RESUMEN
The elemental halogens include chlorine, bromine, and phosgene. Halogen gas can be directly weaponized and employed in warfare or terrorism. Industrial stockpiles or halogen transport can provide targets for terrorist attack as well as an origin for accidental release creating a risk for potential mass-casualty incidents. Pregnant and post-partum women represent a substantial and vulnerable subset of the population who may be at particular risk during an attack or accidental exposure. We review the effects of halogen exposure on the parturient with a focus on bromine toxicity. Bromine is the most extensively studied agent in the context of pregnancy and to-date murine models form the basis for the majority of current knowledge. Pregnancy potentiates the acute lung injury after halogen exposure. In addition, halogen exposure precipitates a preeclamptic-like syndrome in mice. This phenotype is characterized by systemic and pulmonary hypertension, endothelial dysfunction, decreased cardiac output, placental injury and fetal growth restriction. This constellation contributes to increased maternal and fetal mortality observed after bromine exposure. Angiogenic imbalance is noted with overexpression of the soluble fms-like tyrosine kinase-1 (sFlt-1) form of the vascular endothelial growth factor receptor 1 reminiscent of human preeclampsia. Additional research is needed to further explore the effect of halogen gas exposure in pregnancy and to develop therapeutic interventions to mitigate risk to this unique population.
Asunto(s)
Halógenos/toxicidad , Placenta , Preeclampsia , Animales , Femenino , Retardo del Crecimiento Fetal , Ratones , Preeclampsia/inducido químicamente , Embarazo , Factor A de Crecimiento Endotelial VascularRESUMEN
α-Chlorofatty aldehydes (α-ClFALDs) and α-bromofatty aldehydes (α-BrFALDs) are produced in activated neutrophils and eosinophils. This study investigated the ability of α-BrFALD and α-ClFALD to react with the thiols of GSH and protein cysteinyl residues. Initial studies showed that 2-bromohexadecanal (2-BrHDA) and 2-chlorohexadecanal (2-ClHDA) react with GSH producing the same fatty aldehyde-GSH adduct (FALD-GSH). In both synthetic and cellular reactions, FALD-GSH production was more robust with 2-BrHDA compared with 2-ClHDA as precursor. NaBr-supplemented phorbol myristate acetate (PMA)-activated neutrophils formed more α-BrFALD and FALD-GSH compared with non-NaBr-supplemented neutrophils. Primary human eosinophils, which preferentially produce hypobromous acid and α-BrFALD, accumulated FALD-GSH following PMA stimulation. Mice exposed to Br2 gas had increased levels of both α-BrFALD and FALD-GSH in the lungs, as well as elevated systemic plasma levels of FALD-GSH in comparison to mice exposed to air. Similar relative reactivity of α-ClFALD and α-BrFALD with protein thiols was shown using click analogs of these aldehydes. Collectively, these data demonstrate that GSH and protein adduct formation are much greater as a result of nucleophilic attack of cysteinyl residues on α-BrFALD compared with α-ClFALD, which was observed in both primary leukocytes and in mice exposed to bromine gas.
