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Rationale: CD148/PTRJ (receptor-like protein tyrosine phosphatase η) exerts antifibrotic effects in experimental pulmonary fibrosis via interactions with its ligand syndecan-2; however, the role of CD148 in human pulmonary fibrosis remains incompletely characterized. Objectives: We investigated the role of CD148 in the profibrotic phenotype of fibroblasts in idiopathic pulmonary fibrosis (IPF). Methods: Conditional CD148 fibroblast-specific knockout mice were generated and exposed to bleomycin and then assessed for pulmonary fibrosis. Lung fibroblasts (mouse lung and human IPF lung), and precision-cut lung slices from human patients with IPF were isolated and subjected to experimental treatments. A CD148-activating 18-aa mimetic peptide (SDC2-pep) derived from syndecan-2 was evaluated for its therapeutic potential. Measurements and Main Results: CD148 expression was downregulated in IPF lungs and fibroblasts. In human IPF lung fibroblasts, silencing of CD148 increased extracellular matrix production and resistance to apoptosis, whereas overexpression of CD148 reversed the profibrotic phenotype. CD148 fibroblast-specific knockout mice displayed increased pulmonary fibrosis after bleomycin challenge compared with control mice. CD148-deficient fibroblasts exhibited hyperactivated PI3K/Akt/mTOR signaling, reduced autophagy, and increased p62 accumulation, which induced NF-κB activation and profibrotic gene expression. SDC2-pep reduced pulmonary fibrosis in vivo and inhibited IPF-derived fibroblast activation. In precision-cut lung slices from patients with IPF and control patients, SDC2-pep attenuated profibrotic gene expression in IPF and normal lungs stimulated with profibrotic stimuli. Conclusions: Lung fibroblast CD148 activation reduces p62 accumulation, which exerts antifibrotic effects by inhibiting NF-κB–mediated profibrotic gene expression. Targeting the CD148 phosphatase with activating ligands such as SDC2-pep may represent a potential therapeutic strategy in IPF.

Chronic Obstructive Pulmonary Disease (COPD) pathogenesis involves a failure to maintain alveolar homeostasis due to repetitive injury and inflammation. In order to improve our understanding of cell-specific mechanisms contributing to COPD pathogenesis, we analysed single-cell RNA sequencing (scRNAseq) profiles of explanted parenchymal lung tissue from 17 subjects with advanced COPD requiring transplant and 15 control donor lungs. We identified a subpopulation of alveolar type II epithelial cells that uniquely expressHHIPand have aberrant stress tolerance profiles in COPD. Amongst endothelial cells, we identified overlapping and unique shifts in transcriptional profiles of endothelial subtypes that may contribute to vascular inflammation and susceptibility to injury. We also identified population composition changes amongst alveolar macrophages. Finally, application of integrative analyses to our scRNAseq data identified cell-specific contributions to COPD heritability and dysfunctional cell-cell communication pathways that occur within the COPD alveolar niche. These findings provide cell type-specific resolution of transcriptional changes associated with advanced COPD that may underlie disease pathogenesis.

Human lung single-cell atlas reveals the complexity and diversity of aberrant cellular populations in pulmonary fibrosis., We provide a single-cell atlas of idiopathic pulmonary fibrosis (IPF), a fatal interstitial lung disease, by profiling 312,928 cells from 32 IPF, 28 smoker and nonsmoker controls, and 18 chronic obstructive pulmonary disease (COPD) lungs. Among epithelial cells enriched in IPF, we identify a previously unidentified population of aberrant basaloid cells that coexpress basal epithelial, mesenchymal, senescence, and developmental markers and are located at the edge of myofibroblast foci in the IPF lung. Among vascular endothelial cells, we identify an ectopically expanded cell population transcriptomically identical to bronchial restricted vascular endothelial cells in IPF. We confirm the presence of both populations by immunohistochemistry and independent datasets. Among stromal cells, we identify IPF myofibroblasts and invasive fibroblasts with partially overlapping cells in control and COPD lungs. Last, we confirm previous findings of profibrotic macrophage populations in the IPF lung. Our comprehensive catalog reveals the complexity and diversity of aberrant cellular populations in IPF.

Rheumatoid arthritis (RA) is commonly associated with pulmonary disease that can affect any anatomic compartment of the thorax. The most common intrathoracic manifestations of RA include interstitial lung disease, airway disease, pleural disease, rheumatoid nodules, and drug-induced toxicity. Patients with RA with thoracic involvement often present with nonspecific respiratory symptoms, although many are asymptomatic. Therefore, clinicians should routinely consider pulmonary disease when evaluating any patient with RA, particularly one with known risk factors. The optimal screening, diagnostic, and treatment strategies for RA-associated pulmonary disease remain uncertain and are the focus of ongoing investigation.

