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Idiopathic pulmonary fibrosis: Current and future treatment

Glass, Daniel S; Grossfeld, David; Renna, Heather A; Agarwala, Priya; Spiegler, Peter; DeLeon, Joshua; Reiss, Allison B
OBJECTIVES/OBJECTIVE:Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease characterized by dry cough, fatigue, and progressive exertional dyspnea. Lung parenchyma and architecture is destroyed, compliance is lost, and gas exchange is compromised in this debilitating condition that leads inexorably to respiratory failure and death within 3-5 years of diagnosis. This review discusses treatment approaches to IPF in current use and those that appear promising for future development. DATA SOURCE/METHODS:The data were obtained from the Randomized Controlled Trials and scientific studies published in English literature. We used search terms related to IPF, antifibrotic treatment, lung transplant, and management. RESULTS:Etiopathogenesis of IPF is not fully understood, and treatment options are limited. Pathological features of IPF include extracellular matrix remodeling, fibroblast activation and proliferation, immune dysregulation, cell senescence, and presence of aberrant basaloid cells. The mainstay therapies are the oral antifibrotic drugs pirfenidone and nintedanib, which can improve quality of life, attenuate symptoms, and slow disease progression. Unilateral or bilateral lung transplantation is the only treatment for IPF shown to increase life expectancy. CONCLUSION/CONCLUSIONS:Clearly, there is an unmet need for accelerated research into IPF mechanisms so that progress can be made in therapeutics toward the goals of increasing life expectancy, alleviating symptoms, and improving well-being.
PMID: 35001525
ISSN: 1752-699x
CID: 5175912

Understanding Accelerated Atherosclerosis in Systemic Lupus Erythematosus: Toward Better Treatment and Prevention

Reiss, Allison B; Jacob, Benna; Ahmed, Saba; Carsons, Steven E; DeLeon, Joshua
Systemic lupus erythematosus (SLE) carries a significant risk of cardiovascular disease (CVD). The prevalence of premature CVD is especially noteworthy because it occurs in premenopausal women with SLE who would otherwise have very low rates of CVD. While traditional risk factors likely play a role in development of CVD in the setting of SLE, they do not fully explain the excess risk. The pathogenesis of CVD in SLE is not fully understood, but the inflammatory nature of SLE is believed to be a key factor in accelerating atherosclerosis. Systemic inflammation may lead to an abnormal lipid profile with elevated triglycerides, total cholesterol, and low-density lipoprotein cholesterol and dysfunctional high-density lipoprotein cholesterol. Additionally, the inflammatory milieu of SLE plasma promotes endothelial dysfunction and vascular injury, early steps in the progression of atherosclerotic CVD. Despite the overall headway that has been achieved in treating lupus, innovative therapeutics specifically targeting the progression of atherosclerosis within the lupus population are currently lacking. However, there have been advancements in the development of promising modalities for diagnosis of subclinical atherosclerosis and detection of high CVD risk patients. Due to the significant impact of CVD on morbidity and mortality, research addressing prevention and treatment of CVD in SLE needs to be prioritized. This review explores the intricate interplay of SLE-specific properties that contribute to atherosclerosis and CVD within this population, as well as screening methods and possible therapies.
PMID: 33821395
ISSN: 1573-2576
CID: 4839112

Alzheimer Disease Clinical Trials Targeting Amyloid: Lessons Learned From Success in Mice and Failure in Humans

