Faculty Bibliography
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23
Longitudinal Lower Airway Microbial Signatures of Acute Cellular Rejection in Lung Transplantation
PMID: 38358857
ISSN: 1535-4970
CID: 5633542
American journal of respiratory & critical care medicine. 2023:208(10):1101-1114.DOI: 10.1164/rccm.202210-1865OC
Lower Airway Dysbiosis Augments Lung Inflammatory Injury in Mild-to-Moderate Chronic Obstructive Pulmonary Disease
PMID: 37677136
ISSN: 1535-4970
CID: 5606572
TGFβ-2 Haploinsufficiency Causes Early Death in Mice with Marfan Syndrome
To assess the contribution of individual TGF-β isoforms to aortopathy in Marfan syndrome (MFS), we quantified the survival and phenotypes of mice with a combined fibrillin1 (the gene defective in MFS) hypomorphic mutation and a TGF-β1, 2, or 3 heterozygous null mutation. The loss of TGF-β2, and only TGF-β2, resulted in 80% of the double mutant animals dying earlier, by post-natal day 20, than MFS only mice. Death was not from thoracic aortic rupture, as observed in MFS mice, but was associated with hyperplastic aortic valve leaflets, aortic regurgitation, enlarged aortic root, increased heart weight, and impaired lung alveolar septation. Thus, there appears to be a relationship between loss of fibrillin1 and TGF-β2 in the post-natal development of the heart, aorta and lungs.
PMID: 37217119
ISSN: 1569-1802
CID: 5543662
American journal of respiratory cell & molecular biology. 2023:68(5):523-536.DOI: 10.1165/rcmb.2022-0269OC
Hedgehog and PDGF Signaling Intersect During Postnatal Lung Development
Normal lung development critically depends on Hedgehog (HH) and Platelet-derived growth factor (PDGF) signaling, which coordinate mesenchymal differentiation and proliferation. PDGF signaling is required for postnatal alveolar septum formation by myofibroblasts. Recently, we demonstrated a requirement for HH in postnatal lung development involving alveolar myofibroblast differentiation. Given shared features of HH and PDGF signaling and their impact/convergence on this key cell type, we sought to clarify their relationship during murine postnatal lung development. Timed experiments revealed that HH inhibition phenocopies the key lung myofibroblast phenotypes of Pdgfa and Pdgfra knockouts during secondary alveolar septation. Utilizing a dual signaling reporter, Gli1IZ;PdgfraEGFP
PMID: 36693140
ISSN: 1535-4989
CID: 5419542
Behcet's disease risk-variant HLA-B51/ERAP1-Hap10 alters human CD8 T cell immunity
OBJECTIVES/OBJECTIVE:, the classical risk factor for the disease. The mechanistic implications and biological consequences of this epistatic relationship are unknown. Here, we aimed to determine its biological relevance and functional impact. METHODS:LCL, analysed the HLA class I-bound peptidome for peptide length differences and assessed immunogenicity of genome-edited cells in CD8 T cell co-culture systems. RESULTS:KO cells showed peptidomes with longer peptides above 9mer and significant differences in their ability to stimulate alloreactive CD8 T cells compared with wild-type control cells. CONCLUSIONS:at the cellular level and point to an HLA-B51-restricted process. Our findings suggest that variant ERAP1-Hap10 partakes in BD pathogenesis by generating HLA-B51-restricted peptides, causing a change in immunodominance of the ensuing CD8 T cell response.
PMID: 35922122
ISSN: 1468-2060
CID: 5288102
Gpr125 is a unifying hallmark of multiple mammary progenitors coupled to tumor latency
Gpr125 is an orphan G-protein coupled receptor, with homology to cell adhesion and axonal guidance factors, that is implicated in planar polarity and control of cell movements. By lineage tracing we demonstrate that Gpr125 is a highly specific marker of bipotent mammary stem cells in the embryo and of multiple long-lived unipotent basal mammary progenitors in perinatal and postnatal glands. Nipple-proximal Gpr125+ cells express a transcriptomic profile indicative of chemo-repulsion and cell movement, whereas Gpr125+ cells concentrated at invasive ductal tips display a hybrid epithelial-mesenchymal phenotype and are equipped to bind chemokine and growth factors and secrete a promigratory matrix. Gpr125 progenitors acquire bipotency in the context of transplantation and cancer and are greatly expanded and massed at the pushing margins of short latency MMTV-Wnt1 tumors. High Gpr125 expression identifies patients with particularly poor outcome within the basal breast cancer subtype highlighting its potential utility as a factor to stratify risk.
