Murine Lung Responses to Ambient Particulate Matter: Genomic Analysis and Influence on Airway Hyperresponsiveness

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The mechanistic links between exposure to airborne particulate matter (PM) pollution and the associated increases in cardiovascular morbidity and mortality, particularly in people with congestive heart failure (CHF), have not been identified. To advance understanding of this issue, genetically engineered mice (CREB A133 ) exhibiting severe dilated cardiomyopathic changes were exposed to ambient PM collected in Baltimore. CREB A133 mice, which display aberrant cardiac physiology and anatomy reminiscent of human CHF, displayed evidence of basal autonomic aberrancies (compared with wild-type mice) with PM exposure via aspiration, producing significantly reduced heart rate variability, respiratory dysynchrony, and increased ventricular arrhythmias. Carotid body afferent nerve responses to hypoxia and hyperoxia-induced respiratory depression were pronounced in PM-challenged CREB A133 mice, and denervation of the carotid bodies significantly reduced PM-mediated cardiac arrhythmias. Genome-wide expression analyses of CREB A133 left ventricular tissues demonstrated prominent Na 1 and K 1 channel pathway gene dysregulation. Subsequent PM challenge increased tyrosine phosphorylation and nitration of the voltage-gated type V cardiac muscle a-subunit of the Na 1 channel encoded by SCN5A. Ranolazine, a Na 1 channel modulator that reduces late cardiac Na 1 channel currents, attenuated PM-mediated cardiac arrhythmias and shortened PMelongated QT intervals in vivo. These observations provide mechanistic insights into the epidemiologic findings in susceptibility of human CHF populations to PM exposure. Our results suggest a multiorgan pathobiology inherent to the CHF phenotype that is exaggerated by PM exposure via heightened carotid body sensitivity and cardiac Na 1 channel dysfunction.

Section: Pm Characteristicsmentioning

confidence: 99%

Particulate Matter Induces Cardiac Arrhythmias via Dysregulation of Carotid Body Sensitivity and Cardiac Sodium Channels

Wang¹,

Lang²,

Moreno‐Vinasco³

et al. 2012

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“…Total lung RNA was extracted with a TRIzol/RNeasy kit (Invitrogen, Carlsbad, CA), as previously reported (18). Gene expression analysis was performed with Affymetrix Rat expression set 230_2.…”

Section: Rna Isolation and Microarraymentioning

confidence: 99%

A Sphingosine 1–Phosphate 1 Receptor Agonist Modulates Brain Death–Induced Neurogenic Pulmonary Injury

Sammani

Park

Zaidi

et al. 2011

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Lung transplantation remains the only viable therapy for patients with end-stage lung disease. However, the full utilization of this strategy is severely compromised by a lack of donor lung availability. The vast majority of donor lungs available for transplantation are from individuals after brain death (BD). Unfortunately, the early autonomic storm that accompanies BD often results in neurogenic pulmonary edema (NPE), producing varying degrees of lung injury or leading to primary graft dysfunction after transplantation. We demonstrated that sphingosine 1-phosphate (S1P)/analogues, which are major barrier-enhancing agents, reduce vascular permeability via the S1P1 receptor, S1PR1. Because primary lung graft dysfunction is induced by lung vascular endothelial cell barrier dysfunction, we hypothesized that the S1PR1 agonist, SEW-2871, may attenuate NPE when administered to the donor shortly after BD. Significant lung injury was observed after BD, with increases of approximately 60% in bronchoalveolar lavage (BAL) total protein, cell counts, and lung tissue wet/dry (W/D) weight ratios. In contrast, rats receiving SEW-2871 (0.1 mg/kg) 15 minutes after BD and assessed after 4 hours exhibited significant lung protection (z 50% reduction, P ¼ 0.01), as reflected by reduced BAL protein/albumin, cytokines, cellularity, and lung tissue wet/dry weight ratio. Microarray analysis at 4 hours revealed a global impact of both BD and SEW on lung gene expression, with a differential gene expression of enriched immune-response/inflammation pathways across all groups. Overall, SEW served to attenuate the BD-mediated up-regulation of gene expression. Two potential biomarkers, TNF and chemokine CC motif receptor-like 2, exhibited gene array dysregulation. We conclude that SEW-2871 significantly attenuates BD-induced lung injury, and may serve as a potential candidate to improve human donor availability.Keywords: neurogenic pulmonary edema; lung injury; sphingosine 1-phosphate; sphingolipids; lung transplant donors Over the past decade, lung transplantation has become an increasingly important mode of therapy for patients with a variety of endstage lung diseases. The vast majority of lung donors are individuals with brain death (BD). However, the early autonomic storm accompanying brain BD triggers the development of systemic and pulmonary inflammatory responses, which lead to increased pulmonary endothelial permeability (1, 2) and to the sympathetic vasoconstriction of the systemic and pulmonary vasculature. These changes, in addition to possible ischemiareperfusion injury, disrupt the integrity of the alveolar capillary membrane, resulting in neurogenic pulmonary edema (NPE) (1-4). Increased pulmonary interstitial and alveolar fluid accumulation usually develops rapidly after acute injury to the central nervous system (1), and any preventive treatment should be given early after BD (3). This lung injury mimics a form of acute respiratory distress syndrome (ARDS), the most devastating form of acute lung injury (ALI), with excessive ...

