Dyspnea and exercise intolerance are commonly reported post-acute sequelae of SARS-CoV-2 infection (PASC), but routine diagnostic testing is often normal. Cardiopulmonary exercise testing (CPET) ...offers comprehensive assessment of dyspnea to characterize pulmonary PASC.
We performed a retrospective cohort study of CPET performed on patients reporting dyspnea and/or exercise intolerance following confirmed Covid-19 between August 1, 2020 and March 1, 2021, and compared them to age- and sex-matched patients with unexplained dyspnea referred for CPET at the same center in the pre-Covid-19 era.
Compared to matched unexplained dyspnea comparators, PASC patients shared similar medical comorbidities and subjective dyspnea at referral (mMRC score 1.6 ± 0.9 vs. 1.4 ± 0.9, P = 0.5). Fifteen (83.3%) PASC patients underwent high resolution computed tomography of the chest, of which half (46.7%) were normal, and 17 (94.4%) patients had pulmonary function testing, of which the majority (76.5%) were normal. All patients underwent CPET, and 12 (67%) had normal findings. Compared to matched comparators, PASC patients had similar peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, and ventilatory efficiency measured by the minute ventilation to carbon dioxide production (VE/VCO2) slope.
Despite prominent dyspnea, physiological abnormalities on CPET were mild across a range of initial Covid-19 severity and similar to matched comparators referred for dyspnea without antecedent SARS-CoV-2.
The project was supported by the NHLBI (R01HL131029, R01HL151841, U10HL110337, T32HL116275) and a KL2 award (5KL2TR002542–02) from Harvard Catalyst.
Pulmonary fibrosis is characterized by the accumulation of myofibroblasts in the lung and progressive tissue scarring. Fibroblasts exist across a spectrum of states, from quiescence in health to ...activated myofibroblasts in the setting of injury. Highly activated myofibroblasts have a critical role in the establishment of fibrosis as the predominant source of type 1 collagen and profibrotic mediators. Myofibroblasts are also highly contractile cells and can alter lung biomechanical properties through tissue contraction. Inhibiting signaling pathways involved in myofibroblast activation could therefore have significant therapeutic value. One of the ways myofibroblast activation occurs is through activation of the Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF) pathway, which signals through intracellular actin polymerization. However, concerns surrounding the pleiotropic and ubiquitous nature of these signaling pathways have limited the translation of inhibitory drugs. Herein, we demonstrate a novel therapeutic antifibrotic strategy using myofibroblast-targeted nanoparticles containing a MTRF/SRF pathway inhibitor (CCG-1423), which has been shown to block myofibroblast activation in vitro. Myofibroblasts were preferentially targeted via the angiotensin 2 receptor, which has been shown to be selectively upregulated in animal and human studies. These nanoparticles were nontoxic and accumulated in lung myofibroblasts in the bleomycin-induced mouse model of pulmonary fibrosis, reducing the number of these activated cells and their production of profibrotic mediators. Ultimately, in a murine model of lung fibrosis, a single injection of these drugs containing targeted nanoagents reduced fibrosis as compared with control mice. This approach has the potential to deliver personalized therapy by precisely targeting signaling pathways in a cell-specific manner, allowing increased efficacy with reduced deleterious off-target effects.
Smoking and human immunodeficiency virus 1 (HIV-1) infection are risk factors for chronic obstructive pulmonary disease (COPD), which is among the most common comorbid conditions in people living ...with HIV-1. HIV-1 infection leads to persistent expansion of CD8
T cells, and CD8
T cell-mediated inflammation has been implicated in COPD pathogenesis. In this study, we investigated the effects of HIV-1 infection and smoking on T-cell dynamics in patients at risk of COPD. BAL fluid, endobronchial brushings, and blood from HIV-1 infected and uninfected nonsmokers and smokers were analyzed by flow cytometry, and lungs were imaged by computed tomography. Chemokines were measured in BAL fluid, and CD8
T-cell chemotaxis in the presence of cigarette smoke extract was assessed
. HIV-1 infection increased CD8
T cells in the BAL fluid, but this increase was abrogated by smoking. Smokers had reduced BAL fluid concentrations of the T cell-recruiting chemokines CXCL10 and CCL5, and cigarette smoke extract inhibited CXCL10 and CCL5 production by macrophages and CD8
T-cell transmigration
. In contrast to the T cells in BAL fluid, CD8
T cells in endobronchial brushings were increased in HIV-1-infected smokers, which was driven by an accumulation of effector memory T cells in the airway mucosa and an increase in tissue-resident memory T cells. Mucosal CD8
T-cell numbers inversely correlated with lung aeration, suggesting an association with inflammation and remodeling. HIV-1 infection and smoking lead to retention of CD8
T cells within the airway mucosa.
