Dysfunction In Vascular Disease Research Articles

Eicosapentaenoic Acid (EPA) Modulates Expression of Inflammatory Proteins in Pulmonary Endothelial Cells following Exposure to Air Pollution Particles

Lead Author's Financial Disclosures Nothing to disclose. Study Funding Amarin Pharma Inc. and Elucida Research. Background/Synopsis Air pollution contributes to global mortality by causing systemic inflammation and endothelial dysfunction in vascular disease, including atherosclerosis. The omega-3 fatty acid eicosapentaenoic acid (EPA) reduced cardiovascular events in high-risk patients (REDUCE-IT). EPA and omega-3 fatty acids can improve cardiac function and lipid levels in subjects exposed to air pollution particulate matter (PM) but underlying the mechanism is not understood. Objective/Purpose To test the ability of EPA to modulate expression of inflammatory proteins and related pathways in pulmonary endothelial cells following exposure to air pollution PMs of different sizes. Methods Human pulmonary ECs (PECs) were pretreated with EPA (40 micromolar) for 2 h before addition of particulate matter (PMs) with two different diameter ranges for 8 h. The PMs had an average of 5.9 micrometers from collected urban air (urban PMs) and 2.8 micrometers (fine PMs). PMs were delivered to the cells at 50 microgram/mL. Cell extracts from each treatment group were analyzed with LC/MS-based proteomics to measure relative expression levels of proteins. Only significant (p<0.05) changes in expression between treatment groups >1- fold were analyzed using differential enrichment analysis of proteomics data (DEP) and included in gene set enrichment analysis (GSEA). Results EPA significantly modulated expression of 205 and 347 proteins relative to fine and urban PMs, respectively. Among pathways modulated by both PMs was neutrophil degranulation (Gene Ontology ID: 0043312), where fine and urban PMs modulated 36 and 13 proteins, respectively. Common to both PMs were eight proteins, including 1.5-fold and 1.3-fold increases in C-X-C motif chemokine 6 (CXCL6). EPA treatment modulated 22 and 35 proteins associated with neutrophil degranulation compared to fine and urban PMs, respectively. Relative to fine PMs, EPA increased expression of heat shock protein 90-β; and decreased expression of interleukin enhancer-binding factor 2 (ILF2). Compared to urban PMs, EPA decreased expression of CXCL6 and increased expression of glutathione S-transferase P. Conclusions EPA significantly modulated expression of various inflammatory proteins in pulmonary ECs during exposure to multiple air pollution PMs. These findings support a novel vascular benefit for EPA under inflammatory conditions caused by air pollution PMs. Nothing to disclose.

Effects of enriched-potassium diet on cardiorespiratory outcomes in experimental non-ischemic chronic heart failure

BackgroundChronic heart failure (CHF) is a global health problem. Increased sympathetic outflow, cardiac arrhythmogenesis and irregular breathing patterns have all been associated with poor outcomes in CHF. Several studies showed that activation of the renin-angiotensin system (RAS) play a key role in CHF pathophysiology. Interestingly, potassium (K+) supplemented diets showed promising results in normalizing RAS axis and autonomic dysfunction in vascular diseases, lowering cardiovascular risk. Whether subtle increases in dietary K+ consumption may exert similar effects in CHF has not been previously tested. Accordingly, we aimed to evaluate the effects of dietary K+ supplementation on cardiorespiratory alterations in rats with CHF.MethodsAdult male Sprague–Dawley rats underwent volume overload to induce non-ischemic CHF. Animals were randomly allocated to normal chow diet (CHF group) or supplemented K+ diet (CHF+K+ group) for 6 weeks. Cardiac arrhythmogenesis, sympathetic outflow, baroreflex sensitivity, breathing disorders, chemoreflex function, respiratory–cardiovascular coupling and cardiac function were evaluated.ResultsCompared to normal chow diet, K+ supplemented diet in CHF significantly reduced arrhythmia incidence (67.8 ± 15.1 vs. 31.0 ± 3.7 events/hour, CHF vs. CHF+K+), decreased cardiac sympathetic tone (ΔHR to propranolol: − 97.4 ± 9.4 vs. − 60.8 ± 8.3 bpm, CHF vs. CHF+K+), restored baroreflex function and attenuated irregular breathing patterns. Additionally, supplementation of the diet with K+ restores normal central respiratory chemoreflex drive and abrogates pathological cardio-respiratory coupling in CHF rats being the outcome an improved cardiac function.ConclusionOur findings support that dietary K+ supplementation in non-ischemic CHF alleviate cardiorespiratory dysfunction.