PMID: 35302059
ISSN: 2041-1723
CID: 5181672
COVID-19 and Respiratory System Disorders: Current Knowledge, Future Clinical, and Translational Research Questions
The severe acute respiratory syndrome coronavirus-2 emerged as a serious human pathogen in late 2019, causing the disease coronavirus disease 2019 (COVID-19). The most common clinical presentation of severe COVID-19 is acute respiratory failure consistent with the acute respiratory distress syndrome. Airway, lung parenchymal, pulmonary vascular, and respiratory neuromuscular disorders all feature in COVID-19. This article reviews what is known about the effects of severe acute respiratory syndrome coronavirus-2 infection on different parts of the respiratory system, clues to understanding the underlying biology of respiratory disease, and highlights current and future translation and clinical research questions.
PMID: 32960072
ISSN: 1524-4636
CID: 4605602
Lung-derived HMGB1 is detrimental for vascular remodeling of metabolically imbalanced arterial macrophages
Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA). However, the mechanism underlying the pathological dialogue between the lungs and aorta is undefined. Here, we find that inflicting acute lung injury (ALI) to mice doubles their incidence of AAA and accelerates macrophage-driven proteolytic damage of the aortic wall. ALI-induced HMGB1 leaks and is captured by arterial macrophages thereby altering their mitochondrial metabolism through RIPK3. RIPK3 promotes mitochondrial fission leading to elevated oxidative stress via DRP1. This triggers MMP12 to lyse arterial matrix, thereby stimulating AAA. Administration of recombinant HMGB1 to WT, but not Ripk3-/- mice, recapitulates ALI-induced proteolytic collapse of arterial architecture. Deletion of RIPK3 in myeloid cells, DRP1 or MMP12 suppression in ALI-inflicted mice repress arterial stress and brake MMP12 release by transmural macrophages thereby maintaining a strengthened arterial framework refractory to AAA. Our results establish an inter-organ circuitry that alerts arterial macrophages to regulate vascular remodeling.
PMID: 32855420
ISSN: 2041-1723
CID: 4575922
Advances in Targeted Therapy for Progressive Fibrosing Interstitial Lung Disease
Progressive fibrosing interstitial lung disease (PF-ILD) has been redefined as a new clinical syndrome that shares similar genetics, pathophysiology, and natural history to idiopathic pulmonary fibrosis (IPF). IPF is the most common form of idiopathic interstitial pneumonias, which is progressive in nature and is associated with significant mortality. Therapies targeting an inflammatory and/or immune response have not been consistently effective or well tolerated in patients with IPF. The two antifibrotic drugs approved for IPF treatment, nintedanib and pirfenidone, have been shown to reduce lung function decline in PF-ILD. Novel uses of antifibrotic therapy are emerging due to a paucity of evidence-based treatments for multiple ILD subtypes. In this review, we describe the current body of knowledge on antifibrotic therapy and immunomodulators in PF-ILD, drawing from experience in IPF where appropriate.
PMID: 32591895
ISSN: 1432-1750
CID: 4494722
The Hedgehog target Gli1 is not required for bleomycin-induced lung fibrosis
Sonic Hedgehog (SHH) signaling, a developmental pathway promoting lung mesenchymal expansion and differentiation during embryogenesis, has been increasingly recognized as a profibrotic factor in mature lung, where it might contribute to the pathogenesis of lung fibrosis. Pathway inhibition at the level of the downstream Gli transcription factors Gli1 and Gli2 (by GANT61) ameliorates lung fibrosis in the bleomycin model, whereas inhibition proximally at the level of HH ligand (by anti Hh antibody 5E1) or Smo (by GDC-0449) of the canonical pathway does not, implicating Gli1 and/or Gli2 as a key target. The fact that both the Gli1-labelled cell lineage and Gli1 expressing cells expand during fibrosis formation and contribute significantly to the pool of myofibroblasts in the fibrosis scars suggests a fibrogenic role for Gli1. Therefore to further dissect the roles of Gli1 and Gli2 in lung fibrosis we evaluated Gli1 KO and control mice in the bleomycin model. Monitoring of Gli1+/+ (n = 12), Gli1lZ/+ (n = 37) and Gli1lZ/lZ (n = 18) mice did not reveal differences in weight loss or survival. Lung evaluation at the 21-day endpoint did not show differences in lung fibrosis formation (as judged by morphology and trichrome staining), Ashcroft score, lung collagen content, lung weight, BAL protein content or BAL cell differential count. Our data suggest that Gli1 is not required for bleomycin-induced lung fibrosis.
PMID: 30982371
ISSN: 1521-0499
CID: 3810282
