Publications by authors named "Changwan Ryu"

24 Publications

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Defective early B cell tolerance checkpoints in patients with systemic sclerosis allow the production of self-antigen-specific clones.

Arthritis Rheumatol 2021 Jul 19. Epub 2021 Jul 19.

Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.

Objective: Early selection steps preventing autoreactive naïve B cell production are often impaired in patients with autoimmune diseases, but central and peripheral B cell tolerance checkpoints have not been assessed in patients with systemic sclerosis (SSc).

Methods: Using an in-vitro PCR-based approach that allows the expression of recombinant antibodies cloned from single B cells, we tested the reactivity of antibodies expressed by 212 CD19 CD21 CD10 IgM CD27 new emigrant/transitional and 190 CD19 CD21 CD10 IgM CD27 mature naïve B cells from ten patients with SSc.

Results: Patients with SSc displayed elevated proportions of polyreactive and anti-nuclear new emigrant/transitional B cells that recognize topoisomerase I when compared to healthy donors, suggesting defective central B cell tolerance contributes to the production of serum autoantibodies characteristic of the disease. Frequencies of autoreactive mature naïve B cells were also significantly increased in SSc patients and revealed an impaired peripheral B cell tolerance checkpoint.

Conclusion: Defective counterselection of developing autoreactive naïve B cells in SSc leads to the production of self-antigen specific B cells that may secrete autoantibodies and allow the formation of immune complexes, which promote fibrosis in SSc.
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http://dx.doi.org/10.1002/art.41927DOI Listing
July 2021

Elevated IL-15 concentrations in the sarcoidosis lung are independent of granuloma burden and disease phenotypes.

Am J Physiol Lung Cell Mol Physiol 2021 06 14;320(6):L1137-L1146. Epub 2021 Apr 14.

Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut.

Sarcoidosis is a systemic granulomatous disease predominantly affecting the lungs. The mechanisms promoting disease pathogenesis and progression are unknown, although interleukin-15 (IL-15) has been associated with the immune-mediated inflammation of sarcoidosis. Because the identification of a mechanistically based, clinically relevant biomarker for sarcoidosis remains elusive, we hypothesized this role for IL-15. Pulmonary sarcoidosis granuloma formation was modeled using trehalose 6,6'-dimicolate (TDM), which was administered into wild-type and three lineages of mice: those overexpressing IL-15, deficient in IL-15, and deficient in IL-15 receptor α. The number of granulomas per lung was counted and normalized to the wild type. IL-15 concentrations were measured in the bronchoalveolar lavage (BAL) from healthy controls and subjects with sarcoidosis in our cohort, where associations between IL-15 levels and clinical manifestations were sought. Findings were validated in another independent sarcoidosis cohort. TDM administration resulted in similar granuloma numbers across all lineages of mice. IL-15 concentrations were elevated in the BAL of both human cohorts, irrespective of disease phenotypes. In exploratory analysis, an association with obesity was observed, and various other soluble mediators were identified in the BAL of both cohorts. Although IL-15 is enriched in the sarcoidosis lung, it was independent of disease pathogenesis or clinical manifestations in our mouse model and human cohorts of sarcoidosis. An association with obesity perhaps reflects the ongoing inflammatory processes of these comorbid conditions. Our findings showed that IL-15 is redundant for disease pathogenesis and clinical progression of sarcoidosis.
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http://dx.doi.org/10.1152/ajplung.00575.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285626PMC
June 2021

Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension.

JCI Insight 2021 03 22;6(6). Epub 2021 Mar 22.

Yale Cardiovascular Research Center, Section of Cardiovascular Medicine.

