Nanodomains in cardiopulmonary disorders and the impact of air pollution

Air pollution is a major environmental threat and each year about 7 million people reported to die as a result of air pollution. Consequently, exposure to air pollution is linked to increased morbidity and mortality world-wide. Diesel automotive engines are a major source of urban air pollution in the western societies encompassing particulate matter and diesel exhaust particles (DEP). Air pollution is envisioned as primary cause for cardiovascular dysfunction, such as ischemic heart disease, cardiac dysrhythmias, heart failure, cerebrovascular disease and stroke. Air pollution also causes lung dysfunction, such as chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and specifically exacerbations of these diseases. DEP induces inflammation and reactive oxygen species production ultimately leading to mitochondrial dysfunction. DEP impair structural cell function and initiate the epithelial-to-mesenchymal transition, a process leading to dysfunction in endothelial as well as epithelial barrier, hamper tissue repair and eventually leading to fibrosis. Targeting cyclic adenosine monophosphate (cAMP) has been implicated to alleviate cardiopulmonary dysfunction, even more intriguingly cAMP seems to emerge as a potent regulator of mitochondrial metabolism. We propose that targeting of the mitochondrial cAMP nanodomain bear the therapeutic potential to diminish air pollutant - particularly DEP - induced decline in cardiopulmonary function

Dimethyl Fumarate Attenuates Lung Inflammation and Oxidative Stress Induced by Chronic Exposure to Diesel Exhaust Particles in Mice

Air pollution is mainly caused by burning of fossil fuels, such as diesel, and is associated with increased morbidity and mortality due to adverse health effects induced by inflammation and oxidative stress. Dimethyl fumarate (DMF) is a fumaric acid ester and acts as an antioxidant and anti-inflammatory agent. We investigated the potential therapeutic effects of DMF on pulmonary damage caused by chronic exposure to diesel exhaust particles (DEPs). Mice were challenged with DEPs (30 µg per mice) by intranasal instillation for 60 consecutive days. After the first 30 days, the animals were treated daily with 30 mg/kg of DMF by gavage for the remainder of the experimental period. We demonstrated a reduction in total inflammatory cell number in the bronchoalveolar lavage (BAL) of mice subjected to DEP + DMF as compared to those exposed to DEPs alone. Importantly, DMF treatment was able to reduce lung injury caused by DEP exposure. Intracellular total reactive oxygen species (ROS), peroxynitrite (OONO), and nitric oxide (NO) levels were significantly lower in the DEP + DMF than in the DEP group. In addition, DMF treatment reduced the protein expression of kelch-like ECH-associated protein 1 (Keap-1) in lung lysates from DEP-exposed mice, whereas total nuclear factor κB (NF-κB) p65 expression was decreased below baseline in the DEP + DMF group compared to both the control and DEP groups. Lastly, DMF markedly reduced DEP-induced expression of nitrotyrosine, glutathione peroxidase-1/2 (Gpx-1/2), and catalase in mouse lungs. In summary, DMF treatment effectively reduced lung injury, inflammation, and oxidative and nitrosative stress induced by chronic DEP exposure. Consequently, it may lead to new therapies to diminish lung injury caused by air pollutants

EEG for Diagnosis and Prognosis of Acute Nonhypoxic Encephalopathy: History and Current Evidence

The term encephalopathy encompasses a wide variety of complex syndromes caused by a large number of different toxic, metabolic, infectious, and degenerative derangements. Acute encephalopathy typically presents with a fluctuating course involving alteration of mental status or confusion and decreased (or rarely increased) motor activity. There usually are lethargy, cognitive impairment, altered memory and mental processing of information, and disturbed sleep-wake cycles. Encephalopathy mainly occurs in the elderly and is frequently encountered in intensive care units and postoperatively. Despite new diagnostic procedures and advances in intensive medical care, acute encephalopathy constitutes a significant cause of morbidity and mortality in hospitalized patients. EEG enables rapid bedside electrophysiological monitoring providing dynamic real-time information on neocortical brain activity and dysfunction. Hence, EEG complements clinical and neuroimaging assessments of encephalopathic patients. Progressive slowing of EEG background activity with increasing cerebral compromise, the emergence of episodic electrographic transients, seizures, and decreased EEG reactivity to external stimuli provide important diagnostic and prognostic information. The aim of this review was to provide a comprehensive overview of the current evidence for the diagnostic and prognostic value of EEG in adult intensive care unit patients with acute nonhypoxic encephalopathy

Independent impact of infections on the course and outcome of status epilepticus: a 10-year cohort study