“…We recently described in a murine model strong evidence for PM-mediated vascular barrier dysfunction with increased protein leakage into bronchoalveolar lavage (BAL) (9), a marker of acute inflammatory lung damage (10). Increased endothelial monolayer permeability is also observed in inflammatory pulmonary conditions, such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis (11), and devastating lung disorders with mortality exceeding 30% (12), as well as more subacute and chronic inflammatory disorders such as asthma.…”

mentioning

confidence: 99%

Particulate Matter Disrupts Human Lung Endothelial Barrier Integrity via ROS- and p38 MAPK–Dependent Pathways

Wang¹,

Chiang²,

Moreno‐Vinasco³

et al. 2010

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Epidemiologic studies have linked exposure to airborne pollutant particulate matter (PM) with increased cardiopulmonary mortality and morbidity. The mechanisms of PM-mediated lung pathophysiology, however, remain unknown. We tested the hypothesis that PM, via enhanced oxidative stress, disrupts lung endothelial cell (EC) barrier integrity, thereby enhancing organ dysfunction. Using PM collected from Ft. McHenry Tunnel (Baltimore, MD), we assessed PM-mediated changes in transendothelial electrical resistance (TER) (a highly sensitive measure of barrier function), reactive oxygen species (ROS) generation, and p38 mitogen-activated protein kinase (MAPK) activation in human pulmonary artery EC. PM induced significant dose (10-100 mg/ml)-and time (0-10 h)-dependent EC barrier disruption reflected by reduced TER values. Exposure of human lung EC to PM resulted in significant ROS generation, which was directly involved in PM-mediated EC barrier dysfunction, as N-acetyl-cysteine (NAC, 5 mM) pretreatment abolished both ROS production and barrier disruption induced by PM. Furthermore, PM induced p38 MAPK activation and HSP27 phosphorylation, events that were both attenuated by NAC. In addition, PM-induced EC barrier disruption was partially prevented by the p38 MAP kinase inhibitor SB203580 (10 mM) as well as by reduced expression of either p38 MAPK b or HSP27 (siRNA). These results demonstrate that PM induces ROS generation in human lung endothelium, resulting in oxidative stress-mediated EC barrier disruption via p38 MAPK-and HSP27-dependent pathways. These findings support a novel mechanism for PM-induced lung dysfunction and adverse cardiopulmonary outcomes.Keywords: endothelial permeability; HSP27; particulate matter; p38 MAP kinase; ROS Growing epidemiologic evidence supports the linkage of exposure to ambient particulate matter (PM) to deleterious cardiopulmonary health effects and increased cardiopulmonary mortality and morbidity (1). Exposure risk is especially increased in susceptible populations including individuals with asthma, chronic obstructive pulmonary disease (COPD), cardiac arrhythmias, and congestive heart failure (CHF). Various mechanisms have been proposed to explain the cardiopulmonary health effects of PM, including pulmonary and systemic oxidative stress and inflammation (2), enhanced coagulation (3), and altered cardiac autonomic function (4).After inhalation, fine/ultrafine PM passes rapidly into systemic circulation, potentially interacting with endothelial cells (ECs) (5) with induction of atherosclerotic plaque formation (6), endothelium-dependent dilation in the systemic microcirculation (7), and increased oxidative stress in vascular EC via NAD(P)H oxidase and mitochondrial pathways (8). Although the actual mechanism(s) for PM-mediated acceleration of cardiopulmonary events is unknown, it is likely to be multifaceted, with endothelial dysfunction as a critical component.We recently described in a murine model strong evidence for PM-mediated vascular barrier dysfunction with increased prote...