Excess macrophages and smooth muscle cells (SMCs) characterize many cardiovascular diseases, but crosstalk between these cell types is poorly defined. Pulmonary hypertension (PH) is a lethal disease in which lung arteriole SMCs proliferate and migrate, coating the normally unmuscularized distal arteriole. We hypothesized that increased macrophage platelet-derived growth factor-B (PDGF-B) induces pathological SMC burden in PH. Our results indicate that clodronate attenuates hypoxia-induced macrophage accumulation, distal muscularization, PH, and right ventricle hypertrophy (RVH). With hypoxia exposure, macrophage Pdgfb mRNA was upregulated in mice, and LysM‑Cre mice carrying floxed alleles for hypoxia-inducible factor 1a, hypoxia-inducible factor 2a, or Pdgfb had reduced macrophage Pdgfb and were protected against distal muscularization and PH. Conversely, LysM‑Cre von-Hippel Lindaufl/fl mice had increased macrophage Hifa and Pdgfb and developed distal muscularization, PH, and RVH in normoxia. Similarly, Pdgfb was upregulated in macrophages from human idiopathic or systemic sclerosis-induced pulmonary arterial hypertension patients, and macrophage-conditioned medium from these patients increased SMC proliferation and migration via PDGF-B. Finally, in mice, orotracheal administration of nanoparticles loaded with Pdgfb siRNA specifically reduced lung macrophage Pdgfb and prevented hypoxia-induced distal muscularization, PH, and RVH. Thus, macrophage-derived PDGF-B is critical for pathological SMC expansion in PH, and nanoparticle-mediated inhibition of lung macrophage PDGF-B has profound implications as an interventional strategy for PH.
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http://dx.doi.org/10.1172/jci.insight.139067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026182PMC
March 2021

Macrophage-derived netrin-1 drives adrenergic nerve-associated lung fibrosis.

J Clin Invest 2021 01;131(1)

Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.

Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1-expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1's receptor, deleted in colorectal carcinoma; and therapeutic α1 adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1+ macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α1 adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1-driven adrenergic processes and introduced α1 blockers as a potentially new fibrotic therapy.
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http://dx.doi.org/10.1172/JCI136542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773383PMC
January 2021

A Clinic Blueprint for Post-Coronavirus Disease 2019 RECOVERY: Learning From the Past, Looking to the Future.

Chest 2021 03 4;159(3):949-958. Epub 2020 Nov 4.

Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT.

The severe acute respiratory syndrome coronavirus 2 pandemic poses extraordinary challenges. The tremendous number of coronavirus disease 2019 (COVID-19) cases in the United States has resulted in a large population of survivors with prolonged postinfection symptoms. The creation of multidisciplinary post-COVID-19 clinics to address both persistent symptoms and potential long-term complications requires an understanding of the acute disease and the emerging data regarding COVID-19 outcomes. Experience with severe acute respiratory syndrome and Middle East respiratory syndrome, post-acute respiratory distress syndrome complications, and post-intensive care syndrome also informs anticipated sequelae and clinical program design. Post-COVID-19 clinical programs should be prepared to care for individuals previously hospitalized with COVID-19 (including those who required critical care support), nonhospitalized individuals with persistent respiratory symptoms following COVID-19, and individuals with preexisting lung disease complicated by COVID-19. Effective multidisciplinary collaboration models leverage lessons learned during the early phases of the pandemic to overcome the unique logistical challenges posed by pandemic circumstances. Collaboration between physicians and researchers across disciplines will provide insight into survivorship that may shape the treatment of both acute disease and chronic complications. In this review, we discuss the aims, general principles, elements of design, and challenges of a successful multidisciplinary model to address the needs of COVID-19 survivors.
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http://dx.doi.org/10.1016/j.chest.2020.10.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641526PMC
March 2021

A 50-Year-Old Woman With Limited Scleroderma Presenting With Shortness of Breath.

Chest 2020 07 2;158(1):e37-e40. Epub 2020 Jul 2.

Yale University School of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, New Haven, CT. Electronic address:

Case Presentation: A 50-year-old woman with a medical history significant for limited scleroderma (SSc) complicated by interstitial lung disease (ILD) and pulmonary arterial hypertension presented to our institution with acute on chronic shortness of breath. Ten years before presentation, she was diagnosed with SSc. Two years before presentation, she was found to have ILD, for which she was started on mycophenolate mofetil and low-dose prednisone. One year before presentation, she noted worsening dyspnea on exertion (New York Heart Association Functional Class III) and required supplemental oxygen, up to 5 L, despite findings of stable ILD on a maintenance dose of mycophenolate mofetil. A subsequent right heart catheterization showed findings consistent with severe pulmonary arterial hypertension: right atrial pressure of 19 mm Hg, pulmonary arterial pressure of 98/39 mm Hg with a mean pulmonary arterial pressure of 58 mm Hg, right ventricular pressure of 59/6 mm Hg, pulmonary arterial wedge pressure of 10 mm Hg, cardiac output of 4.2 L/min with a cardiac index of 2.7 L/min/m, and a calculated pulmonary vascular resistance of 11.43 Wood units. She had no significant vasoreactivity on inhaled nitric oxide challenge. She was started on IV treprostinil that had been up-titrated over the course of 6 months before presentation. On admission, she denied any cough, fevers, chills, chest pains, palpitations, or lower extremity edema. She denied any sick contacts or any recent travel. She denied any periods of prolonged immobility.
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http://dx.doi.org/10.1016/j.chest.2020.02.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097629PMC
July 2020

Bioactive Plasma Mitochondrial DNA Is Associated With Disease Progression in Scleroderma-Associated Interstitial Lung Disease.

