Pulmonary toxicity of e-cigarettes Chun, Lauren F; Moazed, Farzad; Calfee, Carolyn S ...
American journal of physiology. Lung cellular and molecular physiology,
08/2017, Letnik:
313, Številka:
2
Journal Article
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Electronic cigarettes (e-cigarettes or e-cigs) are designed to heat and aerosolize mixtures of vegetable glycerin, propylene glycol, nicotine, and flavoring additives, thus delivering nicotine by ...inhalation in the absence of combustion. These devices were originally developed to facilitate smoking cessation and have been available in the United States for over a decade. Since 2010, e-cig use has expanded rapidly, especially among adolescents, despite a paucity of short- and long-term safety data. Patterns of use have shifted to include never smokers and many dual users of e-cigs and combustible tobacco products. Over the last several years, research into the potential toxicities of e-cig aerosols has grown exponentially. In the interim, regulatory policymakers across the world have struggled with how to regulate an increasingly diverse array of suppliers and products, against a backdrop of strong advocacy from users, manufacturers, and tobacco control experts. Herein we provide an updated review of the pulmonary toxicity profile of these devices, summarizing evidence from cell culture, animal models, and human subjects. We highlight the major gaps in our current understanding, emphasize the challenges confronting the scientific and regulatory communities, and identify areas that require more research in this important and rapidly evolving field.
In this issue of the Journal, Morrison and colleagues (pp. 1275-1286) report that conditioned media (CM) of bone marrow-derived mesenchymal stromal cells (MSCs) (MSC-CM) contain extracellular ...vesicles that alter the function of macrophages so that they acquire the capacity to reduce experimental acute lung injury (2). For the in vitro studies, human-derived monocytes were differentiated into alveolar-like macrophages that produced increased quantities of tumor necrosis factor (TNF)-a and IL-8 when exposed to endotoxin or bronchoalveolar lavage from patients with acute respiratory distress syndrome (ARDS). ...independent of extracellular vesicles, several secreted soluble factors are present in MSC-CM, including IL-1 receptor antagonist, tumor necrosis-stimulated gene 6 protein, keratinocyte growth factor, angiopoietin-1, lipoxin A4, and prostaglandin E2, all of which have therapeutic effects experimentally in acute lung injury (14). ...MSCs have been effective in neonatal models of perinatal lung injury (17). ...it is possible that the direct cell contact from intact MSCs in the acutely injured organ might generate soluble factors that can diffuse through the injured tissues and release exosomes and microvesicles that transfer to injured cells and favorably affect the resolution properties of recruited monocytes and tissue macrophages.
Biomarkers can prognosticate outcome and enable risk-stratification. In severe infection, focusing on multiple markers reflecting pathophysiological mechanisms of organ injury could enhance ...management and pathway-directed therapeutics. Limited data exist on the performance of multiplex biomarker platforms. Our goal was to compare endothelial and immune activation biomarkers in severe pediatric infections using two multiplex platforms. Frozen plasma from 410 children presenting to the Jinja Regional Hospital in Uganda with suspected infection was used to measure biomarkers of endothelial (Angiopoietin-2, sFlt-1, sVCAM-1, sICAM-1) and immune (IL-6, IP-10, sTNFR-1, CHI3L1) activation. Two multiplex platforms (Luminex®, EllaTM) based on monoclonal antibody sandwich immunoassays using biotin-streptavidin conjugate chemistry were selected with reagents from R&D Systems. The two platforms differed in ease and time of completion, number of samples per assay, and dynamic concentration range. Intra-assay variability assessed using a coefficient of variation (CV%) was 2.2-3.4 for Luminex® and 1.2-2.9 for EllaTM. Correlations for biomarker concentrations within dynamic range of both platforms were best for IL-6 (ρ = 0.96, p<0.0001), IP-10 (ρ = 0.94, p<0.0001) and sFlt-1 (ρ = 0.94, p<0.0001). Agreement between concentrations obtained by both methods assessed by the Bland-Altman test varied, with best agreement for CHI3L1. Our data suggest that biomarkers of endothelial and immune activation can be readily measured with multiplex platforms. Luminex® and EllaTM produced reliable results with excellent CV% values. The EllaTM platform was more automated and completed in 75 minutes, potentially compatible with near-patient use. Trends in concentrations obtained by these methods were highly correlated, although absolute values varied, suggesting caution is required when comparing data from different multiplex platforms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although substantial progress has been made in the treatment and prevention of COVID-19, more effective treatments for patients with COVID-19 who require hospitalization are still needed. One ...promising immunomodulatory strategy is inhibition of interleukin 6 (IL-6), based on the hypothesis that SARS-CoV-2 creates injury to the lung and other organs in part through activation of cytokine and downstream proinflammatory networks. While several clinical trials have investigated the effect of IL-6 receptor antagonists (IL-6ra) in patients with COVID-19, the results have not been consistent, with some trials reporting benefit and others no benefit. Investigators from the World Health Organization Rapid Evidence Appraisal for COVID Therapies (REACT) Working Group have provided a much-needed meta-analysis of 27 randomized trials of IL-6ra that included 10,930 patients with COVID-19 who were treated between Oct 2020 and Jan 2021.