Reiss, Allison B; Montufar, Natalie; DeLeon, Joshua; Pinkhasov, Aaron; Gomolin, Irving H; Glass, Amy D; Arain, Hirra A; Stecker, Mark M
BACKGROUND:The goal of slowing or halting the development of Alzheimer disease (AD) has resulted in the huge allocation of resources by academic institutions and pharmaceutical companies to the development of new treatments. The etiology of AD is elusive, but the aggregation of amyloid-β and tau peptide and oxidative processes are considered critical pathologic mechanisms. The failure of drugs with multiple mechanisms to meet efficacy outcomes has caused several companies to decide not to pursue further AD studies and has left the field essentially where it has been for the past 15 years. Efforts are underway to develop biomarkers for detection and monitoring of AD using genetic, imaging, and biochemical technology, but this is of minimal use if no intervention can be offered. REVIEW SUMMARY/RESULTS:In this review, we consider the natural progression of AD and how it continues despite present attempts to modify the amyloid-related machinery to alter the disease trajectory. We describe the mechanisms and approaches to AD treatment targeting amyloid, including both passive and active immunotherapy as well as inhibitors of enzymes in the amyloidogenic pathway. CONCLUSION/CONCLUSIONS:Lessons learned from clinical trials of amyloid reduction strategies may prove crucial for the leap forward toward novel therapeutic targets to treat AD.
PMID: 33646990
ISSN: 2331-2637
CID: 4801212

Effect of oxytocin on lipid accumulation under inflammatory conditions in human macrophages

Karten, Ariel; Vernice, Nicholas A; Renna, Heather A; Carsons, Steven E; DeLeon, Joshua; Pinkhasov, Aaron; Gomolin, Irving H; Glass, Daniel S; Reiss, Allison B; Kasselman, Lora J
INTRODUCTION AND AIMS/OBJECTIVE:Oxytocin (OT) is a neuropeptide hormone secreted by the posterior pituitary gland. Deficits in OT action have been observed in patients with behavioral and mood disorders, some of which correlate with an increased risk of cardiovascular disease (CVD). Recent research has revealed a wider systemic role that OT plays in inflammatory modulation and development of atherosclerotic plaques. This study investigated the role that OT plays in cholesterol transport and foam cell formation in LPS-stimulated THP-1 human macrophages. METHODS:THP-1 differentiated macrophages were treated with media, LPS (100 ng/ml), LPS + OT (10 pM), or LPS + OT (100 pM). Changes in gene expression and protein levels of cholesterol transporters were analyzed by real time quantitative PCR (RT-qPCR) and Western blot, while ox-LDL uptake and cholesterol efflux capacity were evaluated with fluorometric assays. RESULTS:RT-qPCR analysis revealed a significant increase in ABCG1 gene expression upon OT + LPS treatment, compared to LPS alone (p = 0.0081), with Western blotting supporting the increase in expression of the ABCG1 protein. Analysis of ox-LDL uptake showed a significantly lower fluorescent value in LPS + OT (100pM) -treated cells when compared to LPS alone (p < 0.0001). While not statistically significant (p = 0.06), cholesterol efflux capacity increased with LPS + OT treatment. CONCLUSION/CONCLUSIONS:We demonstrate here that OT can attenuate LPS-mediated lipid accumulation in THP-1 macrophages. These findings support the hypothesis that OT could be used to reduce pro-inflammatory and potentially atherogenic changes observed in patients with heightened CVD risk. This study suggests further exploration of OT effects on monocyte and macrophage cholesterol handling in vivo.
PMID: 33434610
ISSN: 1096-0945
CID: 4746722

Idiopathic pulmonary fibrosis: Molecular mechanisms and potential treatment approaches

Glass, Daniel S; Grossfeld, David; Renna, Heather A; Agarwala, Priya; Spiegler, Peter; Kasselman, Lora J; Glass, Amy D; DeLeon, Joshua; Reiss, Allison B
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease with high mortality that commonly occurs in middle-aged and older adults. IPF, characterized by a decline in lung function, often manifests as exertional dyspnea and cough. Symptoms result from a fibrotic process driven by alveolar epithelial cells that leads to increased migration, proliferation, and differentiation of lung fibroblasts. Ultimately, the differentiation of fibroblasts into myofibroblasts, which synthesize excessive amounts of extracellular matrix proteins, destroys the lung architecture. However, the factors that induce the fibrotic process are unclear. Diagnosis can be a difficult process; the gold standard for diagnosis is the multidisciplinary conference. Practical biomarkers are needed to improve diagnostic and prognostic accuracy. High-resolution computed tomography typically shows interstitial pneumonia with basal and peripheral honeycombing. Gas exchange and diffusion capacity are impaired. Treatments are limited, although the anti-fibrotic drugs pirfenidone and nintedanib can slow the progression of the disease. Lung transplantation is often contraindicated because of age and comorbidities, but it improves survival when successful. The incidence and prevalence of IPF has been increasing and there is an urgent need for improved therapies. This review covers the detailed cellular and molecular mechanisms underlying IPF progression as well as current treatments and cutting-edge research into new therapeutic targets.
PMID: 32487481
ISSN: 2212-5353
CID: 4468982

