Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all ...collagen-producing cells in normal and fibrotic lungs. We characterize multiple collagen-producing subpopulations with distinct anatomical localizations in different compartments of murine lungs. One subpopulation, characterized by expression of Cthrc1 (collagen triple helix repeat containing 1), emerges in fibrotic lungs and expresses the highest levels of collagens. Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and CTHRC1-expressing fibroblasts present uniquely in fibrotic lungs. Immunostaining and in situ hybridization show that these cells are concentrated within fibroblastic foci. We purify collagen-producing subpopulations and find disease-relevant phenotypes of Cthrc1-expressing fibroblasts in in vitro and adoptive transfer experiments. Our atlas of collagen-producing cells provides a roadmap for studying the roles of these unique populations in homeostasis and pathologic fibrosis.
Influenza viral infections often lead to increased mortality in older people. However, the mechanisms by which aging impacts immunity to influenza lung infection remain unclear. We employed a murine ...model of influenza infection to identify these mechanisms. With aging, we found reduced numbers of alveolar macrophages, cells essential for lung homeostasis. We also determined that these macrophages are critical for influenza-induced mortality with aging. Furthermore, aging vastly alters the transcriptional profile and specifically downregulates cell cycling pathways in alveolar macrophages. Aging impairs the ability of alveolar macrophages to limit lung damage during influenza infection. Moreover, aging decreases alveolar macrophage phagocytosis of apoptotic neutrophils, downregulates the scavenging receptor CD204, and induces retention of neutrophils during influenza infection. Thus, aging induces defective phagocytosis by alveolar macrophages and increases lung damage. These findings indicate that therapies that enhance the function of alveolar macrophages may improve outcomes in older people infected with respiratory viruses.
More than 300 million people carry a diagnosis of asthma, with data to suggest that they are at a higher risk for infection or adverse outcomes from severe acute respiratory syndrome coronavirus 2. ...Asthma is remarkably heterogeneous, and it is currently unclear how patient-intrinsic factors may relate to coronavirus disease 2019.
We sought to identify and characterize subsets of patients with asthma at increased risk for severe acute respiratory syndrome coronavirus 2 infection.
Participants from 2 large asthma cohorts were stratified using clinically relevant parameters to identify factors related to angiotensin-converting enzyme-2 (ACE2) expression within bronchial epithelium. ACE-2–correlated gene signatures were used to interrogate publicly available databases to identify upstream signaling events and novel therapeutic targets.
Stratifying by type 2 inflammatory biomarkers, we identified subjects who demonstrated low peripheral blood eosinophils accompanied by increased expression of the severe acute respiratory syndrome coronavirus 2 receptor ACE2 in bronchial epithelium. Genes highly correlated with ACE2 overlapped with type 1 and 2 IFN signatures, normally induced by viral infections. T-cell recruitment and activation within bronchoalveolar lavage cells of ACE2-high subjects was reciprocally increased. These patients demonstrated characteristics corresponding to risk factors for severe coronavirus disease 2019, including male sex, history of hypertension, low peripheral blood, and elevated bronchoalveolar lavage lymphocytes.
ACE2 expression is linked to upregulation of viral response genes in a subset of type 2–low patients with asthma with characteristics resembling known risk factors for severe coronavirus disease 2019. Therapies targeting the IFN family and T-cell–activating factors may therefore be of benefit in a subset of patients.
Idiopathic pulmonary fibrosis (IPF) is a lethal chronic lung disorder with no effective treatment and a prognosis worse than that of lung cancer. Despite extensive research efforts, its etiology and ...pathogenesis still remain largely unknown. Current experimental evidence has shifted the disease paradigm from chronic inflammation towards the premise of abnormal epithelial wound repair in response to repeated epigenetic injurious stimuli in genetically predisposed individuals. Epigenetics is defined as the study of heritable changes in gene function by factors other than an individual's DNA sequence, providing valuable information regarding adaption of genes to environmental changes. Although cancer is the most studied disease with relevance to epigenetic modifications, recent data support the idea that epigenomic alterations may lead to variable disease phenotypes, including fibroproliferative lung disorders such as IPF. This review article summarizes the latest experimental and translational epigenetic studies in the research field of chronic lung disorders, mainly focusing on IPF, highlights current methodology limitations, and underlines future directions and perspectives.
The authors discuss evidence suggesting that embryonic signaling pathways involved in epithelium/mesenchymal communication and epithelial cell plasticity may be aberrantly switched on in idiopathic ...pulmonary fibrosis.