Matthay et al discuss the study by Hue and colleagues that compared patients with COVID-19 acute respiratory distress syndrome (ARDS) to patients who had classical ARDS. ARDS from severe acute ...respiratory syndrome coronavirus 2 (SARS-CoV-2) viral pneumonia has been the most serious and lethal consequence of coronavirus disease (COVID-19) since the pandemic began in March of 2020. Currently there have been 8 million cases of COVID-19 in the US and over 220,000 deaths. In the study, the patients with COVID-19 ARDS displayed a phenotype of impaired adaptive immune responses that was associated with severe lymphopenia and delayed lymphocyte activation.
Recent research on extracellular vesicles (EVs) has provided new insights into pathogenesis and potential therapeutic options for acute respiratory distress syndrome (ARDS). EVs are membrane-bound ...anuclear structures that carry important intercellular communication mechanisms, allowing targeted transfer of diverse biologic cargo, including protein, mRNA, and microRNA, among several different cell types. In this review, we discuss the important role EVs play in both inducing and attenuating inflammatory lung injury in ARDS as well as in sepsis, the most important clinical cause of ARDS. We discuss the translational challenges that need to be overcome before EVs can also be used as prognostic biomarkers in patients with ARDS and sepsis. We also consider how EVs may provide a platform for novel therapeutics in ARDS.
Pathologic features of idiopathic pulmonary fibrosis (IPF) include genetic predisposition, activation of the unfolded protein response, telomere attrition, and cellular senescence. The mechanisms ...leading to alveolar epithelial cell (AEC) senescence are poorly understood. MicroRNAs (miRNAs) have been reported as regulators of cellular senescence. Senescence markers including p16, p21, p53, and senescence-associated β-galactosidase (SA-βgal) activity were measured in type II AECs from IPF lungs and unused donor lungs. miRNAs were quantified in type II AECs using gene expression arrays and quantitative RT-PCR. Molecular markers of senescence (p16, p21, and p53) were elevated in IPF type II AECs. SA-βgal activity was detected in a greater percentage in type II AECs isolated from IPF patients (23.1%) compared to patients with other interstitial lung diseases (1.2%) or normal controls (0.8%). The relative levels of senescence-associated miRNAs miR-34a, miR-34b, and miR-34c, but not miR-20a, miR-29c, or miR-let-7f were significantly higher in type II AECs from IPF patients. Overexpression of miR-34a, miR-34b, or miR-34c in lung epithelial cells was associated with higher SA-βgal activity (27.8%, 35.1%, and 38.2%, respectively) relative to control treated cells (8.8%). Targets of miR-34 miRNAs, including E2F1, c-Myc, and cyclin E2, were lower in IPF type II AECs. These results show that markers of senescence are uniquely elevated in IPF type II AECs and suggest that the miR-34 family of miRNAs regulate senescence in IPF type II AECs.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hyperoxic acute lung injury Kallet, Richard H; Matthay, Michael A
Respiratory care
58, Številka:
1
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Prolonged breathing of very high F(IO(2)) (F(IO(2)) ≥ 0.9) uniformly causes severe hyperoxic acute lung injury (HALI) and, without a reduction of F(IO(2)), is usually fatal. The severity of HALI is ...directly proportional to P(O(2)) (particularly above 450 mm Hg, or an F(IO(2)) of 0.6) and exposure duration. Hyperoxia produces extraordinary amounts of reactive O(2) species that overwhelms natural anti-oxidant defenses and destroys cellular structures through several pathways. Genetic predisposition has been shown to play an important role in HALI among animals, and some genetics-based epidemiologic research suggests that this may be true for humans as well. Clinically, the risk of HALI likely occurs when F(IO(2)) exceeds 0.7, and may become problematic when F(IO(2)) exceeds 0.8 for an extended period of time. Both high-stretch mechanical ventilation and hyperoxia potentiate lung injury and may promote pulmonary infection. During the 1960s, confusion regarding the incidence and relevance of HALI largely reflected such issues as the primitive control of F(IO(2)), the absence of PEEP, and the fact that at the time both ALI and ventilator-induced lung injury were unknown. The advent of PEEP and precise control over F(IO(2)), as well as lung-protective ventilation, and other adjunctive therapies for severe hypoxemia, has greatly reduced the risk of HALI for the vast majority of patients requiring mechanical ventilation in the 21st century. However, a subset of patients with very severe ARDS requiring hyperoxic therapy is at substantial risk for developing HALI, therefore justifying the use of such adjunctive therapies.
Multipotent mesenchymal stem (stromal) cells (MSCs) have shown promising therapeutic effects in preclinical models of both acute respiratory distress syndrome (ARDS) and sepsis. Although initial ...research focused on the ability of MSCs to engraft at sites of tissue injury, increasing evidence suggests that MSCs have their therapeutic effects through mechanisms unrelated to long-term incorporation into host tissue. One of the most compelling of these pathways is the ability of MSCs to interact with injured tissue through the release of soluble bioactive factors. This Review provides an overview of the general properties of MSCs, and then outlines ways in which the paracrine effects of MSCs might reduce lung injury and enhance lung repair in ARDS and sepsis. Finally, we summarise ongoing challenges in MSC research and identify areas in which the discipline might progress in the coming years.
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