin V-fluorescein isothiocyanate (ann-V) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), and necrotic cell death was assessed by propidium iodide (PI) staining. The percentage of cells that were PI-positive increased more than six times with 20 µM AM and approximately doubled with 3.5 µM DEA, relative to control. The percentage of cells that were ann-V-positive decreased by more than 80% after 24-h exposure to 10 µM AM but more than doubled after 24-h incubation with 3.5 µM DEA. Incubation for 24 h with 5.0 µM DEA increased the percentage of cells that were TUNEL-positive more than six times. Incubation with AM (2.5 µM) or DEA (1-2 µM) for 24 h did not significantly alter angiotensinogen mRNA levels. Furthermore, angiotensin II (100 pM-1 µM) alone or in combination with AM or DEA did not alter cytotoxicity, and pretreatment with the angiotensin-converting enzyme inhibitor and antioxidant captopril (3-6 µM) did not protect against AM or DEA cytotoxicity. In conclusion, AM activates primarily necrotic pathways, whereas DEA activates both necrotic and apoptotic pathways, and the renin-angiotensin system does not seem to be involved in AM or DEA cytotoxicity in HPL1A cells.

Selective activation of heme oxygenase-2 by menadione.

While substantial progress has been made in elucidating the roles of heme oxygenases-1 (HO-1) and -2 (HO-2) in mammals, our understanding of the functions of these enzymes in health and disease is still incomplete. A significant amount of our knowledge has been garnered through the use of nonselective inhibitors of HOs, and our laboratory has recently described more selective inhibitors for HO-1. In addition, our appreciation of HO-1 has benefitted from the availability of tools for increasing its activity through enzyme induction. By comparison, there is a paucity of information about HO-2 activation, with only a few reports appearing in the literature. This communication describes our observations of the up to 30-fold increase in the in-vitro activation of HO-2 by menadione. This activation was due to an increase in Vmax and was selective, in that menadione did not increase HO-1 activity.

Recombinant truncated and microsomal heme oxygenase-1 and -2: differential sensitivity to inhibitors.

Recombinant truncated forms of heme oxygenase-1 and -2 (HO-1 and HO-2) were compared with their crude microsomal counterparts from brain and spleen tissue of adult male rats with respect to their inhibition by azole-based, nonporphyrin HO inhibitors. The drugs tested were an imidazole-alcohol, an imidazole-dioxolane, and a triazole-ketone. Both the recombinant and crude forms of HO-2 were similarly inhibited by the 3 drugs. The crude microsomal spleen form of HO-1 was more susceptible to inhibition than was the truncated recombinant form. This difference is attributed to the extra amino acids in the full-length enzyme. These observations may be relevant in the design of drugs as inhibitors of HO and other membrane proteins.

Chronic prenatal ethanol exposure increases disinhibition and perseverative responding in the adult guinea pig.

Cognitive and behavioural deficits, including increased impulsivity and perseveration, are associated with chronic prenatal ethanol exposure (CPEE) in humans. We tested whether these same deficits occur in the guinea pig after CPEE treatment. Pregnant guinea pigs received oral administration of ethanol (4 g/kg maternal body weight/day), or isocaloric-sucrose/pair-feeding throughout gestation. Young adult offspring were trained in lever-pressing paradigms to work for a sucrose-pellet food reward. CPEE increased No-Go, but not Go, responses in the Go/No-Go paradigm, indicative of a disinhibition deficit in these animals. Perseverative responses in the Cued Alternation task were also increased in CPEE offspring. These data show that CPEE induces behavioural deficits in the guinea pig that are remarkably similar to the executive function deficits that follow prenatal ethanol exposure in humans.

Altered water-maze search behavior in adult guinea pigs following chronic prenatal ethanol exposure: lack of mitigation by postnatal fluoxetine treatment.