Arthritis Rheumatol 2020 11 8;72(11):1905-1915. Epub 2020 Oct 8.

Yale University School of Medicine, New Haven, Connecticut.

Objective: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterized by variable clinical outcomes, activation of innate immune pattern-recognition receptors (PRRs), and accumulation of α-smooth muscle actin (α-SMA)-expressing myofibroblasts. The aim of this study was to identify an association between these entities and mitochondrial DNA (mtDNA), an endogenous ligand for the intracellular DNA-sensing PRRs Toll-like receptor 9 (TLR-9) and cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING), which has yet to be determined.

Methods: Human lung fibroblasts (HLFs) from normal donors and SSc-ILD explants were treated with synthetic CpG DNA and assayed for α-SMA expression and extracellular mtDNA using quantitative polymerase chain reaction for the human MT-ATP6 gene. Plasma MT-ATP6 concentrations were evaluated in 2 independent SSc-ILD cohorts and demographically matched controls. The ability of SSc-ILD and control plasma to induce TLR-9 and cGAS/STING activation was evaluated with commercially available HEK 293 reporter cells. Plasma concentrations of type I interferons (IFNs), interleukin-6 (IL-6), and oxidized DNA were measured using electrochemiluminescence and enzyme-linked immunosorbent assay-based methods. Extracellular vesicles (EVs) precipitated from plasma were evaluated for MT-ATP6 concentrations and proteomics via liquid chromatography mass spectrometry.

Results: Normal HLFs and SSc-ILD fibroblasts developed increased α-SMA expression and MT-ATP6 release following CpG stimulation. Plasma mtDNA concentrations were increased in the 2 SSc-ILD cohorts, reflective of ventilatory decline, and were positively associated with both TLR-9 and cGAS/STING activation as well as type I IFN and IL-6 expression. Plasma mtDNA was not oxidized and was conveyed by EVs displaying a proteomics profile consistent with a multicellular origin.

Conclusion: These findings demonstrate a previously unrecognized connection between EV-encapsulated mtDNA, clinical outcomes, and intracellular DNA-sensing PRR activation in SSc-ILD. Further study of these interactions could catalyze novel mechanistic and therapeutic insights into SSc-ILD and related disorders.
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http://dx.doi.org/10.1002/art.41418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081728PMC
November 2020

Reduced Sialylation and Bioactivity of the Antifibrotic Protein Serum Amyloid P in the Sera of Patients with Idiopathic Pulmonary Fibrosis.

Immunohorizons 2020 06 23;4(6):352-362. Epub 2020 Jun 23.

Department of Biology, Texas A&M University, College Station, TX 77843; and

Pulmonary fibrosis is a chronic and generally fatal disorder characterized by progressive formation of scar-like tissue in the lungs. Sialic acids are often found as the terminal sugar on extracellular glycoconjugates such as protein glycosylations. Sialidases, also known as neuraminidases, desialylate glycoconjugates. Serum amyloid P (SAP), a pentameric serum glycoprotein that has two sialic acids on each polypeptide, inhibits the differentiation of monocytes into fibrocytes and promotes human PBMCs to accumulate high extracellular levels of IL-10. When SAP is desialylated with sialidase, the effects of SAP on fibrocyte differentiation and IL-10 accumulation are strongly inhibited. Intriguingly, in patients with pulmonary fibrosis, there are increased levels of sialidase activity in the bronchoalveolar lavage fluid, increased levels of sialidases in the lungs, and decreased levels of SAP in the sera. To elucidate the role of SAP desialylation in idiopathic pulmonary fibrosis (IPF) pathogenesis, we purified SAP from the serum of IPF patients and healthy controls and measured the extent of sialylation and bioactivity of the purified SAP. We find that some IPF patients have abnormally high levels of the sialidase NEU3 in their sera and that the SAP in the sera of IPF patients has an abnormally high extent of desialylation and an abnormally low ability to inhibit fibrocyte differentiation and induce extracellular IL-10 accumulation by PBMC. These results suggest that SAP desialylation may play a role in IPF pathogenesis and that inhibiting NEU3 could be a potential therapeutic target for IPF.
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http://dx.doi.org/10.4049/immunohorizons.2000043DOI Listing
June 2020

GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis.