Asunto(s)
Aldehídos/sangre , Bromo/sangre , Peroxidasa del Eosinófilo/sangre , Glutatión Transferasa/sangre , Peroxidasa/sangre , Animales , Bromo/administración & dosificación , Química Clic , Peroxidasa del Eosinófilo/metabolismo , Glutatión Transferasa/metabolismo , Voluntarios Sanos , Humanos , Ratones , Peroxidasa/metabolismo , Células RAW 264.7RESUMEN
Acute ozone (O3) inhalation has been shown to cause airway and pulmonary epithelial injury with accompanying inflammation responses. Robust evidence exists that O3 induces airway hyperresponsiveness (AHR) in humans and in animal models. Several pathways exist that culminate in airway smooth muscle contraction, but the mechanism(s) by which O3 elicits AHR are unclear. Here, we review the recent report by Kasahara et al. (Kasahara DI, Mathews JA, Park CY, Cho Y, Hunt G, Wurmbrand AP, Liao JK, Shore SA. Am J Physiol Lung Cell Mol Physiol 309: L736-L746, 2015.) describing the role of two Rho kinase (ROCK) isoforms in O3-induced AHR utilizing a murine haploinsufficiency model. Compared with wild-type (WT) mice, the authors report that ROCK1(+/-) and ROCK2(+/-) mice exhibited significantly reduced AHR following acute exposure to O3. Additionally, WT mice treated with fasudil, an FDA-approved ROCK1/2 inhibitor, recapitulated reduction in AHR as seen in ROCK haplotypes. It was suggested that, although the two ROCK isoforms are both induced by Rho, they have different mechanisms by which they mediate O3-induced AHR: ROCK1 via hyaluronan signaling vs. ROCK2 acting downstream of inflammation at the level of airway smooth muscle contraction. These observations provide an important framework to develop novel ROCK-targeting therapies for acute O3-induced AHR.
Asunto(s)
Ozono/efectos adversos , Isoformas de Proteínas/metabolismo , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/metabolismo , Quinasas Asociadas a rho/metabolismo , Animales , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/metabolismo , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismoRESUMEN
Cigarette smoking causes acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction and is associated with delayed mucociliary clearance and chronic bronchitis. Roflumilast is a clinically approved phosphodiesterase 4 inhibitor that improves lung function in patients with chronic bronchitis. We hypothesized that its therapeutic benefit was related in part to activation of CFTR. Primary human bronchial epithelial (HBE) cells, Calu-3, and T84 monolayers were exposed to whole cigarette smoke (WCS) or air with or without roflumilast treatment. CFTR-dependent ion transport was measured in modified Ussing chambers. Airway surface liquid (ASL) was determined by confocal microscopy. Intestinal fluid secretion of ligated murine intestine was monitored ex vivo. Roflumilast activated CFTR-dependent anion transport in normal HBE cells with a half maximal effective concentration of 2.9 nM. Roflumilast partially restored CFTR activity in WCS-exposed HBE cells (5.3 ± 1.1 µA/cm(2) vs. 1.2 ± 0.2 µA/cm(2) [control]; P < 0.05) and was additive with ivacaftor, a specific CFTR potentiator approved for the treatment of CF. Roflumilast improved the depleted ASL depth of HBE monolayers exposed to WCS (9.0 ± 3.1 µm vs. 5.6 ± 2.0 µm [control]; P < 0.05), achieving 79% of that observed in air controls. CFTR activation by roflumilast also induced CFTR-dependent fluid secretion in murine intestine, increasing the wet:dry ratio and the diameter of ligated murine segments. Roflumilast activates CFTR-mediated anion transport in airway and intestinal epithelia via a cyclic adenosine monophosphate-dependent pathway and partially reverses the deleterious effects of WCS, resulting in augmented ASL depth. Roflumilast may benefit patients with chronic obstructive pulmonary disease with chronic bronchitis by activating CFTR, which may also underlie noninfectious diarrhea caused by roflumilast.