Role of moesin in the effect of glucagon-like peptide-1 on advanced glycation end products-induced endothelial barrier dysfunction

Glucagon-like peptide-1 (GLP-1) analogues have been found to exert protective effect on endothelial barrier dysfunction in vascular diseases. Moesin phosphorylation participates in the process of advanced glycation end products (AGEs) induced disruption of endothelial barrier integrity. Whether and how GLP-1 modulating moesin phosphorylation in endothelium under diabetic condition needs further clarification. Consistent with previous studies, our data showed that hyperglycemia and AGEs promoted moesin phosphorylation in ECs in vivo and vitro experiments. With or without AGEs incubation, overexpression of moesin and activated mutant moesin T558D increased ECs permeability, whereas knockdown of moesin decreased ECs permeability. Inhibition of Rho/ROCK, p38/MAPK and PKC β signal pathways also decreased moesin phosphorylation in ECs incubated with AGEs. Importantly, GLP-1 inhibited moesin phosphorylation in AGE-induced ECs in a dose-dependent manner. Intriguingly, the effects of GLP-1 elicited on moesin phosphorylation in ECs under diabetic condition were blunted by inhibition of cAMP/PKA and stimulation of Rho/ROCK, p38 and PKC β signaling pathways. Therefore, this study verified that the stabilizing effect of GLP-1 on the moesin phosphorylation mediated endothelial barrier function is mediated by GLP-1R/cAMP/PKA activation and subsequent down-regulation of Rho/ROCK, p38 and PKC β signaling pathways.

The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes.

Mitochondrial dysfunction is known to be associated with a wide range of human pathologies, such as cancer, metabolic, and cardiovascular diseases. One of the possible ways of mitochondrial involvement in the cellular damage is excessive production of reactive oxygen and nitrogen species (ROS and RNS) that cannot be effectively neutralized by existing antioxidant systems. In mitochondria, ROS and RNS can contribute to protein and mitochondrial DNA (mtDNA) damage causing failure of enzymatic chains and mutations that can impair mitochondrial function. These processes further lead to abnormal cell signaling, premature cell senescence, initiation of inflammation, and apoptosis. Recent studies have identified numerous mtDNA mutations associated with different human pathologies. Some of them result in imbalanced oxidative phosphorylation, while others affect mitochondrial protein synthesis. In this review, we discuss the role of mtDNA mutations in cancer, diabetes, cardiovascular diseases, and atherosclerosis. We provide a list of currently described mtDNA mutations associated with each pathology and discuss the possible future perspective of the research.

Assessing bleeding risk in 18 children with Osteogenesis imperfecta

Assessing bleeding risk in 18 children with <i>Osteogenesis imperfecta</i>

SWI/SNF (BAF) complexes: From framework to a functional role in endothelial mechanotransduction.

Endothelial cells (ECs) are constantly subjected to an array of mechanical cues, especially shear stress, due to their luminal placement in the blood vessels. Blood flow can regulate various aspects of endothelial biology and pathophysiology by regulating the endothelial processes at the transcriptomic, proteomic, miRNomic, metabolomics, and epigenomic levels. ECs sense, respond, and adapt to altered blood flow patterns and shear profiles by specialized mechanisms of mechanosensing and mechanotransduction, resulting in qualitative and quantitative differences in their gene expression. Chromatin-regulatory proteins can regulate transcriptional activation by modifying the organization of nucleosomes at promoters, enhancers, silencers, insulators, and locus control regions. Recent research efforts have illustrated that SWI/SNF (SWItch/Sucrose Non-Fermentable) or BRG1/BRM-associated factor (BAF) complex regulates DNA accessibility and chromatin structure. Since the discovery, the gene-regulatory mechanisms of the BAF complex associated with chromatin remodeling have been intensively studied to investigate its role in diverse disease phenotypes. Thus far, it is evident that (1) the SWI/SNF complex broadly regulates the activity of transcriptional enhancers to control lineage-specific differentiation and (2) mutations in the BAF complex proteins lead to developmental disorders and cancers. It is unclear if blood flow can modulate the activity of SWI/SNF complex to regulate EC differentiation and reprogramming. This review emphasizes the integrative role of SWI/SNF complex from a structural and functional standpoint with a special reference to cardiovascular diseases (CVDs). The review also highlights how regulation of this complex by blood flow can lead to the discovery of new therapeutic interventions for the treatment of endothelial dysfunction in vascular diseases.

