Paul A. Reyfman's research while affiliated with University of Illinois at Chicago and other places
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Publications (51)
Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyze the transcriptomes of 611,398 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung...
Introduction
The current framework for investigating respiratory diseases is based on defining lung health as the absence of lung disease. In order to develop a comprehensive approach to prevent the development of lung disease, there is a need to evaluate the full spectrum of lung health spanning from ideal to impaired lung health. The American Lun...
Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonar...
Some patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) develop severe pneumonia and the acute respiratory distress syndrome (ARDS)1. Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from other types of pneumonia2. We c...
Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using g...
Background:
CF patients demonstrate clinical heterogeneity and much remains unknown about how to risk stratify individuals for disease progression. The most common cystic fibrosis mutation, F508del, is a protein folding mutation that has been shown in vitro to negatively affect proteostasis and CFTR transcription. Since CFTR is expressed in the na...
Background & aims
Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in no...
Background
The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. A subset of COVID-19 patients progresses to severe disease, with high mortality and limited treatment options. Detailed knowledge of the expression regulation of genes...
Cigarette smoking, the leading cause of chronic obstructive pulmonary disease (COPD), has been implicated as a risk factor for severe disease in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we show that mice with lung epithelial cell-specific loss of function of Miz1 , which we identified as a negati...
The complex cellular heterogeneity of the lung poses a unique challenge to researchers in the field. While the use of bulk RNA sequencing has become a ubiquitous technology in systems biology, the technique necessarily averages out individual contributions to the overall transcriptional landscape of a tissue. Single-cell RNA sequencing (scRNA-seq)...
Influenza A virus (IAV) infection significantly contributes to global mortality each year. Previous studies have shown that monocyte-derived alveolar macrophages recruited to the lung drive injury during influenza infection. However, the exact timing and mechanism of macrophage-driven lung damage is unknown. Here, we define three distinct patterns...
Mitochondrial complex I regenerates NAD+ and proton pumps for TCA cycle function and ATP production, respectively. Mitochondrial complex I dysfunction has been implicated in many brain pathologies including Leigh syndrome and Parkinson’s disease. We sought to determine whether NAD+ regeneration or proton pumping, i.e., bioenergetics, is the dominan...
People with ataxia-telangiectasia (A-T) display phenotypic variability with regard to progression of immunodeficiency, sino-pulmonary disease, and neurologic decline. To determine the association between differential gene expression, epigenetic state, and phenotypic variation among people with A-T, we performed transcriptional and genome-wide DNA m...
We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmiss...
Aging is among the most important risk factors for the development of pulmonary fibrosis. We found that a small molecule that specifically inhibits translational inhibition induced by activation of the integrated stress response (ISRIB) attenuated the severity of pulmonary fibrosis in young and old mice. The more severe fibrosis in old compared to...
Ontologically distinct populations of macrophages differentially contribute to organ fibrosis through unknown mechanisms.
We applied lineage tracing, single-cell RNA sequencing and single-molecule fluorescence in situ hybridisation to a spatially restricted model of asbestos-induced pulmonary fibrosis.
We demonstrate that tissue-resident alveolar m...
A dysfunctional response to inhaled pathogens and toxins drives a substantial portion of the susceptibility to acute and chronic lung disease in the elderly. We used transcriptomic profiling combined with genetic lineage tracing, heterochronic adoptive transfer, parabiosis and treatment with metformin to show that the lung microenvironment defines...
Ontologically distinct populations of macrophages differentially contribute to organ fibrosis through unknown mechanisms. We applied lineage tracing, spatial methods and single-cell RNA-seq to a spatially-restricted model of asbestos-induced pulmonary fibrosis. We demonstrate that while tissue-resident interstitial macrophages, tissue-resident alve...
Background
The development of acute kidney injury (AKI) during an intensive care unit (ICU) admission is associated with increased morbidity and mortality.
Methods
Our objective was to develop and validate a data driven multivariable clinical predictive model for early detection of AKI among a large cohort of adult critical care patients. We utili...
Rationale: The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives: To determine whether single-cell RNA sequencing can r...
Rationale: The identification of informative elements of the host response to infection may improve the diagnosis and management of bacterial pneumonia. Objectives: To determine whether the absence of alveolar neutrophilia can exclude bacterial pneumonia in critically ill patients with suspected infection and to test whether signatures of bacterial...
Pulmonary fibrosis is a devastating disorder that results in the progressive replacement of normal lung tissue with fibrotic scar. Available therapies slow disease progression, but most patients go on to die or require lung transplantation. Single-cell RNA-seq is a powerful tool that can reveal cellular identity via analysis of the transcriptome, b...
Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Usi...
Primary graft dysfunction is the predominant driver of mortality and graft loss after lung transplantation. Recruitment of neutrophils as a result of ischemia-reperfusion injury is thought to cause primary graft dysfunction; however, the mechanisms that regulate neutrophil influx into the injured lung are incompletely understood. We found that dono...