Asunto(s)
Aminopiridinas/farmacología , Benzamidas/farmacología , Bronquios/efectos de los fármacos , Bronquitis Crónica/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/agonistas , Células Epiteliales/efectos de los fármacos , Inhibidores de Fosfodiesterasa 4/farmacología , Aminofenoles/farmacología , Aminopiridinas/toxicidad , Animales , Benzamidas/toxicidad , Bronquios/metabolismo , Bronquios/fisiopatología , Bronquitis Crónica/metabolismo , Bronquitis Crónica/fisiopatología , Células Cultivadas , AMP Cíclico , Ciclopropanos/farmacología , Ciclopropanos/toxicidad , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Diarrea/inducido químicamente , Diarrea/metabolismo , Relación Dosis-Respuesta a Droga , Células Epiteliales/metabolismo , Humanos , Secreciones Intestinales/metabolismo , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Potenciales de la Membrana , Ratones , Depuración Mucociliar/efectos de los fármacos , Inhibidores de Fosfodiesterasa 4/toxicidad , Quinolonas/farmacología , Humo/efectos adversos , Fumar/efectos adversos , Factores de TiempoRESUMEN
Background Circulating levels of sFLT-1 (soluble fms-like tyrosine kinase 1), the extracellular domain of vascular endothelial growth factor (VEGF) receptor 1, and its ratio to levels of placental growth factor are markers of the occurrence and severity of preeclampsia. Methods and Results C57BL/6 pregnant mice on embryonic day 14.5 (E14.5), male, and non-pregnant female mice were exposed to air or to Br2 at 600 ppm for 30 minutes and were treated with vehicle or with VEGF-121 (100 µg/kg, subcutaneously) daily, starting 48 hours post-exposure. Plasma, bronchoalveolar lavage fluid, lungs, fetuses, and placentas were collected 120 hours post-exposure. In Br2-exposed pregnant mice, there was a time-dependent and significant increase in plasma levels of sFLT-1 which correlated with increases in mouse lung wet/dry weights and bronchoalveolar lavage fluid protein content. Supplementation of exogenous VEGF-121 improved survival and weight gain, reduced lung wet/dry weights, decreased bronchoalveolar lavage fluid protein levels, enhanced placental development, and improved fetal growth in pregnant mice exposed to Br2. Exogenous VEGF-121 administration had no effect in non-pregnant mice. Conclusions These results implicate inhibition of VEGF signaling driven by sFLT-1 overexpression as a mechanism of pregnancy-specific injury leading to lung edema, maternal mortality, and fetal growth restriction after bromine gas exposure.
Asunto(s)
Retardo del Crecimiento Fetal/prevención & control , Pulmón/efectos de los fármacos , Placenta/efectos de los fármacos , Edema Pulmonar/prevención & control , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Animales , Bromo , Modelos Animales de Enfermedad , Femenino , Desarrollo Fetal/efectos de los fármacos , Retardo del Crecimiento Fetal/sangre , Retardo del Crecimiento Fetal/inducido químicamente , Retardo del Crecimiento Fetal/fisiopatología , Inyecciones Subcutáneas , Pulmón/patología , Ratones Endogámicos C57BL , Placenta/patología , Placentación/efectos de los fármacos , Embarazo , Edema Pulmonar/sangre , Edema Pulmonar/inducido químicamente , Edema Pulmonar/patología , Transducción de Señal , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
Inhalation of oxidant gases has been implicated in adverse outcomes in pregnancy, but animal models to address mechanisms and studies to identify potential pregnancy-specific therapies are lacking. Herein, we show that inhalation of bromine at 600 parts per million for 30 minutes by pregnant mice on the 15th day of embryonic development results in significantly lower survival after 96 hours than an identical level of exposure in nonpregnant mice. On the 19th embryonic day, bromine-exposed pregnant mice have increased systemic blood pressure, abnormal placental development, severe fetal growth restriction, systemic inflammation, increased levels of circulating antiangiogenic short fms-like tyrosine kinase-1, and evidence of pulmonary and cardiac injury. Treatment with tadalafil, an inhibitor of type 5 phosphodiesterase, by oral gavage 1 hour post-exposure and then once daily thereafter, attenuated systemic blood pressures, decreased inflammation, ameliorated pulmonary and cardiac injury, and improved maternal survival (from 36% to 80%) and fetal growth. These pathological changes resemble those seen in preeclampsia. Nonpregnant mice did not exhibit any of these pathological changes and were not affected by tadalafil. These findings suggest that pregnant women exposed to bromine may require particular attention and monitoring for signs of preeclampsia-like symptoms.