Therapeutic targets for endothelial dysfunction in vascular diseases.

Vascular endothelial cells are located on the surface of the blood vessels. It has been recognized as an important barrier to the regulationof vascular homeostasis by regulating the blood flow of micro- or macrovascular vessels. Indeed, endothelial dysfunction is an initial stage of vascular diseases and is an important prognostic indicator of cardiovascular and metabolic diseases such as atherosclerosis, hypertension, heart failure, or diabetes. Therefore, in order to develop therapeutic targets for vascular diseases, it is important to understand the key factors involved in maintaining endothelial function and the signaling pathways affecting endothelial dysfunction. The purpose of this review is to describe the function and underlying signaling pathway of oxidative stress, inflammatory factors, shear stress, and epigenetic factors in endothelial dysfunction, and introduce recent therapeutic targets for the treatment of cardiovascular diseases.

Effect of prolonged treatment with phosphodiesterase-5-inhibitors on endothelial dysfunction in vascular diseases and vascular risk conditions: A systematic review analysis and meta-analysis of randomized double-blind placebo-controlled trials.

To challenge the argument that continuous use of phosphodiesterase-5-selective inhibitors may reduce endothelial cell dysfunction in patients with vascular diseases or vascular risk conditions. This study included systematic reviews and meta-analysis of randomized double-blind placebo-controlled trials dealing with the prolonged use of phosphodiesterase-5-selective inhibitors. The risk of bias and quality of trials were assessed by the Cochrane algorithm. Fixed or random effect models, standardised mean differences and heterogeneity were estimated in the study. Systematic search for randomized double-blind placebo-controlled trials was done in PubMed, Scopus, CINAHL, Science direct and the Cochrane Library. Randomized double-blind placebo-controlled trials reporting measures of endothelial cell dysfunction and/or endothelial cell activation were included. On the whole, 469 subjects were allocated to the phosphodiesterase-5-selective inhibitor group, while 463 were assigned to the placebo group in 13 randomized double-blind placebo-controlled trials. Flow-mediated dilation of the brachial artery was found to improve after the administration of phosphodiesterase-5-selective inhibitors (P<0.0001). The results were questioned by the elevated and uncorrectable heterogeneity (I2 =92%) and the asymmetry of the funnel plot suggested a publication bias. Phosphodiesterase-5-selective inhibitors have no effect on endothelial cell dysfunction, as assessed in the resistance vessels by digital arterial tonometry. The blood level of endothelin-1 was observed to be decreased in phosphodiesterase-5-selective inhibitors arm (P=0.03), although the effect disappeared once the publication bias and heterogeneity were corrected. The effect of phosphodiesterase-5-selective inhibitors on biomarkers of endothelial cell activation was found to be inconsistent. The results on the benefits of a prolonged use of phosphodiesterase-5-selective inhibitors, with the objective of lowering endothelial cell dysfunction in patients with vascular diseases or vascular risk conditions are not convincing. This is because of the overall low quality of evidence, giving an unclear scientific support to this treatment. Systematic review registration: PROSPERO registration: CRD42017055399.

Protective Effect of Pyrogallol-Phloroglucinol-6,6-Bieckol from Ecklonia cava on Monocyte-Associated Vascular Dysfunction.

Ecklonia cava (E. cava) can alleviate vascular dysfunction in diseases associated with poor circulation. E. cava contains various polyphenols with different functions, but few studies have compared the effects of these polyphenols. Here, we comparatively investigated four major compounds present in an ethanoic extract of E. cava. These four major compounds were isolated and their effects were examined on monocyte-associated vascular inflammation and dysfunctions. Pyrogallol-phloroglucinol-6,6-bieckol (PPB) significantly inhibited monocyte migration in vitro by reducing levels of inflammatory macrophage differentiation and of its related molecular factors. In addition, PPB protected against monocyte-associated endothelial cell death by increasing the phosphorylations of PI3K-AKT and AMPK, decreasing caspase levels, and reducing monocyte-associated vascular smooth muscle cell proliferation and migration by decreasing the phosphorylations of ERK and AKT. The results of this study show that four compounds were effective for reduction of monocyte-associated vascular inflammation and dysfunctions, but PPB might be more useful for the treatment of vascular dysfunction in diseases associated with poor circulation.