Cholesterol deficiency as a mechanism for autism: A valproic acid model (3367755) [Meeting Abstract]

Behbodikhah, J; Renna, H A; Peltier, M R; Kasselman, L J; Pinkhasov, A; Arita, Y; Wisniewski, T; DeLeon, J; Reiss, A B
Purpose of Study Autism spectrum disorders (ASDs) are neurodevelopmental disorders with lifelong consequences and poorly understood pathophysiology. Dysregulated cholesterol metabolism is implicated in ASD etiology. Cholesterol is essential for neuroactive steroid production, myelin sheath formation, and normal brain development. Early postnatal or in utero exposure to the antiepileptic drug valproic acid (VPA), a branched short-chain fatty acid, causes autism-like neural and behavioral deficits in humans and rodents. This study examines the link between VPA and cholesterol deficit in cultured human neurons and microglia. Methods Used SHSY-5Y human neuroblastoma cells and HMC3 human microglial cells were exposed to VPA at 0, 250, 1000 and 5000 muM for 24h, N=3 per condition. Expression of critical genes that regulate cholesterol transport were quantified by RT-PCR using specific primers for each. These include the efflux proteins ABCA1, ABCG1, 27-hydroxylase (27-OHase) and 24-hydroxylase (24-OHase), and the influx scavenger receptor CD36 - all vital for brain cholesterol balance. Expression of these target genes was normalized to concurrently measured GAPDH mRNA levels. Summary of Results In SH-SY5Y neurons, VPA exposure caused a concentration-dependent increase in ABCA1 (P <0.001), ABCG1, 27-OHase (P <0.001) (figure 1), and CD36 (P=0.015). In HMC3, VPA exposure caused a concentration- dependent increase in ABCG1 (80-fold at highest dose, P<=0.001) and 24-OHase (P < 0.001) with a reduction in ABCA-1 (P=0.002) and an increase in CD36 (P<0.001). Conclusions This study shows that VPA has a dramatic hypocholesterolemic effect on two key cell types that compose the developing brain. The net impact of the changes observed in these cholesterol-related genes would be outflow and metabolism. Further, enhanced 27-OHase activity produces an oxysterol metabolite with neurotoxic effects that include downregulating synaptic proteins and decreasing neurite number and length. Together, our results suggest that VPA impairs brain cholesterol homeostasis. A better understanding of the involvement of cholesterol in the mechanisms by which VPA leads to ASDs may translate into novel preventative therapies for this serious disorder
ISSN: 1708-8267
CID: 4486482