Systems immunology is a growing field that attempts to integrate high-throughput experiments with sophisticated computational analysis and modeling approaches.¹ In the field of systems immunology, single-cell transcriptomic profiling (RNA-seq) is an experimental technique that has proven effective for delineating molecular heterogeneity within immu...
Citations
... Due to its high efficacy, low cost, and safety, the biguanide metformin is the most widely used oral anti-diabetic drug. In addition, potential clinical applications other than diabetes have been proposed, such as cancer prevention and treatment [1], anti-aging [2], anti-haze [3] activity, and other applications. Among them, validation of metformin's anti-tumor clinical efficacy and exploration of the underlying mechanism have become a hot spot in the field of cancer research. ...
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... 18 BAL with quantitative cell counts and cultures discriminates between colonization and infection with much greater accuracy than tracheal aspirates. [19][20][21] Although antibiotic stewardship can also reduce some unnecessary carbapenem use 22 (absent a clear microbiologic diagnosis), empiricism will continue to drive carbapenem consumption. ...
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... Multiple machine learning models for the AKI prediction in the ICU have been proposed. Zimmerman et al. [18] used a selection of variables from the MIMIC dataset to predict the levels of creatinine on the second and third days of ICU admission, as well as AKI thereafter. Logistic regression, random forest, and neural networks were used, with the highest AUC of 0.78. ...
... We know that neutrophils and monocytes constitute the first line of defense for innate immunity. Monocytes in donor grafts play an important role in recruiting granulocytes and promoting allograft dysfunction (54). The infiltration of activated neutrophils in organs promotes the expression of pro-inflammatory factors and chemokines, such as CCR2 (C-C motif chemokine receptor 2), leading to organ dysfunction. ...
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... However, growth factor availability from neighbouring cells may not always limit TRM number or location as macrophages can be autocrine for CSF1 [17], [18]. Alveolar macrophages in the asbestos-induced fibrotic niche produce PDGF that supports CSF1-producing fibroblasts, but these macrophages, in both humans and mice, can themselves produce CSF1 [19]. Autocrine CSF1 may therefore allow fibrosis to spread. ...
... Our understanding of the phenotype and function of resident and monocyte-derived macrophages and infiltrating monocytes in the context of chronic injury and fibrosis has been revolutionized in the past decade (8,(10)(11)(12)(13)(14)(15)(16). As a result, a growing research area is now dedicated to comprehend the interplay between ontogeny and polarization from birth to adulthood, in healthy and disease state (16)(17)(18)(19). ...
... Although additional factors, including age and the presence of chronic airway disease (including for instance asthma and chronic rhinosinusitis (CRS)) might influence susceptibility to their contribution is yet to be rigorously studied and results have been inconsistent. For instance, while Bunyavanich et al [11], reported that ACE2 expression in nasal epithelia increases with age, similar studies observed no association between age and ACE2 expression [12]. Lower ACE2 expression levels have also been noted in patients with asthma [13], while lower levels of TMPRSS2 were noted . ...
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... Our in situ analysis showed a wide expression of ACE2, the major SARS-CoV-2 receptor, in epithelial cells and interstitial macrophages, a profile that could further support local viral replication. We detected macrophages positive for SARS-CoV-2 mRNA, in line with recently published data [22,32], raising the possibility that these cells could affect the course of the disease at two levels: by contributing to local viral spread and by producing pro-inflammatory mediators [33]. The lung tissue of our COVID-19 cohort harbored a similar frequency of CD3 T cells as the non-COVID-19-DAD control group, with the majority of T cells expressing CD4 in both cohorts. ...
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... This includes recent international efforts towards building a human Lung Cell Atlas in health and disease 9 . A first draft of the cellular composition of mouse and human lung has been established [10][11][12][13][14] , and several recent single cell profiling studies reported cellular and molecular changes associated with pulmonary fibrosis [15][16][17][18] . However, this nascent draft of a human Lung Cell Atlas currently lacks extension into the complexity of the proteome layer. ...
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... miRNA-223-3p is anticipated to target ETC2 (epithelial cell transformation-2), SMAD1, FGFR2 (fibroblast growth factor 2 receptor), FGF2 (fibroblast growth factor 2), FOXO3 (Forkhead box O3), SPP1 (osteopontin), MMP16 (matrix metalloproteinase 16), PTEN, BCL2L11, and JAK-STAT signalling pathway. ETC2, a factor with established roles in cytokinesis and extracellular-signal-regulated kinase (ERK) signalling, was reported to be increased in IPF 55 . SMAD1 is a protein mediating TGF-b signalling, activated by α-SMA, that was delineated to be elevated in the skin of patients with SSc i liver fibrosis 56 . ...
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