Levels of Soluble Endothelium Adhesion Molecules and Complications among Sickle Cell Disease Patients in Ghana.

Background: Soluble adhesion molecules are involved in the gathering and joining of inflammatory cells to vascular endothelium. Therefore, they serve as potential markers of endothelial dysfunction in vascular diseases including sickle cell disease (SCD). In Ghana, there are scarcely any report on the levels of adhesion molecules among SCD patients. The current study aimed to determine plasma levels of ICAM-1, VCAM-1 and E-Selectin as markers of endothelial dysfunction in SCD patients in steady state, complications and controls. Methodology: This was a cross-sectional study involving 60 HbAA controls, 46 HbSS steady state, 57 HbSS VOC, 18 HbSC VOC, 21 HbSS with leg ulcer and 11 HbSS with priapism. Blood samples were collected from all the study subjects (n = 213) and processed into plasma. The plasma levels of VCAM-1, ICAM-1 and E-Selectin concentrations of SCD patients and controls were measured using a double sandwich ELISA technique. Demographic information was also collected from the study subjects. Results: Levels of all soluble proteins (ICAM-1, VCAM-1 and E-Selectin) were significantly higher in HbSS steady-state patients compared to non-SCD controls (p < 0.001). Generally, SCD patients with complications had relatively higher levels of the soluble proteins compared to those in the steady-state. Of the SCD patients with complications, those with vaso-occlusion crisis (HbSS VOC) had relatively higher levels of ICAM-1, VCAM-1 and E-Selectin at (62.42 ng/mL ± 26.09), (634.99 ng/mL ± 324.31) and (236.77 ng/mL ± 114.40) respectively; Conclusion: Although levels of adhesion molecules were high in all the SCD patients with complications, those with vaso-occlusive crisis had higher levels. This might reflect an ongoing endothelial dysfunction in these patients. SCD patients with vaso-occlusive crisis presents with a more severe pathophysiology condition.

High-density lipoprotein carbamylation and dysfunction in vascular disease.

High-density lipoprotein (HDL) is cardioprotective because of its anti-atherogenic properties. Nevertheless, our goal to optimize HDL cholesterol (HDL-C) levels have had little effects on the atherothrombotic burden and suggests a closer look be taken at HDL function and dysfunction. HDL is a group of complex macromolecules composed of a lipid- and proteome that work in synergy to execute its anti-inflammatory, anti-atherogenic, and anti-thrombotic effects. However, throughout its life-span in circulation, HDL undergoes significant modification. Carbamylation, a non-enzymatic and irreversible post-translational modification of protein, is one effector of HDL which has growing evidence that it plays a crucial role in the development and progression of atherosclerotic cardiovascular disease (ASCVD), particularly in chronic kidney disease (CKD). We summarize HDL's function, susceptibility to modification, and discuss HDL carbamylation and its effect in cardiovascular disease.

Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension.

The impairment of vasodilator nitric oxide (NO) production is well accepted as a typical marker of endothelial dysfunction in vascular diseases, including in the pathophysiology of pulmonary arterial hypertension (PAH), but the molecular mechanisms accounting for loss of NO production are unknown. We hypothesized that low NO production by pulmonary arterial endothelial cells in PAH is due to inactivation of NO synthase (eNOS) by aberrant phosphorylation of the protein. To test the hypothesis, we evaluated eNOS levels, dimerization, and phosphorylation in the vascular endothelial cells and lungs of patients with PAH compared with controls. In mechanistic studies, eNOS activity in endothelial cells in PAH lungs was found to be inhibited due to phosphorylation at T495. Evidence pointed to greater phosphorylation/activation of protein kinase C (PKC) α and its greater association with eNOS as the source of greater phosphorylation at T495. The presence of greater amounts of pT495-eNOS in plexiform lesions in lungs of patients with PAH confirmed the pathobiological mechanism in vivo. Transfection of the activating mutation of eNOS (T495A/S1177D) restored NO production in PAH cells. Pharmacological blockade of PKC activity by β-blocker also restored NO formation by PAH cells, identifying one mechanism by which β-blockers may benefit PAH and cardiovascular diseases through recovery of endothelial functions.

