A5053913643- Systemic Sclerosis and Related Diseases
- Immune cells in cancer
- Asthma and respiratory diseases
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Neonatal Respiratory Health Research
- IL-33, ST2, and ILC Pathways
- Immune Cell Function and Interaction
- Respiratory viral infections research
- Kruppel-like factors research
- Immunodeficiency and Autoimmune Disorders
- Pulmonary Hypertension Research and Treatments
- Adenosine and Purinergic Signaling
- Peroxisome Proliferator-Activated Receptors
- Medical Imaging and Pathology Studies
- Immunotherapy and Immune Responses
- Cytokine Signaling Pathways and Interactions
- Immune Response and Inflammation
- T-cell and B-cell Immunology
- Fibroblast Growth Factor Research
- Connective Tissue Growth Factor Research
- Sphingolipid Metabolism and Signaling
- NF-κB Signaling Pathways
- Cancer Cells and Metastasis
- Extracellular vesicles in disease
- Eosinophilic Disorders and Syndromes
University of Pittsburgh
2012-2024
University of Pittsburgh Medical Center
2018
Pulmonary and Allergy Associates
2015-2017
Western Michigan University
2016
Stryker (United States)
2016
A comprehensive understanding of the changes in gene expression cell types involved idiopathic pulmonary fibrosis (IPF) will shed light on mechanisms underlying loss alveolar epithelial cells and development honeycomb cysts fibroblastic foci. We sought to understand IPF lung transcriptomes gain insight into innate immune aspects pathogenesis. investigated pathogenesis using single-cell RNA-sequencing fresh explants, comparing human fibrotic lower lobes reflecting late disease, upper early...
Severe asthma (SA) is a challenge to control, as patients are not responsive high doses of systemic corticosteroids (CS). In contrast, mild-moderate (MMA) low inhaled CS, indicating that Th2 cells, which dominant in MMA, do solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and determined IFN-γ (Th1) immune responses exacerbated the airways individuals with SA, reduced IL-17 responses. We developed protocol recapitulates complex response...
Objectives Myofibroblasts are key effector cells in the extracellular matrix remodelling of systemic sclerosis-associated interstitial lung disease (SSc-ILD); however, diversity fibroblast populations present healthy and SSc-ILD is unknown has prevented specific study myofibroblast transcriptome. We sought to identify define transcriptomes myofibroblasts other mesenchymal cell human lungs understand how alterations phenotypes lead fibrosis. Methods performed droplet-based, single-cell...
Abstract Bacterial pneumonia is a significant healthcare burden worldwide. Failure to resolve inflammation after infection precipitates lung injury and an increase in morbidity mortality. Gram-negative bacteria are common increased levels of the mito-damage-associated molecular pattern (DAMP) cardiolipin can be detected lungs. Here we show that mice infected with Klebsiella pneumoniae develop accumulation cardiolipin. Cardiolipin inhibits resolution by suppressing production...
In this study, we sought a comprehensive understanding of myeloid cell types driving fibrosis in diffuse cutaneous systemic sclerosis (dcSSc) skin.We analyzed the transcriptomes 2,465 cells from skin biopsy specimens 12 dcSSc patients and 10 healthy control subjects using single-cell RNA sequencing. Monocyte-derived dendritic (mo-DCs) were assessed immunohistochemical staining immunofluorescence analyses targeting ficolin-1 (FCN-1).A t-distributed stochastic neighbor embedding analysis...
Severe asthma (SA) is a significant problem both clinically and economically, given its poor response to corticosteroids (CS). We recently reported complex type 1-dominated (IFN-γ-dominated) immune in more than 50% of severe asthmatics despite high-dose CS treatment. Also, IFN-γ was found be critical for increased airway hyperreactivity (AHR) our model SA. The transcription factor IRF5 expressed M1 macrophages can induce Th1/Th17 cocultured human T cells. Here we show markedly higher...
Objective: The mechanisms that lead to endothelial cell (EC) injury and propagate the vasculopathy in Systemic Sclerosis (SSc) are not well understood. Using single RNA sequencing (scRNA-seq), our goal was identify EC markers signature pathways associated with vascular SSc skin. Methods: We implemented sorting subsequent of cells isolated from healthy control used t-distributed stochastic neighbor embedding (t-SNE) various types. performed pathway analysis using Gene Set Enrichment Analysis...
Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of death in patients with SSc unclear pathogenesis and limited treatment options. Evidence strongly supports an important role for profibrotic secreted phosphoprotein 1 (SPP1)-expressing macrophages SSc-ILD. This study was undertaken to define transcriptome chromatin structural changes SPP1 SSc-ILD order better understand their promoting fibrosis identify transcription factors associated open driving...