Ingestion of ethanol during pregnancy can result in teratogenic effects in humans, including significant and long-lasting neurobehavioral deficits. Similar results are seen in guinea pigs with chronic prenatal ethanol exposure (CPEE) via maternal ethanol administration, which produces deficits in Morris water-maze performance and impaired hippocampal functioning (e.g., decreased long-term potentiation, LTP). In this study, we tested whether postnatal treatment with fluoxetine, a selective serotonin reuptake inhibitor, decreases some of the neurobehavioral impairments produced by CPEE. Timed, pregnant guinea pigs received oral administration of ethanol (4g/kg maternal body weight) or isocaloric sucrose pair feeding (control) for 5 days/week throughout gestation. Offspring of the CPEE and control groups were randomly assigned to receive either fluoxetine (10mg/kg body weight/day) or saline intraperitoneally from postnatal day 10 to 48. Subsequent behavioral tests in the Morris water-maze revealed a significant increase in thigmotaxic swimming in CPEE offspring without apparent signs of impairment in spatial mapping of the hidden escape platform. Measures of hippocampal short- and long-term plasticity (paired-pulse facilitation, frequency facilitation, and LTP) were unaffected by CPEE, consistent with the behavioral data indicating normal hippocampal functioning. Postnatal fluoxetine administration resulted in a significant loss of body weight, but did not affect the increased thigmotaxic swimming following CPEE. These results indicate that changes in search strategies in the water-maze might be a highly sensitive index of CPEE-induced neurobehavioral toxicity that can occur in the absence of significant hippocampal dysfunction. Further, these data demonstrate that fluoxetine, at the selected treatment regime, does not mitigate the thigmotaxic swimming response to CPEE in the guinea pig.

Effectiveness of novel imidazole-dioxolane heme oxygenase inhibitors in renal proximal tubule epithelial cells.

To enhance our understanding of the physiological roles of heme oxygenase (HO) isozymes, HO-1 (inducible) and HO-2 (constitutive), we developed novel imidazole-based HO inhibitors. Unlike the metalloporphyrins, these imidazole-dioxolane compounds are selective for the in vitro inhibition of HO with minimal effects on other heme-dependent enzymes such as nitric oxide synthase and soluble guanylyl cyclase. In the current study, we tested the hypothesis that these novel HO inhibitors are effective in intact cells by extending their application to cultured, renal proximal tubule epithelial cells (LLC-PK1). HO-1 and HO-2 protein expression was enhanced by pretreatment of cells with hemin, transduction with adenovirus encoding human HO-1, and transfection with cDNA for HO-2, respectively. Total HO activity was measured by determining the formation of carbon monoxide (CO), whereas cell viability and apoptosis were measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the expression of activated caspase-3. Gliotoxin/tumor necrosis factor-alpha (TNF-alpha) produced cytotoxicity in wild-type LLC-PK1 cells (P < 0.05) but not in HO-1 and HO-2 overexpressing or wild type cells pretreated with hemin (10 microM). The presence of imidazole-dioxolane HO inhibitors (2-25 microM) decreased cell viability (P < 0.05). A CO-releasing molecule reversed, in a dose-dependent manner, the cytotoxic effects and caspase-3 activation induced by the combination of gliotoxin/TNF-alpha and the HO inhibitors, suggesting an important role for CO in protection against renal toxicity. These data demonstrate a protective role of both HO-1 and HO-2 against gliotoxin/TNF-alpha-induced cytotoxicity in LLC-PK1 cells. The novel imidazole-dioxolane compounds can be used as effective inhibitors of HO activity in cell culture.

Effects of maternal administration of vitamins C and E on ethanol neurobehavioral teratogenicity in the guinea pig.