Targeted subendothelial matrix oxidation by myeloperoxidase triggers myosin II-dependent de-adhesion and alters signaling in endothelial cells

During inflammation, myeloperoxidase (MPO) released by circulating leukocytes accumulates within the subendothelial matrix by binding to and transcytosing the vascular endothelium. Oxidative reactions catalyzed by subendothelial-localized MPO are implicated as a cause of endothelial dysfunction in vascular disease. While the subendothelial matrix is a key target for MPO-derived oxidants during disease, the implications of this damage for endothelial morphology and signaling are largely unknown. We found that endothelial-transcytosed MPO produced hypochlorous acid (HOCl) that reacted locally with the subendothelial matrix and induced covalent cross-linking of the adhesive matrix protein fibronectin. Real-time biosensor and live cell imaging studies revealed that HOCl-mediated matrix oxidation triggered rapid membrane retraction from the substratum and adjacent cells (de-adhesion). De-adhesion was linked with the alteration of Tyr-118 phosphorylation of paxillin, a key adhesion-dependent signaling process, as well as Rho kinase-dependent myosin light chain-2 phosphorylation. De-adhesion dynamics were dependent on the contractile state of cells, with myosin II inhibition with blebbistatin attenuating the rate of membrane retraction. Rho kinase inhibition with Y-27632 also conferred protection, but not during the initial phase of membrane retraction, which was driven by pre-existing actomyosin tensile stress. Notably, diversion of MPO from HOCl production by thiocyanate or nitrite attenuated de-adhesion and associated signaling responses, despite the latter substrate supporting MPO-catalyzed fibronectin nitration. These data show that subendothelial-localized MPO employs a novel “outside-in” mode of redox signaling, involving HOCl-mediated matrix oxidation. These MPO-catalyzed oxidative events are likely to play a previously unrecognized role in altering endothelial integrity and signaling during inflammatory vascular disorders.

Mitochondria in vascular disease

Mitochondria are often regarded as the powerhouse of the cell by generating the ultimate energy transfer molecule, ATP, which is required for a multitude of cellular processes. However, the role of mitochondria goes beyond their capacity to create molecular fuel, to include the generation of reactive oxygen species, the regulation of calcium, and activation of cell death. Mitochondrial dysfunction is part of both normal and premature ageing, but can contribute to inflammation, cell senescence, and apoptosis. Cardiovascular disease, and in particular atherosclerosis, is characterized by DNA damage, inflammation, cell senescence, and apoptosis. Increasing evidence indicates that mitochondrial damage and dysfunction also occur in atherosclerosis and may contribute to the multiple pathological processes underlying the disease. This review summarizes the normal role of mitochondria, the causes and consequences of mitochondrial dysfunction, and the evidence for mitochondrial damage and dysfunction in vascular disease. Finally, we highlight areas of mitochondrial biology that may have therapeutic targets in vascular disease.

Hyperglycemia-induced endoplasmic reticulum stress in endothelial cells

Objective Hyperglycemia-induced endothelial cell dysfunction in vascular disease can occur due to increased oxidative stress and a concomitant increase in endoplasmic reticulum (ER) stress. To investigate whether these cellular stresses are independent or causally linked, we determined whether or not specific glycolytic intermediates that induce oxidative stress also induce ER stress. Methods Human umbilical vein endothelial cells were treated with dextrose, partially metabolizable (e.g., fructose and galactose) and non-metabolizable sugars (e.g., 3-O-methyglucose), and various intermediates of the glycolytic and tricarboxylic acid pathways. Activation of the unfolded protein response and subsequent generation of ER stress was measured by the ER stress-responsive alkaline phosphatase method, and superoxide (SO) generation was measured using the hydro-ethidene–fluorescence method. The mitochondrial origin of the SO and the generation of ER stress by dextrose and the intermediate metabolites were confirmed with experiments using allopurinol and diphenyleneiodonium chloride to block SO generation by xanthine oxidase and nicotinamide adenosine dinucleotide phosphate oxidase, respectively. Results Although ER stress could be induced by glycolytic intermediates up to and including pyruvate, the SO generation occurred in the presence of glycolytic and mitochondrial metabolites. Conclusion Although the mitochondria are the site of signals generated by dextrose to initiate oxidative stress, the dextrose-induced ER stress, unlike SO generation, does not require pyruvate oxidation in the mitochondria.