Am J Physiol Lung Cell Mol Physiol 2019 10 21;317(4):L510-L521. Epub 2019 Aug 21.

Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania.

Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 (), as the most significantly upregulated secreted protein. expression is induced in response to telomere dysfunction and bleomycin challenge in mice. mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of , and circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that GDF15 is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes.
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http://dx.doi.org/10.1152/ajplung.00062.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842909PMC
October 2019

Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis.

Eur Respir J 2019 08 29;54(2). Epub 2019 Aug 29.

Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA

Sarcoidosis is an unpredictable granulomatous disease in which African Americans disproportionately experience aggressive phenotypes. Mitochondrial DNA (mtDNA) released by cells in response to various stressors contributes to tissue remodelling and inflammation. While extracellular mtDNA has emerged as a biomarker in multiple diseases, its relevance to sarcoidosis remains unknown. We aimed to define an association between extracellular mtDNA and clinical features of sarcoidosis.Extracellular mtDNA concentrations were measured using quantitative PCR for the human gene in bronchoalveolar (BAL) and plasma samples from healthy controls and patients with sarcoidosis from The Yale Lung Repository; associations between concentrations and Scadding stage, extrapulmonary disease and demographics were sought. Results were validated in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cohort.Relative to controls, concentrations in sarcoidosis subjects were robustly elevated in the BAL fluid and plasma, particularly in the plasma of patients with extrapulmonary disease. Relative to Caucasians, African Americans displayed excessive concentrations in the BAL fluid and plasma, for which the latter compartment correlated with significantly higher odds of extrapulmonary disease.Enrichments in extracellular mtDNA in sarcoidosis are associated with extrapulmonary disease and African American descent. Further study into the mechanistic basis of these clinical findings may lead to novel pathophysiologic and therapeutic insights.
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http://dx.doi.org/10.1183/13993003.01762-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088542PMC
August 2019

Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3.

Life Sci Alliance 2019 06 13;2(3). Epub 2019 May 13.

Molecular Microbiology and Immunology, Brown University, Providence, RI, USA

TGF-β1 is a critical mediator of tissue fibrosis in health and disease whose effects are augmented by chitinase 1 (CHIT1). However, the mechanisms that CHIT1 uses to regulate TGF-β1-mediated fibrotic responses have not been defined. Here, we demonstrate that CHIT1 enhances TGF-β1-stimulated fibrotic cellular and tissue responses and TGF-β1 signaling. Importantly, we also demonstrate that these effects are mediated by the ability of CHIT1 to inhibit TGF-β1 induction of its feedback inhibitor, SMAD7. CHIT1 also interacted with TGF-β receptor associated protein 1 (TGFBRAP1) and forkhead box O3 (FOXO3) with TGFBRAP1 playing a critical role in CHIT1 enhancement of TGF-β1 signaling and effector responses and FOXO3 playing a critical role in TGF-β1 induction of SMAD7. These pathways were disease relevant because the levels of CHIT1 were increased and inversely correlated with SMAD7 in tissues from patients with idiopathic pulmonary fibrosis or scleroderma-associated interstitial lung disease. These studies demonstrate that CHIT1 regulates TGF-β1/SMAD7 axis via TGFBRAP1 and FOXO3 and highlight the importance of these pathways in the pathogenesis of pulmonary fibrosis.
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http://dx.doi.org/10.26508/lsa.201900350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516052PMC
June 2019

New Applications of Old Drugs as Novel Therapies in Idiopathic Pulmonary Fibrosis. Metformin, Hydroxychloroquine, and Thyroid Hormone.

Am J Respir Crit Care Med 2019 Jun;199(12):1561-1563

Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1164/rccm.201809-1700RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051474PMC
June 2019

LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis.

Circulation 2019 01;139(5):679-693

Departments of Medicine (Cardiovascular Medicine) (Y.X., A.C.O., Y.J., K.A.M., J.H.), Yale University, New Haven, CT.