Adenosine and the Cardiovascular System

Reiss, Allison B; Grossfeld, David; Kasselman, Lora J; Renna, Heather A; Vernice, Nicholas A; Drewes, Wendy; Konig, Justin; Carsons, Steven E; DeLeon, Joshua
Adenosine is an endogenous nucleoside with a short half-life that regulates many physiological functions involving the heart and cardiovascular system. Among the cardioprotective properties of adenosine are its ability to improve cholesterol homeostasis, impact platelet aggregation and inhibit the inflammatory response. Through modulation of forward and reverse cholesterol transport pathways, adenosine can improve cholesterol balance and thereby protect macrophages from lipid overload and foam cell transformation. The function of adenosine is controlled through four G-protein coupled receptors: A1, A2A, A2B and A3. Of these four, it is the A2A receptor that is in a large part responsible for the anti-inflammatory effects of adenosine as well as defense against excess cholesterol accumulation. A2A receptor agonists are the focus of efforts by the pharmaceutical industry to develop new cardiovascular therapies, and pharmacological actions of the atheroprotective and anti-inflammatory drug methotrexate are mediated via release of adenosine and activation of the A2A receptor. Also relevant are anti-platelet agents that decrease platelet activation and adhesion and reduce thrombotic occlusion of atherosclerotic arteries by antagonizing adenosine diphosphate-mediated effects on the P2Y12 receptor. The purpose of this review is to discuss the effects of adenosine on cell types found in the arterial wall that are involved in atherosclerosis, to describe use of adenosine and its receptor ligands to limit excess cholesterol accumulation and to explore clinically applied anti-platelet effects. Its impact on electrophysiology and use as a clinical treatment for myocardial preservation during infarct will also be covered. Results of cell culture studies, animal experiments and human clinical trials are presented. Finally, we highlight future directions of research in the application of adenosine as an approach to improving outcomes in persons with cardiovascular disease.
PMID: 30972618
ISSN: 1179-187x
CID: 3854092

Macrophage lipid accumulation in the presence of immunosuppressive drugs mycophenolate mofetil and cyclosporin A

Voloshyna, Iryna; Teboul, Isaac; Kasselman, Lora J; Salama, Michael; Carsons, Steven E; DeLeon, Joshua; Mattana, Joseph; Miyawaki, Nobuyuki; Reiss, Allison B
OBJECTIVE:Mycophenolate (MPA) and cyclosporin A (CsA) are two immunosuppressive agents currently used for the treatment of autoimmune diseases. However, reports regarding their effects on inflammation and lipid handling are controversial. Here, we compare the effect of these two drugs on the expression of proteins involved in cholesterol handling and lipid accumulation in a macrophage cell system utilizing M0, M1 and M2 human macrophages and in murine bone marrow-derived macrophages (BMDM). METHODS:. RESULTS:In M0 macrophages, MPA increased expression of ABCA1 and CXCL16 in a concentration-dependent manner. In M1 THP-1 macrophages, MPA caused a significant increase of 27-hydroxylase mRNA and CD36 and SR-A1 receptor mRNAs. Exposure of M2 macrophages to MPA also stimulated expression of 27-hydroxylase, while downregulating all evaluated scavenger receptors. In contrast, CsA had no impact on cholesterol efflux in M0 and M1 macrophages, but significantly augmented expression of ABCA1 and 27-hydroxylase in M2 macrophages. CsA significantly increased expression of the LOX1 receptor in naïve macrophages, downregulated expression of CD36 and SR-A1 in the M1 subpopulation and upregulated expression of all evaluated scavenger receptors. However, CsA enhanced foam cell transformation in M0 and M2 macrophages, while MPA had no effect on foam cell formation unless used at a high concentration in the M2 subtype. CONCLUSIONS:Our results clearly underline the importance of further evaluation of the effects of these drugs when used in atherosclerosis-prone patients with autoimmune or renal disease.
PMID: 31227843
ISSN: 1420-908x
CID: 3954772

Human Lupus Plasma Pro-Atherogenic Effects on Cultured Macrophages Are Not Mitigated by Statin Therapy: A Mechanistic LAPS Substudy