Peripheral mural cell recruitment requires cell-autonomous heparan sulfate

AbstractBlood vessel maturation and stability require recruitment of mural cells (MCs) to the nascent vessel. Loss or detachment of MCs causes vascular dysfunction in diseases. N-sulfation of heparan sulfate (HS) is required for platelet-derived growth factor B (PDGF-B) retention and platelet-derived growth factor receptor-β (PDGFR-β) signaling during MC recruitment. To analyze the specific role of MC-derived HS in this process, we inactivated HS synthesis in MCs. MC-specific loss of HS causes embryonic lethality associated with vascular patterning defects, edema, and hemorrhages during late gestation. MC recruitment in the skin is impaired, correlating with defective PDGFR-β and transforming growth factor-β (TGF-β)–SMAD signaling. Accumulation of rounded cells positive for MC markers close to the vessels indicates defective polarization and migration of local MC progenitors. In contrast, MC recruitment and signaling in the central nervous system (CNS) are unaffected by MC HS loss. Our results suggest that HS is selectively required in a cell-autonomous manner, acting in cis with PDGFR-β and TGF-β receptors during induction/polarization and migration of local progenitor cells to the nascent vessel. Once MCs are in contact with the vessel, as during CNS vascularization, endothelial HS appears sufficient to facilitate PDGFR-β activation in trans.

Oxidative stress and endothelial dysfunction in vascular disease

In response to physiologic stimuli, endothelial cells dynamically regulate arterial vascular tone by producing vasodilators and vasoconstrictors. Risk factors for atherosclerosis, such as diabetes, smoking, hypercholesterolemia, and hypertension, interfere with this response, promoting endothelial dysfunction and atherosclerosis. This review explores whether oxidative stress might be a common feature of both endothelial dysfunction and atherosclerosis. Using biomarkers to assess endothelial function might provide insights into the pathways for oxidative stress in vascular disease. However, currently available markers of oxidative stress and endothelial function are unsuitable for routine clinical use because they are too expensive and inadequately validated. Thus, there is a need to develop and validate new markers that could be used to both measure oxidative stress and monitor therapies that specifically interrupt oxidative pathways in vascular tissue. Such markers might eventually help to identify susceptible individuals at a stage when cardiovascular complications could be prevented.

The Effect of Daily Apolipoprotein A-I Mimetic Therapy on T15-Type Autoantibodies Against Oxidized Phosphatidylcholine in a Murine Model of Asthma

RATIONALE: Phospholipid derived proinflammatory lipids have been shown to regulate mononuclear and vascular cell dysfunction in vascular disease. T15-type antibodies bind proinflammatory lipids such as oxidized phosphatidylcholine (ox-PC) and therefore may be utilized as a marker of inflammation. The apolipoprotein (apo) A-I mimetic, D-4F has been shown to bind and remove pro-inflammatory lipids and therefore may play a pivotal role in decreasing pulmonary inflammation similar to what occurs in asthma. METHODS: C57/Black 6 mice were sensitized with ovalbumin, divided into two groups and received: (1) intranasal D-4F (20 μg) once a day for 4 weeks or (2) no treatment for 4 weeks. Normal mice were also maintained as additional controls. At the time of sacrifice samples were collected for eosinophil peroxidase activity (EPO) in the bronchioalveolar lavage fluid (BAL), lung histology, and serum IgE levels. Data were analyzed to compare sensitized D-4F treated group with the sensitized untreated and normal, untreated unsensitized groups using student t test. RESULTS: D-4F therapy resulted in decreases in ox-PC, EPO, serum IgE levels, and inflammation on lung histology. The therapy was tolerated without evidence of toxicity. CONCLUSIONS: D-4F therapy resulted in a significant decrease in lung inflammation, serum IgE levels and EPO in experimental asthma. This study also demonstrates efficacy of D-4F to decrease proinflammatory phospholipids in the lung in a murine model of asthma. This novel drug may provide a safe and effective alternative to currently available therapies in treating asthma.