Background: Vascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor β (TGF-β) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM (Lin11, Isl-1 & Mec-3) domain protein LIM domain only 7 (LMO7) is a TGF-β1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown.

Methods: We use carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle-specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula and cardiac allograft vasculopathy samples to assess the role of LMO7 in neointima and fibrosis.

Results: We demonstrate that LMO7 is induced postinjury and by TGF-β in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-β signaling, ECM deposition, and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and after TGF-β treatment. TGF-β neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-β signaling by inducing expression of Tgfb1 mRNA, TGF-β protein, αv and β3 integrins that promote activation of latent TGF-β, and downstream effectors SMAD3 phosphorylation and connective tissue growth factor. Mechanistically, the LMO7 LIM domain interacts with activator protein 1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting activator protein 1-dependent TGF-β autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula and cardiac allograft vasculopathy samples, and inversely correlates with SMAD3 phosphorylation in cardiac allograft vasculopathy.

Conclusions: LMO7 is induced by TGF-β and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-β pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371979PMC
January 2019

A rare presentation of pulmonary sarcoidosis as a solitary lung mass: a case report.

J Med Case Rep 2018 Apr 13;12(1):94. Epub 2018 Apr 13.

Department of Internal Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, 300 Cedar Street, TAC 441 South, P.O. Box 208057, New Haven, CT, 06520, USA.

Background: Sarcoidosis is a multisystem, chronic granulomatous disease of unknown etiology that predominantly affects the lungs. Pulmonary sarcoidosis classically presents with constitutional symptoms and computed tomographic scan findings of bilateral, symmetric micronodules in a peribronchovascular distribution with upper and middle lung zone predominance accompanied by bilateral, symmetric hilar lymphadenopathy. A solitary lung mass is a rare finding for pulmonary sarcoidosis, and with its associated constitutional symptoms, it strongly mimics a malignancy. We aimed to provide further insight into the broad differential diagnosis of a lung mass by describing our experiences in the care of a patient who presented with clinical and radiographic features of lung cancer who was ultimately found to have an atypical manifestation of stage II pulmonary sarcoidosis.

Case Presentation: A 44-year-old African American woman with a history of childhood asthma and type 2 diabetes mellitus presented with shortness of breath. After being treated for a presumed asthma exacerbation with prednisone, she experienced worsening dyspnea, night sweats, and unintentional weight loss. Further evaluation revealed a large left lower lobe mass and hilar lymphadenopathy. A computed tomography-guided biopsy of the lung mass revealed a multifocal non-necrotizing granuloma with multinucleated giant cells. Although consistent with sarcoidosis, this finding could represent a sarcoid-like reaction secondary to an occult malignancy. A more extensive repeat biopsy via bronchoscopy and mediastinoscopy revealed granulomatous inflammation without evidence of malignancy or infection. These procedures confirmed the diagnosis of pulmonary sarcoidosis, and she was started on treatment with high-dose prednisone. Her treatment course was complicated by hyperglycemia necessitating insulin therapy, but after 3 months of therapy, she reported improvement in her dyspnea, and repeat imaging revealed a significant decrease in the size of the lung mass and lymphadenopathy. Given her clinical and radiographic response, she was continued on a prednisone taper.

Conclusions: Atypical manifestations of pulmonary sarcoidosis are diagnostically challenging because the clinical and radiographic features of the disease mimic those of a malignancy. We aimed to illustrate a unique etiology of a lung mass and the importance of maintaining a broad differential diagnosis. Nonetheless, with the possibility of a malignancy, a high index of suspicion is necessary for timely diagnosis and optimal management.
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http://dx.doi.org/10.1186/s13256-018-1632-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897926PMC
April 2018

S100A12 as a marker of worse cardiac output and mortality in pulmonary hypertension.

Respirology 2018 08 2;23(8):771-779. Epub 2018 Apr 2.

Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

Background And Objective: Molecular biomarkers are needed to refine prognostication and phenotyping of pulmonary hypertension (PH) patients. S100A12 is an emerging biomarker of various inflammatory diseases. This study aims to determine the prognostic value of S100A12 in PH.

