Understanding the Retention of Vaping Additives in the Lungs: Model Lung Surfactant Membrane Perturbation by Vitamin E and Vitamin E Acetate.

Deviations from the normal physicochemical and functional properties of pulmonary surfactants are associated with the incidence of lung injury and other respiratory disorders. This study aims to evaluate the alteration of the 2D molecular organization and morphology of pulmonary surfactant model membranes by the electronic cigarette additives α-tocopherol (vitamin E) and α-tocopherol acetate (vitamin E acetate), which have been associated with lung injury, termed e-cigarette or vaping-use-associated lung injury (EVALI). The model membranes used contained a 7:3 molar ratio of DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) and POPG (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol) to which α-tocopherol and α-tocopherol acetate were added to form mixtures of up to 20 mol % additive. The properties of the neat tocopherol additives and DPPC/POPG (7:3) mixtures with increasing molar proportions of additive were evaluated by surface pressure-area isotherms, excess area calculations, Brewster angle microscopy, grazing incidence X-ray diffraction, X-ray reflectivity, and atomic force microscopy. The addition of either additive alters the essential phase balance of the model pulmonary surfactant membrane by generating a greater proportion of the fluid phase. Despite this net fluidization, both tocopherol additives have space-filling effects on the liquid-expanded and condensed phases, yielding negative excess areas in the liquid-expanded phase and reduced tilt angles in the condensed phase. Both tocopherol additives alter the stability of the fluid phase, pushing the eventual collapse of this phase to higher surface pressures than the model membrane in the absence of an additive.

In vitro and in vivo approaches to assess atherosclerosis following exposure to low-dose mixtures of arsenic and cadmium.

Worldwide, millions of people are co-exposed to arsenic and cadmium. Environmental exposure to both metals is linked with a higher risk of atherosclerosis. While studies have characterized the pro-atherosclerotic effects of arsenic and cadmium as single agents, little is known about the potential effects of metal mixtures, particularly at low doses. Here, we used a combination of in vitro and in vivo models to assess the effects of low-dose metals individually and as mixtures on early events and plaque development associated with atherosclerosis. In vitro, we investigated early pro-atherogenic changes in macrophages and endothelial cells with metal treatments. The combined cytotoxic effects of both metals at low concentrations were dose interactive, specifically, synergistic in macrophages, but antagonistic in endothelial cells. Despite this differential behavior across cell types, the mixtures did not initiate early pro-atherogenic events: neither reactive oxygen species generation in macrophages nor adhesion molecule expression on endothelial cells. In vivo, we utilized the well-characterized hyperlipidemic apolipoprotein E knock-out (ApoE-/-) mouse model. Previously, we have shown that low concentrations of arsenic (down to 10 ppb) enhance atherosclerosis in ApoE-/- mice. This model has also been used with cadmium to demonstrate pro-atherogenic effects, although at concentrations above human-relevant exposures. In both sexes, there are some small increases in atherosclerotic lesion size, but very few changes in plaque constituents in the ApoE-/- mouse model. Together, these results suggests that low-dose metal mixtures are not significantly more pro-atherogenic than either metal alone.

Mechanisms of Metal-Induced Hepatic Inflammation.

PURPOSE OF REVIEW: Worldwide, there is an increasing prevalence of hepatic diseases. The most common diseases include alcoholic-associated liver disease (ALD), metabolic dysfunction-associated fatty liver disease/ metabolic dysfunction-associated steatohepatitis (MAFLD/MASH) and viral hepatitis. While there are many important mediators of these diseases, there is increasing recognition of the importance of the inflammatory immune response in hepatic disease pathogenesis. RECENT FINDINGS: Hepatic inflammation triggers the onset and progression of liver diseases. Chronic and sustained inflammation can lead to fibrosis, then cirrhosis and eventually end-stage cancer, hepatocellular carcinoma. Importantly, growing evidence suggest that metal exposure plays a role in hepatic disease pathogenesis. While in recent years, studies have linked metal exposure and hepatic steatosis, studies emphasizing metal-induced hepatic inflammation are limited. Hepatic inflammation is an important hallmark of fatty liver disease. This review aims to summarize the mechanisms of arsenic (As), cadmium (Cd) and chromium (Cr)-induced hepatic inflammation as they contribute to hepatic toxicity and to identify data gaps for future investigation.

STAT6 mutations enriched at diffuse large B-cell lymphoma relapse reshape the tumor microenvironment.

Diffuse large B-cell lymphoma (DLBCL) relapses in approximately 40% of patients following frontline therapy. We reported that STAT6D419 mutations are enriched in relapsed/refractory DLBCL (rrDLBCL) samples, suggesting that JAK/STAT signaling plays a role in therapeutic resistance. We hypothesized that STAT6D419 mutations can improve DLBCL cell survival by reprogramming the microenvironment to sustain STAT6 activation. Thus, we investigated the role of STAT6D419 mutations on DLBCL cell growth and its microenvironment. We found that phospho-STAT6D419N was retained in the nucleus longer than phospho-STAT6WT following IL-4 stimulation, and STAT6D419N recognized a more restricted DNA-consensus sequence than STAT6WT. Upon IL-4 induction, STAT6D419N expression led to a higher magnitude of gene expression changes, but in a more selective list of gene targets compared with STATWT. The most significantly expressed genes induced by STAT6D419N were those implicated in survival, proliferation, migration, and chemotaxis, in particular CCL17. This chemokine, also known as TARC, attracts helper T-cells to the tumor microenvironment, especially in Hodgkin's lymphoma. To this end, in DLBCL, phospho-STAT6+ rrDLBCL cells had a greater proportion of infiltrating CD4+ T-cells than phospho-STAT6- tumors. Our findings suggest that STAT6D419 mutations in DLBCL lead to cell autonomous changes, enhanced signaling, and altered composition of the tumor microenvironment.

E-cigarette exposure causes early pro-atherogenic changes in an inducible murine model of atherosclerosis.

Introduction: Evidence suggests that e-cigarette use (vaping) increases cardiovascular disease risk, but decades are needed before people who vape would develop pathology. Thus, murine models of atherosclerosis can be utilized as tools to understand disease susceptibility, risk and pathogenesis. Moreover, there is a poor understanding of how risk factors for atherosclerosis (i.e., hyperlipidemia, high-fat diet) intersect with vaping to promote disease risk. Herein, we evaluated whether there was early evidence of atherosclerosis in an inducible hyperlipidemic mouse exposed to aerosol from commercial pod-style devices and e-liquid. Methods: Mice were injected with adeno-associated virus containing the human protein convertase subtilisin/kexin type 9 (PCSK9) variant to promote hyperlipidemia. These mice were fed a high-fat diet and exposed to room air or aerosol derived from JUUL pods containing polyethylene glycol/vegetable glycerin (PG/VG) or 5% nicotine with mango flavoring for 4 weeks; this timepoint was utilized to assess markers of atherosclerosis that may occur prior to the development of atherosclerotic plaques. Results: These data show that various parameters including weight, circulating lipoprotein/glucose levels, and splenic immune cells were significantly affected by exposure to PG/VG and/or nicotine-containing aerosols. Discussion: Not only can this mouse model be utilized for chronic vaping studies to assess the vascular pathology but these data support that vaping is not risk-free and may increase CVD outcomes later in life.