Inhalation of environmental antigens such as allergens does not always induce inflammation in the respiratory tract. While antigen-presenting cells (APCs), including dendritic and macrophages, take up inhaled antigens, cell-intrinsic molecular mechanisms that prevent an inflammatory response during this process, activation transcription factor NF-κB, are well understood. Here, we show nuclear receptor PPARγ plays a critical role blocking NF-κB to preserve immune tolerance. Tolerance...
Systemic scleroderma (SSc) is an autoimmune disease that affects over 2.5 million people globally. SSc results in dysfunctional connective tissues with excessive profibrotic signaling, affecting skin, cardiovascular, and particularly lung tissue. Over three-quarters of individuals develop pulmonary fibrosis within 5 years, the main cause mortality. No approved medicines to manage currently exist. Recent research suggests signaling by transforming growth factor β (TGF-β) directly tied SSc....
Pulmonary hypertension (PH) is a common complication of systemic sclerosis (SSc) and leading cause mortality among patients with this disease. PH can also occur as an idiopathic condition (idiopathic pulmonary arterial hypertension). Investigation transcriptomic alterations in vascular populations critical to elucidating cellular mechanisms underlying pathobiology SSc-associated PH.
We reported previously that c-kit ligation by membrane-bound stem cell factor (mSCF) boosts IL-6 production in dendritic cells (DCs) and a Th17-immune response. However, Th17 establishment also requires heterodimeric IL-23, but the mechanisms regulate IL-23 gene expression DCs are not fully understood. show IL-23p19 lung is dependent on mSCF, which regulated metalloproteinase MMP-9. Th1-inducing conditions enhanced MMP-9 activity, causing cleavage of whereas opposite was true for...
Background: AVID200 is a novel, potent TGF-beta receptor ectodomain-based trap designed to selectively neutralize 1 and 3. These two isoforms have been implicated as central mediators of the pathogenesis systemic sclerosis (SSc). avoids inhibition 2, isoform that supports normal cardiac function hematopoiesis. Objectives: This first-in-human study (AVID200-01; NCT03831438 ) Phase 1, open label, multicenter, cohort dose-escalation trial evaluate safety, tolerability, pharmacokinetic (PK)...
Given the poor treatment options for pulmonary arterial hypertension associated systemic sclerosis (SSc-PAH) patients, we sought to determine clinical safety and efficacy of Dimethylfumarate (DMF), an Nrf2 agonist, effects on biomarkers oxidative stress SSc-PAH in exploratory interventional trial.The primary objectives were assess with DMF patients SSc-PAH.This was investigator-initiated, double-blind, randomized, placebo-controlled trial conducted at two sites United States. The endpoint...
Accumulation of excessive extracellular matrix (ECM) components from lung fibroblasts is a feature systemic sclerosis-associated interstitial disease (SSc-ILD), and there increasing evidence that innate immune signaling pathways contribute to these processes. Toll-like receptors (TLRs) are sensors activated by danger signals derived pathogens or host molecular patterns. Several damage-associated pattern (DAMP) molecules elevated in SSc-ILD plasma, including ligands activate TLR9, an sensor...
Abstract Objective Single-cell RNA sequencing(scRNA-seq) was performed to cells from whole human skin without pre-purifying reveal the transcriptional landscape and heterogeneity of macrophages dendritic cell (Mϕ/DC) subsets. Methods sequencing implemented ten enzymatically-digested biopsies analysis with Seurat, then gene ontology (GO) enrichment immunofluorescent staining. Results Upon scRNA-seq, 27869 samples were analyzed in Seurat 22 distinct clusters identified using smart local moving...
Abstract Bacterial pneumonia remains a significant burden worldwide. Although an inflammatory response in the lung is required to fight against pathogenic microorganisms, persistent inflammation leads collateral tissue damage and precipitates acute injury. Recently we have shown that interleukin (IL)-10 essential for resolution of with Klebsiella pneumoniae, bacterium commonly associated hospital-acquired pneumonia. IL-10-/- mice cleared bacteria, they displayed increased morbidity...
Abstract Dendritic cells (DCs) play a central role in regulating immune tolerance and activation but the molecular axis within DCs that dictates outcome is unknown. We investigated of Peroxisome proliferator-activated receptor-gamma (PPARγ) establishment airways using an experimental model. Using mice with selective deletion PPARγ CD11c+ (PPARγΔ) to ablate expression DCs, we show DC-specific exerts dual whose collective goal response inhaled antigen not only promote de novo Foxp3 T actively...
Abstract Severe asthma (SA) constitutes only 5-10% of all asthmatics but accounts for 50% the healthcare costs and morbidity associated with disease. SA patients remain symptomatic despite treatment high doses corticosteroids (CS), mainstay therapy. The presence neutrophils in has been correlated refractoriness to CS, fatal exacerbations severity. To date, our understanding pathological mechanisms central neutrophil-prominent is minimal primarily because lack a suitable animal model,...