Methods: Exploratory microarray analysis performed on peripheral blood mononuclear cells (PBMC) collected from idiopathic pulmonary fibrosis (IPF) patients suggested an association between S100A12 and both PH and mortality. So the current study was designed to evaluate for an association between S100A12 in peripheral blood collected from two well-phenotyped PH cohorts in two other centres to derive and validate an association between S100A12 protein serum concentrations and mortality.

Results: The majority of the patients in the discovery and validation cohorts were either World Health Organization (WHO) group 1 (pulmonary arterial hypertension (PAH)) or 3 (lung disease-associated) PH. In the discovery PH cohort, S100A12 was significantly increased in patients with PH (n = 51) compared to controls (n = 22) (29.8 vs 15.7 ng/mL, P < 0.001) and negatively correlated with cardiac output (r = -0.58, P < 0.001) in PH patients. When S100A12 data were pooled from both cohorts, PAH and non-PAH PH patients had higher S100A12 compared to healthy external controls (32.6, 30.9, 15.7 ng/mL; P < 0.001). S100A12 was associated with an increased risk in overall mortality in PH patients in both the discovery (n = 51; P = 0.008) and validation (n = 40; P < 0.001) cohorts.

Conclusion: S100A12 levels are increased in PH patients and are associated with increased mortality.
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http://dx.doi.org/10.1111/resp.13302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047907PMC
August 2018

A novel endobronchial approach to massive hemoptysis complicating silicone Y-stent placement for tracheobronchomalacia: A case report.

Medicine (Baltimore) 2018 Feb;97(8):e9980

Yale School of Medicine, Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine Yale School of Medicine, Department of Thoracic Surgery, New Haven, CT, USA.

Rationale: Airway stabilization for severe, symptomatic tracheobronchomalacia (TBM) may be accomplished by silicone Y-stent placement. Common complications of the Y-stent include mucus plugging and granulation tissue formation.

Patient Concerns: We describe a rare case of massive hemoptysis originating from a silicone Y-stent placed for TBM.

Diagnoses: An emergent bronchoscopy showed an actively bleeding, pulsatile vessel at the distal end of the left bronchial limb of the Y-stent. It was felt that the bleeding was caused by, or at least impacted by, the distal left bronchial limb of the Y-stent eroding into the airway wall.

Interventions: We hypothesized that placement of oxidized regenerated cellulose (ORC) would provide initial hemostasis, and the subsequent placement of a biocompatible surgical sealant would lead to definitive resolution.

Outcomes: ORC provided sufficient hemostasis and the subsequent synthetic polymer reinforced the tissue for complete cessation of the bleed.

Lessons: The combined use of ORC and a biocompatible surgical sealant provided long-term management for life-threatening hemoptysis, and potentially morbid procedures such as embolization or surgery were avoided by advanced endobronchial therapy.
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http://dx.doi.org/10.1097/MD.0000000000009980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842006PMC
February 2018

Antifibrotic role of vascular endothelial growth factor in pulmonary fibrosis.

JCI Insight 2017 Aug 17;2(16). Epub 2017 Aug 17.

Yale University School of Medicine, New Haven, Connecticut, USA.

The chronic progressive decline in lung function observed in idiopathic pulmonary fibrosis (IPF) appears to result from persistent nonresolving injury to the epithelium, impaired restitution of the epithelial barrier in the lung, and enhanced fibroblast activation. Thus, understanding these key mechanisms and pathways modulating both is essential to greater understanding of IPF pathogenesis. We examined the association of VEGF with the IPF disease state and preclinical models in vivo and in vitro. Tissue and circulating levels of VEGF were significantly reduced in patients with IPF, particularly in those with a rapidly progressive phenotype, compared with healthy controls. Lung-specific overexpression of VEGF significantly protected mice following intratracheal bleomycin challenge, with a decrease in fibrosis and bleomycin-induced cell death observed in the VEGF transgenic mice. In vitro, apoptotic endothelial cell-derived mediators enhanced epithelial cell injury and reduced epithelial wound closure. This process was rescued by VEGF pretreatment of the endothelial cells via a mechanism involving thrombospondin-1 (TSP1). Taken together, these data indicate beneficial roles for VEGF during lung fibrosis via modulating epithelial homeostasis through a previously unrecognized mechanism involving the endothelium.
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http://dx.doi.org/10.1172/jci.insight.92192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621899PMC
August 2017

Extracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2017 12;196(12):1571-1581

4 Department of Pathology, Stony Brook University School of Medicine, Stony Brook, New York.

Rationale: Idiopathic pulmonary fibrosis (IPF) involves the accumulation of α-smooth muscle actin-expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor-β1 (TGF-β1) and mechanical influences such as local tissue stiffness. Whereas IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA), have not been identified in IPF.