Infections are frequent in patients with status epilepticus (SE). It remains unclear if infections merely reflect severity of the underlying illness or if they independently predict unfavourable course and outcome. We sought to determine if infections diagnosed within 48 h from SE onset are independent predictors of poor course and outcome and if their effect is modified by clinical characteristics. From 2005 to 2014, pertinent clinical data, microbiology, death, return to functional baseline, and unfavourable outcome in survivors were assessed in SE patients treated in the intensive care units (ICU) of an academic medical care center. Among 352 consecutive patients, 81 (23 %) were diagnosed with infections at SE onset. In-hospital mortality was higher in patients with infections (26 %) compared to 10 % in patients without infections (p < 0.001). Infections at SE onset increased the odds ratios (OR) for prolonged ICU (OR = 4.1, 95 %CI 1.87-6.74) and hospital stay (OR = 5.4, 95 %CI 1.24-9.63), refractory SE (OR = 3.1, 95 %CI 1.79-5.34), prolonged mechanical ventilation (OR = 3.8, 95 %CI 2.15-6.79), no return to functional baseline (OR = 2.1, 95 %CI 1.10-4.02), unfavourable outcome in survivors (OR = 2.0, 95 %CI 1.02-3.81), and death (OR = 2.5, 95 %CI 1.28-4.99). All associations were independent of confounders and without significant effect modification by age, level of consciousness, types and severity of SE, and etiologies. In addition, the number of infections increased the probability of unfavourable course and outcome. Infections at SE onset are frequent and associated with prolonged medical care, treatment refractory SE, higher morbidity and mortality independently of potential confounders calling for the evaluation of treatment strategies

Function of cyclic AMP scaffolds in obstructive lung disease: Focus on epithelial-to-mesenchymal transition and oxidative stress

Over the past decades, research has defined cyclic adenosine monophosphate (cAMP) as one of the central cellular nodes in sensing and integrating multiple pathways, and as a pivotal role player in lung pathophysiology. Obstructive lung disorders, such as chronic obstructive pulmonary disease (COPD), are characterized by a persistent and progressive airflow limitation, and by oxidative stress from endogenous and exogenous insults. The extent of airflow obstruction relies on the relative deposition of different constituents of the extracellular matrix - a process related to epithelial-to-mesenchymal transition, and which subsequently results in airway fibrosis. Oxidative stress from endogenous but also from exogenous sources causes a profound worsening of COPD. The following sections will describe how cAMP scaffolds and their distinguished signalosomes in different subcellular compartments may contribute to COPD. Future research will require translational studies to alleviate disease symptoms by pharmacologically targeting the cAMP scaffolds

Propolis reversed cigarette smoke-induced emphysema through macrophage alternative activation independent of Nrf2

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COPD Patients Exhibit Distinct Gene Expression, Accelerated Cellular Aging, and Bias to M2 Macrophages

COPD, one of world’s leading contributors to morbidity and mortality, is characterized by airflow limitation and heterogeneous clinical features. Three main phenotypes are proposed: overlapping asthma/COPD (ACO), exacerbator, and emphysema. Disease severity can be classified as mild, moderate, severe, and very severe. The molecular basis of inflammatory amplification, cellular aging, and immune response are critical to COPD pathogenesis. Our aim was to investigate EP300 (histone acetylase, HAT), HDAC 2 (histone deacetylase), HDAC3, and HDAC4 gene expression, telomere length, and differentiation ability to M1/M2 macrophages. For this investigation, 105 COPD patients, 42 smokers, and 73 non-smoker controls were evaluated. We identified a reduced HDAC2 expression in patients with mild, moderate, and severe severity; a reduced HDAC3 expression in patients with moderate and severe severity; an increased HDAC4 expression in patients with mild severity; and a reduced EP300 expression in patients with severe severity. Additionally, HDAC2 expression was reduced in patients with emphysema and exacerbator, along with a reduced HDAC3 expression in patients with emphysema. Surprisingly, smokers and all COPD patients showed telomere shortening. COPD patients showed a higher tendency toward M2 markers. Our data implicate genetic changes in COPD phenotypes and severity, in addition to M2 prevalence, that might influence future treatments and personalized therapies

Modulation of Alveolar Macrophage Activity by Eugenol Attenuates Cigarette-Smoke-Induced Acute Lung Injury in Mice

This study investigates the role of eugenol (EUG) on CS-induced acute lung injury (ALI) and how this compound is able to modulate macrophage activity. C57BL/6 mice were exposed to 12 cigarettes/day/5days and treated 15 min/day/5days with EUG. Rat alveolar macrophages (RAMs) were exposed to CSE (5%) and treated with EUG. In vivo, EUG reduced morphological changes inflammatory cells, oxidative stress markers, while, in vitro, it induced balance in the oxidative stress and reduced the pro-inflammatory cytokine release while increasing the anti-inflammatory one. These results suggest that eugenol reduced CS-induced ALI and acted as a modulator of macrophage activity