Consumption of ethanol during human pregnancy can produce a wide spectrum of teratogenic effects, including neurobehavioral dysfunction. This study, in the guinea pig, tested the hypothesis that chronic maternal administration of antioxidant vitamins C plus E, together with ethanol, mitigates ethanol neurobehavioral teratogenicity. Pregnant guinea pigs received one of the following four chronic oral regimens: ethanol and vitamins C plus E; ethanol and vitamin vehicle; isocaloric-sucrose/pair-feeding and vitamins C plus E; or isocaloric-sucrose/pair-feeding and vehicle. Vitamins C (250 mg) plus E (100mg) or vehicle were given daily, and ethanol (4 g/kg maternal body weight/day) (E) or isocaloric-sucrose/pair-feeding was given for 5 consecutive days followed by 2 days of no treatment each week throughout gestation. One neonate from selected litters was studied on postnatal day (PD) 0. Neurobehavioral function was determined by measuring task acquisition and task retention using an 8-day moving-platform version of the Morris water-maze task, starting on PD 45. Thereafter, in vivo electrophysiologic assessment of changes in hippocampal synaptic plasticity was conducted. There was an ethanol-induced decrease in neonatal brain weight compared with sucrose. The vitamins C plus E regimen protected hippocampal weight relative to brain weight in ethanol offspring, and mitigated the ethanol-induced deficit in the task-retention component of the water-maze task. However, in the sucrose group, this Vit regimen produced deficits in both task acquisition and task retention. The vitamins C plus E regimen did not mitigate the ethanol-induced impairment of hippocampal long-term potentiation. These results indicate that maternal administration of this high-dose vitamins C plus E regimen throughout gestation has limited efficacy and potential adverse effects as a therapeutic intervention for E neurobehavioral teratogenicity.

Imidazole-dioxolane compounds as isozyme-selective heme oxygenase inhibitors.

Several imidazole-dioxolane compounds were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds, which include (2R,4R)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-methyl-1,3-dioxolane (1) hydrochloride, are structurally distinct from metalloporphyrin HO inhibitors and lack the aminothiophenol moiety of azalanstat. They were found to be highly selective for the HO-1 isozyme (stress induced) and had substantially less inhibitory potency toward HO-2, the constitutive isozyme. These imidazole-dioxolane compounds are the first of their type known to exhibit this isozyme-selective HO inhibition.

Selectivity of imidazole-dioxolane compounds for in vitro inhibition of microsomal haem oxygenase isoforms.

Haem oxygenases (HO) are involved in the catalytic breakdown of haem to generate carbon monoxide (CO), iron and biliverdin. It is widely accepted that products of haem catabolism are involved in biological signaling in many physiological processes. Conclusions to most studies in this field have gained support from the judicious use of synthetic metalloporphyrins such as chromium mesoporphyrin (CrMP) to selectively inhibit HO. However, metalloporphyrins have also been found to inhibit other haem-dependent enzymes, such as nitric oxide synthase (NOS), cytochromes P-450 (CYPs) and soluble guanylyl cyclase (sGC), induce the expression of HO-1 or exhibit varied toxic effects. To obviate some of these problems, we have been examining non-porphyrin HO inhibitors and the present study describes imidazole-dioxolane compounds with high selectivity for inhibition of HO-1 (rat spleen microsomes) compared to HO-2 (rat brain microsomes) in vitro. (2R,4R)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-methyl-1,3-dioxolane hydrochloride) was identified as the most selective inhibitor with a concentration of 0.6 microM inhibiting HO-1(inducible) by 50% compared with 394 microM for HO-2 (constitutive). These compounds were found to have no effects on the catalytic activities of rat brain NOS and lung sGC, but were potent inhibitors of microsomal CYP2E1 and CYP3A1/3A2 activities. In conclusion, we have identified imidazole-dioxolanes that are able to inhibit microsomal HO in vitro with high selectivity for HO-1 compared to HO-2, and little or no effect on the activities of neuronal NOS and sGC. These molecules could be used to facilitate studies on the elucidation of physiological roles of HO/CO in biological systems.

Optimization of HDR brachytherapy dose distributions using linear programming with penalty costs.

Prostate cancer is increasingly treated with high-dose-rate (HDR) brachytherapy, a type of radiotherapy in which a radioactive source is guided through catheters temporarily implanted in the prostate. Clinicians must set dwell times for the source inside the catheters so the resulting dose distribution minimizes deviation from dose prescriptions that conform to patient-specific anatomy. The primary contribution of this paper is to take the well-established dwell times optimization problem defined by Inverse Planning by Simulated Annealing (IPSA) developed at UCSF and exactly formulate it as a linear programming (LP) problem. Because LP problems can be solved exactly and deterministically, this formulation provides strong performance guarantees: one can rapidly find the dwell times solution that globally minimizes IPSA's objective function for any patient case and clinical criteria parameters. For a sample of 20 prostates with volume ranging from 23 to 103 cc, the new LP method optimized dwell times in less than 15 s per case on a standard PC. The dwell times solutions currently being obtained clinically using simulated annealing (SA), a probabilistic method, were quantitatively compared to the mathematically optimal solutions obtained using the LP method. The LP method resulted in significantly improved objective function values compared to SA (P = 1.54 x 10(-7)), but none of the dosimetric indices indicated a statistically significant difference (P < 0.01). The results indicate that solutions generated by the current version of IPSA are clinically equivalent to the mathematically optimal solutions.