Objectives: We aimed to define an association between mtDNA and fibroblast responses in IPF.

Methods: We evaluated the response of normal human lung fibroblasts (NHLFs) to stimulation with mtDNA and determined whether the glycolytic reprogramming that occurs in response to TGF-β1 stimulation and direct contact with stiff substrates, and spontaneously in IPF fibroblasts, is associated with excessive levels of mtDNA. We measured mtDNA concentrations in bronchoalveolar lavage (BAL) from subjects with and without IPF, as well as in plasma samples from two longitudinal IPF cohorts and demographically matched control subjects.

Measurements And Main Results: Exposure to mtDNA augments α-smooth muscle actin expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGF-β1 or stiff hydrogels are accompanied by the accumulation of extracellular mtDNA. These findings replicate the spontaneous phenotype of IPF fibroblasts. mtDNA concentrations are increased in IPF BAL and plasma, and in the latter compartment, they display robust associations with disease progression and reduced event-free survival.

Conclusions: These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF.
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http://dx.doi.org/10.1164/rccm.201612-2480OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754440PMC
December 2017

Upper Airway Obstruction Requiring Emergent Tracheostomy Secondary to Laryngeal Sarcoidosis: A Case Report.

Am J Case Rep 2017 Feb 13;18:157-159. Epub 2017 Feb 13.

Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA.

BACKGROUND Laryngeal sarcoidosis is a rare extrapulmonary manifestation of sarcoidosis, accounting for 0.33-2.1% of cases. A life-threatening complication of laryngeal sarcoidosis is upper airway obstruction. In this report we describe our experience in the acute and chronic care of a patient who required an emergent tracheostomy, with the aim to provide further insight into this difficult to manage disease. CASE REPORT A 37-year-old African American female with a 10-year history of stage 1 sarcoidosis presented with severe dyspnea. Laryngeal sarcoidosis was diagnosed three years previously, and she remained stable on low-dose prednisone until six months prior to admission, at which time she self-discontinued her prednisone for the homeopathic treatment Nopalea cactus juice. Her physical examination was concerning for impending respiratory failure as she presented with inspiratory stridor and hoarseness. Laryngoscopy showed a retroflexed epiglottis obstructing the glottis with edematous arytenoids and aryepiglottic folds. Otolaryngology performed an emergent tracheostomy to secure her airway and obtained epiglottic biopsies, which were consistent with sarcoidosis. She was eventually discharged home on prednisone 60 mg daily. Following months of corticosteroids, a laryngoscopy showed the epiglottis continuing to obstruct the glottis. The addition of methotrexate to a tapered dosage of prednisone 10 mg daily was unsuccessful, and she remains on prednisone 20 mg daily for disease control. CONCLUSIONS Laryngeal sarcoidosis, a rare extrapulmonary manifestation of sarcoidosis, uncommonly presents as the life-threatening complication of complete upper airway obstruction. As such, laryngeal sarcoidosis is associated with significant morbidity and mortality, requiring a high index of suspicion for timely diagnosis and treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319306PMC
http://dx.doi.org/10.12659/ajcr.902231DOI Listing
February 2017

Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis.

Respirology 2017 04 19;22(3):486-493. Epub 2016 Oct 19.

Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.

Background And Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and variable clinical course. Although matrix metalloproteinase-7 (MMP-7) is emerging as an important IPF biomarker, reproducibility across studies is unclear. We aimed to determine whether a previously reported prognostic threshold for MMP-7 was predictive of mortality in an independent cohort of IPF patients.

Methods: MMP-7 concentrations obtained from heparinized plasma samples were determined by ELISA in 97 patients with IPF and 41 healthy controls. The association of the previously published heparin plasma MMP-7 threshold of 12.1 ng/mL with all-cause mortality or transplant-free survival (TFS) was determined, either as an independent biomarker or as part of the modified personal clinical and molecular mortality index (m-PCMI).