Reiss, Allison B; Arain, Hirra A; Kasselman, Lora J; Renna, Heather A; Zhen, Juan; Voloshyna, Iryna; DeLeon, Joshua; Carsons, Steven E; Petri, Michelle
Background andObjectives: Atherosclerotic cardiovascular disease (CVD) remains a major cause of morbidity and mortality in persons with systemic lupus erythematosus (SLE, lupus). Atherosclerosis, which involves interplay between cholesterol metabolism and cellular inflammatory pathways, is primarily treated with statins since statins have lipid-lowering and anti-inflammatory properties. The Lupus Atherosclerosis Prevention Study (LAPS) was designed to investigate the efficacy of statins against CVD in SLE patients. LAPS demonstrated that 2 years of atorvastatin administration did not reduce atherosclerosis progression in lupus patients. In this LAPs substudy, we use cultured macrophages to explore the atherogenic properties of plasma from LAPS subjects to explain the mechanistic rationale for the inability of statins to reduce CVD in lupus. Materials and Methods: THP-1 differentiated macrophages were treated for 18 h with 10% SLE patient plasma obtained pre- and post-atorvastatin therapy or placebo. Gene expression of the following cholesterol transport genes was measured by qRT-PCR. For efflux-ATP binding cassette transporter (ABC)A1 and ABCG1, 27-hydroxylase, peroxisome proliferator-activated receptor (PPAR)γ, and liver X receptor (LXR)α; and for influx-cluster of differentiation 36 (CD36) and scavenger receptor (ScR)A1. Results: Macrophages exposed to plasma from both statin-treated and placebo-treated groups showed a significant decrease in cholesterol efflux proteins ATP binding cassette (ABC) transporters A1 and ABCG1, an increase in 27-hydroxylase, an increase in the LDL receptor and a decrease in intracellular free cholesterol. No change in influx receptors ScRA1 and CD36, nor nuclear proteins LXRα and PPARγ was observed. Conclusions: Statins do not normalize pro-atherogenic changes induced by lupus and these changes continue to worsen over time. This study provides mechanistic insight into LAPS findings by demonstrating that statins are overall ineffective in altering the balance of cholesterol transport gene expression in human macrophages. Furthermore, our study suggests that statins as a CVD treatment may not be useful in attenuating lipid overload in the SLE environment.
PMID: 31438615
ISSN: 1648-9144
CID: 4054012

Cholesterol efflux alterations in adolescent obesity: role of adipose-derived extracellular vesical microRNAs

Barberio, Matthew D; Kasselman, Lora J; Playford, Martin P; Epstein, Samuel B; Renna, Heather A; Goldberg, Madeleine; DeLeon, Joshua; Voloshyna, Iryna; Barlev, Ashley; Salama, Michael; Ferrante, Sarah C; Nadler, Evan P; Mehta, Nehal; Reiss, Allison B; Freishtat, Robert J
BACKGROUND:Macrophage cholesterol efflux capacity has been identified as a predictor for cardiovascular disease. We assessed the relationship between adipocyte-derived extracellular vesicle microRNAs and macrophage cholesterol efflux capacity. METHODS:) for: (1) cholesterol efflux capacity and lipoprotein profiles; (2) adipocyte-derived extracellular vesicle microRNAs in serum; (3) the role of visceral adipose tissue extracellular vesicle in regulation of cholesterol efflux and cholesterol efflux gene expression in THP-1 macrophages in vitro. RESULTS:Efflux capacity was significantly associated with HDL (r = 0.30, p = 0.01) and LDL (r = 0.33, p = 0.005) particle size. Multivariate-analysis identified six microRNAs associated (p < 0.05) with cholesterol efflux capacity: miR-3129-5p (Beta = 0.695), miR-20b (0.430), miR9-5p (0.111), miR-320d (- 0.190), miR301a-5p (0.042), miR-155-5p (0.004). In response to increasing concentrations (1 μg/mL vs. 3 μg/mL) of VAT extracellular vesicle, cholesterol efflux (66% ± 10% vs. 49% ± 2%; p < 0.01) and expression of ABCA1 (FC = 1.9 ± 0.8 vs 0.5 ± 0.2; p < 0.001), CD36 (0.7 ± 0.4 vs. 2.1 ± 0.8, p = 0.02), CYP27A1 (1.4 ± 0.4 vs. 0.9 ± 0.5; p < 0.05), and LXRA (1.8 ± 1.1 vs. 0.5 ± 0.2; p < 0.05) was altered in THP-1 cells in vitro. CONCLUSION/CONCLUSIONS:Adipocyte-derived extracellular vesicle microRNAs may, in part, be involved macrophage cholesterol efflux regulation.
PMID: 31331347
ISSN: 1479-5876
CID: 4014902