Spatial learning deficits induced by chronic prenatal ethanol exposure can be overcome by non-spatial pre-training.

UNLABELLED: This study tested the hypothesis that behavioural intervention, in the form of non-spatial pre-training, mitigates the deficits in spatial learning tasks induced in guinea pig offspring by chronic prenatal ethanol exposure (CPEE). Timed, pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight/day), isocaloric-sucrose/pair-feeding, or water throughout gestation. Offspring received non-spatial pre-training, in which animals were exposed to the procedural requirements of the water maze in the absence of distal spatial cues, and then were tested in both stationary-platform and moving-platform tasks with spatial cues. Saliva cortisol was quantified in non-trained and pre-trained animals before and after exposure to the water maze. RESULTS: CPEE offspring exhibited performance deficits in the stationary-platform task, and non-spatial pre-training improved performance of CPEE offspring to control levels. In contrast, non-spatial pre-training had no effect on the impaired performance of CPEE offspring in the moving-platform task. Non-trained CPEE offspring had elevated saliva cortisol concentration after water-maze exposure compared to control offspring. Moreover, pre-trained control animals exhibited a sensitization of the cortisol response after repeated exposure to the water maze, and this was not evident in pre-trained CPEE offspring. CONCLUSIONS: These data demonstrate that CPEE produced deficits in spatial learning and memory processes that were partially overcome by non-spatial pre-training; however, more difficult tasks continued to reveal cognitive deficits. For repeated exposure to the water maze, CPEE offspring achieved a level of performance that was not different from control offspring, suggesting that it is the initial rate of acquisition of new learning, rather than the overall ability to learn, that is most adversely affected by CPEE.

View-Dependent Adaptive Cloth Simulation with Buckling Compensation.

This paper describes a method for view-dependent cloth simulation using dynamically adaptive mesh refinement and coarsening. Given a prescribed camera motion, the method adjusts the criteria controlling refinement to account for visibility and apparent size in the camera's view. Objectionable dynamic artifacts are avoided by anticipative refinement and smoothed coarsening, while locking in extremely coarsened regions is inhibited by modifying the material model to compensate for unresolved sub-element buckling. This approach preserves the appearance of detailed cloth throughout the animation while avoiding the wasted effort of simulating details that would not be discernible to the viewer. The computational savings realized by this method increase as scene complexity grows. The approach produces a 2× speed-up for a single character and more than 4× for a small group as compared to view-independent adaptive simulations, and respectively 5× and 9× speed-ups as compared to non-adaptive simulations.

Measurement of endogenous carbon monoxide formation in biological systems.

Endogenous carbon monoxide (CO) formation has been measured in different biological systems using a variety of analytical procedures. The methods include gas chromatography-reduction gas detection, gas chromatography-mass spectroscopic detection, laser sensor-infrared absorption, UV-visible spectrophotometric measurement of CO-hemoglobin or CO-myoglobin complex, and formation of (14)CO from (14)C-heme formed following [2-(14)C]glycine administration. CO formation ranged from a low of 0.029 nmol/mg of protein/h in chorionic villi of term human placenta to a high of 0.28 nmol/mg of protein/h in rat olfactory receptor neurons in culture and rat liver perfusate.

Binding of acetaldehyde to human and Guinea pig placentae in vitro.