Results: MMP-7 plasma concentrations were significantly higher in IPF patients compared to healthy controls (14.40 ± 6.55 ng/mL vs 6.03 ± 2.51 ng/mL, P < 0.001). The plasma MMP-7 threshold of 12.1 ng/mL was significantly associated with both all-cause mortality and TFS (unadjusted Cox proportional hazard ratio (HR) = 25.85 and 15.49, 95% CI: 10.91-61.23 and 5.41-44.34, respectively, P < 0.001). MMP-7 concentrations, split by 12.1 ng/mL, were significantly (P < 0.05) predictive of mortality and TFS after adjusting for age, gender, smoking and baseline pulmonary function parameters, in a multivariate Cox proportional hazards model. MMP-7 concentrations were negatively correlated with diffusing lung capacity of carbon monoxide (DL ) (r = -0.21, P = 0.02), and positively with a mortality risk scoring system (GAP) that combines age, gender, forced vital capacity (FVC) and DL (r = 0.32, P = 0.001).

Conclusion: This study confirms that MMP-7 concentrations could be used to accurately predict outcomes across cohorts and centres, when similar collection protocols are applied.
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http://dx.doi.org/10.1111/resp.12920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352520PMC
April 2017

Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis.

FASEB J 2016 12 8;30(12):4056-4070. Epub 2016 Sep 8.

Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA;

Pulmonary fibrosis is a progressive and often fatal condition that is believed to be partially orchestrated by macrophages. Mechanisms that control migration of these cells into and within the lung remain undefined. We evaluated the contributions of the semaphorin receptor, plexin C1 (PLXNC1), and the exocytic calcium sensor, synaptotagmin 7 (Syt7), in these processes. We evaluated the role of PLXNC1 in macrophage migration by using Boyden chambers and scratch tests, characterized its contribution to experimentally induced lung fibrosis in mice, and defined the mechanism for our observations. Our findings reveal that relative to control participants, patients with idiopathic pulmonary fibrosis demonstrate excessive monocyte migration and underexpression of PLXNC1 in the lungs and circulation, a finding that is recapitulated in the setting of scleroderma-related interstitial lung disease. Relative to wild type, PLXNC1 mouse macrophages are excessively migratory, and PLXNC1 mice show exacerbated collagen accumulation in response to either inhaled bleomycin or inducible lung targeted TGF-β1 overexpression. These findings are ameliorated by replacement of PLXNC1 on bone marrow-derived cells or by genetic deletion of Syt7. These data demonstrate the previously unrecognized observation that PLXNC1 deficiency permits Syt7-mediated macrophage migration and enhances mammalian lung fibrosis.-Peng, X., Moore, M., Mathur, A., Zhou, Y., Sun, H., Gan, Y., Herazo-Maya, J. D., Kaminski, N., Hu, X., Pan, H., Ryu, C., Osafo-Addo, A., Homer, R. J., Feghali-Bostwick, C., Fares, W. H., Gulati, M., Hu, B., Lee, C.-G., Elias, J. A., Herzog, E. L. Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis.
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http://dx.doi.org/10.1096/fj.201600373RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102121PMC
December 2016

Management of an elderly patient with respiratory failure due to double aortic arch.

Respir Med Case Rep 2016 17;17:37-9. Epub 2015 Dec 17.

Yale University School of Medicine, Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, United states.

Vascular rings are congenital malformations of the aortic arch. A double aortic arch (DAA), the most common type of vascular ring, results from the failure of the fourth embryonic branchial arch to regress, leading to an ascending aorta that divides into a left and right arch that fuse together to completely encircle the trachea and esophagus. The subsequent DAA causes compressive effects on the trachea and esophagus that typically manifests in infancy or early childhood. Adult presentations, particularly in the elderly, are exceedingly rare. Historically such patients have a long-standing history of dyspnea on exertion and dysphagia, with many assumed to have obstructive lung or intrinsic cardiac disease. We describe a case of an elderly woman who presented with respiratory failure due to DAA. In her case, surgery was not feasible and we describe our experience with airway stenting.
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http://dx.doi.org/10.1016/j.rmcr.2015.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821450PMC
May 2016

The Airway in Idiopathic Pulmonary Fibrosis: Protecting the Lung or Promoting Disease?

Am J Respir Crit Care Med 2016 05;193(10):1081-2

1 Department of Internal Medicine Yale University School of Medicine New Haven, Connecticut and.

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http://dx.doi.org/10.1164/rccm.201601-0055EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872674PMC
May 2016
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