Biomarkers in idiopathic pulmonary fibrosis Zhang, Yingze; Kaminski, Naftali
Current opinion in pulmonary medicine,
2012-September, 2012-Sep, 2012-09-00, 20120901, Letnik:
18, Številka:
5
Journal Article
Odprti dostop
PURPOSE OF REVIEWThis review examines the recent literature on molecular biomarkers of idiopathic pulmonary fibrosis (IPF). Specific attention is dedicated to the recent studies that identified the ...genes associated with IPF and the peripheral blood biomarkers that predict outcome in IPF.
RECENT FINDINGSMultiple studies attempted to identify diagnostic and predictive biomarkers in IPF. Until recently, these studies were limited in size and lacked replication, but still when taken together provided convincing evidence that changes in blood proteins (KL-6, SP-A, MMP-7, CCL-18, among others) or cells (fibrocytes and T-cell subpopulations) are indicative of the disease presence and outcome. More recently, larger studies have identified gene polymorphisms associated with IPF, as well as protein markers and integrated clinical and molecular prediction rules that accurately predict outcome in patients with IPF.
SUMMARYThe peripheral blood contains disease presence and outcome relevant information, and suggests distinct biologically defined outcome trajectories in patients with IPF. Although recently identified biomarkers should still be validated in multiple clinical contexts, there is sufficient evidence to suggest that collection of peripheral blood biomarkers needs to be incorporated in the design of drug studies and that some of these markers be clinically evaluated in lung transplant prioritization.
Single-cell RNA-sequencing data has revolutionized our ability to understand of the patterns of cell-cell and ligand-receptor connectivity that influence the function of tissues and organs. However, ...the quantification and visualization of these patterns in a way that informs tissue biology are major computational and epistemological challenges. Here, we present Connectome, a software package for R which facilitates rapid calculation and interactive exploration of cell-cell signaling network topologies contained in single-cell RNA-sequencing data. Connectome can be used with any reference set of known ligand-receptor mechanisms. It has built-in functionality to facilitate differential and comparative connectomics, in which signaling networks are compared between tissue systems. Connectome focuses on computational and graphical tools designed to analyze and explore cell-cell connectivity patterns across disparate single-cell datasets and reveal biologic insight. We present approaches to quantify focused network topologies and discuss some of the biologic theory leading to their design.
Uncontrolled extracellular matrix production by fibroblasts in response to tissue injury contributes to fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), a progressive and ultimately ...fatal process that currently has no cure. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in fibrotic lung diseases is unclear. In this study, we found up-regulation of miR-21 in the lungs of mice with bleomycin-induced fibrosis and also in the lungs of patients with IPF. Increased miR-21 expression was primarily localized to myofibroblasts. Administration of miR-21 antisense probes diminished the severity of experimental lung fibrosis in mice, even when treatment was started 5-7 d after initiation of pulmonary injury. TGF-beta1, a central pathological mediator of fibrotic diseases, enhanced miR-21 expression in primary pulmonary fibroblasts. Increasing miR-21 levels promoted, whereas knocking down miR-21 attenuated, the pro-fibrogenic activity of TGF-beta1 in fibroblasts. A potential mechanism for the role of miR-21 in fibrosis is through regulating the expression of an inhibitory Smad, Smad7. These experiments demonstrate an important role for miR-21 in fibrotic lung diseases and also suggest a novel approach using miRNA therapeutics in treating clinically refractory fibrotic diseases, such as IPF.
During lung fibrosis, the epithelium induces signaling to underlying mesenchyme to generate excess myofibroblasts and extracellular matrix; herein, we focus on signaling in the mesenchyme. Our ...studies indicate that platelet-derived growth factor receptor (PDGFR)-β
cells are the predominant source of myofibroblasts and Kruppel-like factor (KLF) 4 is upregulated in PDGFR-β
cells, inducing TGFβ pathway signaling and fibrosis. In fibrotic lung patches, KLF4 is down-regulated, suggesting KLF4 levels decrease as PDGFR-β
cells transition into myofibroblasts. In contrast to PDGFR-β
cells, KLF4 reduction in α-smooth muscle actin (SMA)
cells non-cell autonomously exacerbates lung fibrosis by inducing macrophage accumulation and pro-fibrotic effects of PDGFR-β
cells via a Forkhead box M1 to C-C chemokine ligand 2-receptor 2 pathway. Taken together, in the context of lung fibrosis, our results indicate that KLF4 plays opposing roles in PDGFR-β
cells and SMA
cells and highlight the importance of further studies of interactions between distinct mesenchymal cell types.
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