BACKGROUND: Significant interindividual variability exists following maternal alcohol consumption; not all children born to alcoholic women manifest the symptoms associated with foetal alcohol spectrum disorder (FASD). OBJECTIVE: To investigate the potential role of the placenta as a source of variability by determining if interindividual variability exists in the binding of acetaldehyde to human placenta. METHODS: Acetaldehyde was added to ten different human placental homogenates and subjected to equilibrium dialysis. Homogenates of placentae obtained from guinea pigs chronically exposed to ethanol throughout gestation were also dialysed in the presence of acetaldehyde to look for alterations in binding after chronic alcohol exposure. Nonlinear least-squares regression analysis was used to characterize the binding system involved. RESULTS: It was found that the amount of acetaldehyde bound to human placentae varied by as much as 3-fold among placentae. The binding profile of acetaldehyde was characterized as a two site binding system (Ka(1)=9.8 x 10(5)+/-0.7 x 10(5)l/mol, N(1)=1.1 x 10(-8)+/-0.7 x 10(-8)mol/g tissue; Ka(2)=1.6 x 10(4)+/-0.9 x 10(4)l/mol, N(2)=1.7 x 10(-7)+/-0.4 x 10(-7)mol/g tissue). Chronic alcohol exposure had no effect on the degree of acetaldehyde binding. CONCLUSION: This previously unidentified source of variability may partially explain why some foetuses are adversely affected by prenatal alcohol exposure while others are not.

Differential effects of pirfenidone on acute pulmonary injury and ensuing fibrosis in the hamster model of amiodarone-induced pulmonary toxicity.

Pulmonary toxicity, including fibrosis, is a serious adverse effect associated with the antidysrhythmic drug amiodarone (AM). We tested the potential usefulness of pirfenidone against AM-induced pulmonary toxicity in the hamster model. Intratracheal AM administration resulted in pulmonary fibrosis 21 days posttreatment, as evidenced by an increased hydroxyproline content and histological damage. Dietary pirfenidone administration (0.5% w/w in chow), for 3 days prior to and continuously after AM, prevented fibrosis and suppressed elevation of pulmonary transforming growth factor (TGF)-beta1 mRNA content at 7 and 21 days post-AM. Protection against AM-induced lung damage was not observed when supplementation with pirfenidone was delayed until 7 days following AM administration, suggesting that alteration of early events in AM lung toxicity is necessary for the protective effect of pirfenidone. Both AM and bleomycin, another pulmonary fibrogen, caused inflammation 24 h after intratracheal dosing, measured as increased lactate dehydrogenase activity, protein content, and cellular alterations in bronchoalveolar lavage fluid, with the response to AM markedly greater than that to bleomycin. Administration of AM, but not bleomycin, also caused whole lung mitochondrial dysfunction, alveolar macrophage death, and an influx of eosinophils into the lung, of which pirfenidone was able to decrease only the latter. We conclude that: (1) AM induces alveolar macrophage death and severe, acute pulmonary inflammation with associated eosinophilia following intratracheal administration; (2) mitochondrial dysfunction may play an early role in AM pulmonary injury; and (3) pirfenidone decreases AM-induced pulmonary fibrosis in the hamster, probably through suppression of TGF-beta1 gene expression.

Heme oxygenase expression in selected regions of term human placenta.

Carbon monoxide (CO), formed during heme oxygenase (HO)-catalyzed oxidation of heme, has been proposed to play a complementary role with nitric oxide in the regulation of placental hemodynamics. The objective of this study was to elucidate HO enzymatic activity and HO-1 (inducible) and HO-2 (constitutive) protein content in the microsomal subcellular fraction of homogenate of selected regions of placenta from normotensive and mild pre-eclamptic pregnancies. HO enzymatic activity was measured under optimized conditions by gas chromatography using CO formation as an index of activity, and HO-1 and HO-2 protein content were determined by Western immunoblot analysis. Microsomal HO activity in each of the four placental regions was not different between normotensive and mild pre-eclamptic pregnancies. Microsomal HO-2 protein content was not different between normotensive and mild pre-eclamptic pregnancies, whereas there was increased expression of microsomal HO-1 protein in chorionic villi and fetal membranes from pre-eclamptic pregnancy compared with normotensive pregnancy. Microsomal HO enzymatic activity correlated with HO-2, but not HO-1, protein content.