Significant progress has been made in elucidating the genetics of parenchymal lung diseases, particularly idiopathic interstitial pneumonias (IIPs). IIPs are a heterogeneous group of diffuse interstitial lung diseases of uncertain etiology, diagnosed only after known causes of interstitial lung disease have been excluded. Idiopathic pulmonary fibrosis is the most common IIP. Through candidate gene approaches and genome wide association studies, much light has been shed on the genetic origins of IIPs, enhancing our understanding of risk factors and pathogenesis. However, significant work remains to be accomplished in identifying novel genetic variants and characterizing the function of validated candidate genes in lung pathobiology, their interplay with environmental factors, and ultimately translating these discoveries to patient care.

With the evolution of high throughput sequencing technologies, the past decade has seen an exponential rise in the use of RNA sequencing (RNA-seq). RNA-seq has deepened our understanding of biological systems to unprecedented levels of resolution, identifying not only gene expression signatures but also regulatory RNA molecules that may play critical roles in disease pathogenesis. Pulmonary research has quickly incorporated this technology, from characterizing the IL-17 signature of steroid-unresponsive COPD patients [1] to discovering pathogen-host interactions of M. tuberculosis [2]. This mini-review provides an overview of core features and applications of RNA-seq to familiarize non-experts with the methodology and how it has impacted our understanding of lung pathophysiology.

Aging has been implicated in the development of pulmonary fibrosis, which has seen a sharp increase in incidence in those older than 50 years. Recent studies demonstrate a role for the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome and its regulated cytokines in experimental lung fibrosis. In this study, we tested the hypothesis that age-related NLRP3 inflammasome activation is an important predisposing factor in the development of pulmonary fibrosis. Briefly, young and aged wild-type and NLRP3(-/-) mice were subjected to bleomycin-induced lung injury. Pulmonary fibrosis was determined by histology and hydroxyproline accumulation. Bone marrow and alveolar macrophages were isolated from these mice. NLRP3 inflammasome activation was assessed by co-immunoprecipitation experiments. IL-1β and IL-18 production was measured by ELISA. The current study demonstrated that aged wild-type mice developed more lung fibrosis and exhibited increased morbidity and mortality after bleomycin-induced lung injury, when compared with young mice. Bleomycin-exposed aged NLRP3(-/-) mice had reduced fibrosis compared with their wild-type age-matched counterparts. Bone marrow-derived and alveolar macrophages from aged mice displayed higher levels of NLRP3 inflammasome activation and caspase-1-dependent IL-1β and IL-18 production, which was associated with altered mitochondrial function and increased production of reactive oxygen species. Our study demonstrated that age-dependent increases in alveolar macrophage mitochondrial reactive oxygen species production and NLRP3 inflammasome activation contribute to the development of experimental fibrosis.

Platelets play a pivotal role in atherothrombosis, the major cause of most unstable coronary syndromes [1]. Central to the pathogenesis of occlusive arterial disease is the activation of platelets at sites of vascular injury via pathologically exaggerated and deregulated versions of the protective mechanisms involved in hemostasis [1]. Platelets secrete and express a large number of substances that are crucial mediators of coagulation, inflammation, thrombosis, and atherosclerosis [2,3]. The demonstrated ability of antiplatelet drugs to reduce cardiovascular events has reinforced the major role of platelets in the atherothrombotic process [4]. Although measuring platelet activity by any of a wide variety of methods has been reported to identify individuals at increased risk for cardiovascular events, it remains a research tool that is yet to be included in routine clinical decision-making. Potential reasons include a lack of sufficient data about the optimal method of platelet testing, unknown optimal cut-off for distinguishing increased risk, and the uncertainty about the interpretation and clinical utility of results. Additionally, many methods are costly, are time-consuming, and require specialized equipment. Within an individual, platelets are heterogeneous in size and density. Mean platelet volume (MPV), the most commonly used measure of platelet size, is a potential marker of platelet reactivity. Although there is still uncertainty about the most precise methodology for measuring MPV, it is routinely available in the inpatient and outpatient setting at a relatively low cost. Larger platelets are metabolically and enzymatically more active [5], and have greater prothombotic potential [6]. Elevated MPV is associated with other markers of platelet activity, including increased platelet aggregation, increased thromboxane synthesis and β-thromboglobulin release, and increased expression of adhesion molecules [7]. Furthermore, higher MPV is observed in patients with diabetes mellitus [8], hypertension [9], hypercholesterolemia [10], smoking [11], and obesity [12], suggesting a common mechanism by which these factors may increase the risk of cardiovascular disease. The aim of this systematic review and meta-analysis, the first that we are aware of, is to obtain the best possible estimate of MPV and cardiovascular disease by combining data from all relevant cross-sectional and cohort studies evaluating MPV and cardiovascular disease. The emphasis of this article is to detail: (i) whether there exists an association between MPV and acute myocardial infarction (AMI); (ii) whether elevated MPV is associated with all-cause mortality following a myocardial infarction (MI); and (iii) whether MPV is associated with restenosis following percutaneous coronary intervention (PCI).

Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized.To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD.Subjects enrolled in Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR.A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD.Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.