Background Induction of endogenous regulatory T (Treg) cells represents an exciting new potential modality for treating allergic diseases, such as asthma. Treg cells have been implicated in the ...regulation of asthma, but the anatomic location in which they exert their regulatory function and the mechanisms controlling the migration necessary for their suppressive function in asthma are not known. Understanding these aspects of Treg cell biology will be important for harnessing their power in the clinic. Objective We sought to determine the anatomic location at which Treg cells exert their regulatory function in the sensitization and effector phases of allergic asthma and to determine the chemokine receptors that control the migration of Treg cells to these sites in vivo in both mice and human subjects. Methods The clinical efficacy and anatomic location of adoptively transferred chemokine receptor–deficient CD4+ CD25+ forkhead box protein 3–positive Treg cells was determined in the sensitization and effector phases of allergic airway inflammation in mice. The chemokine receptor expression profile was determined on Treg cells recruited into the human airway after bronchoscopic segmental allergen challenge of asthmatic patients. Results We show that CCR7, but not CCR4, is required on Treg cells to suppress allergic airway inflammation during the sensitization phase. In contrast, CCR4, but not CCR7, is required on Treg cells to suppress allergic airway inflammation during the effector phase. Consistent with our murine studies, human subjects with allergic asthma had an increase in CCR4-expressing functional Treg cells in the lungs after segmental allergen challenge. Conclusion The location of Treg cell function differs during allergic sensitization and allergen-induced recall responses in the lung, and this differential localization is critically dependent on differential chemokine function.
Idiopathic pulmonary fibrosis is a progressive lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar ...formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. We previously identified HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) as YAP inhibitors based on a high-throughput small-molecule screen in primary human lung fibroblasts. Here we report that several Aurora kinase inhibitors were also identified from the top hits of this screen. MK-5108, a highly selective inhibitor for AURKA (Aurora kinase A), induced YAP phosphorylation and cytoplasmic retention and significantly reduced profibrotic gene expression in human lung fibroblasts. The inhibitory effect on YAP nuclear translocation and profibrotic gene expression is specific to inhibition of AURKA, but not Aurora kinase B or C, and is independent of the Hippo pathway kinases LATS1 and LATS2 (Large Tumor Suppressor 1 and 2). Further characterization of the effects of MK-5108 demonstrate that it inhibits YAP nuclear localization indirectly via effects on actin polymerization and TGFβ (Transforming Growth Factor β) signaling. In addition, MK-5108 treatment reduced lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results reveal a novel role for AURKA in YAP-mediated profibrotic activity in fibroblasts and highlight the potential of small-molecule screens for YAP inhibitors for identification of novel agents with antifibrotic activity.
Abstract Pulmonary hypertension is a life-threatening condition that results from a heterogeneous group of diseases, many of which demonstrate characteristic pathologic changes of pulmonary vascular ...inflammation and remodeling. Recent clinical studies indicate obesity to be a risk factor for the development of pulmonary hypertension; however, the mechanisms leading to this association are unknown. Adipocytes secrete multiple bioactive mediators that can influence inflammation and tissue remodeling, suggesting that adipose tissue may directly influence the pathogenesis of pulmonary hypertension. One of these mediators is adiponectin, a protein with a wide range of metabolic, anti-inflammatory, and anti-proliferative activities. Paradoxically, adiponectin is present in high concentration in the serum of lean healthy individuals, but decreases in obesity. Studies suggest that relative adiponectin-deficiency may contribute to the development of inflammatory diseases in obesity, and recent animal studies implicate adiponectin in the pathogenesis of pulmonary hypertension. Most notably, experimental studies show that adiponectin can reduce lung vascular remodeling in response to inflammation and hypoxia. Moreover, mice deficient in adiponectin develop a spontaneous lung vascular phenotype characterized by age-dependent increases in peri-vascular inflammatory cells and elevated pulmonary artery pressures. Emerging evidence indicates adiponectin's effects are mediated through anti-inflammatory and anti-proliferative actions on cells in the lung. This review aims to synthesize the existing data related to adiponectin's effects on the pulmonary vasculature and to discuss how changes in adiponectin levels might contribute to the development of pulmonary hypertension.
Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments permissive to
(
) growth remains ...incompletely understood. We investigated primary bronchoalveolar lavage cells from current and never smokers by performing single-cell RNA sequencing (scRNA-seq), flow cytometry, and functional assays. We observed the enrichment of immature inflammatory monocytes in the lungs of smokers compared with nonsmokers. These monocytes exhibited phenotypes consistent with recent recruitment from blood, ongoing differentiation, increased activation, and states similar to those with chronic obstructive pulmonary disease. Using integrative scRNA-seq and flow cytometry, we identified CD93 as a marker for a subset of these newly recruited smoking-associated lung monocytes and further provided evidence that the recruitment of monocytes into the lung was mediated by CCR2-binding chemokines, including CCL11. We also show that these cells exhibit elevated inflammatory responses upon exposure to
and accelerated intracellular growth of
compared with mature macrophages. This elevated
growth could be inhibited by anti-inflammatory small molecules, providing a connection between smoking-induced pro-inflammatory states and permissiveness to
growth. Our findings suggest a model in which smoking leads to the recruitment of immature inflammatory monocytes from the periphery to the lung, which results in the accumulation of these
-permissive cells in the airway. This work defines how smoking may lead to increased susceptibility to
and identifies host-directed therapies to reduce the burden of TB among those who smoke.
Recruitment of antigen-specific T(H)2 cells into the lung is critical for the development of allergic airway inflammation. Although CCR4 and CCR8 are preferentially expressed on T(H)2 cells and CCR4, ...CCR8, and CXCR3 ligands are increased in asthma, the specific relative contribution of these receptors to antigen-specific T(H)2 cell trafficking into the allergic lung is not known.
To determine the relative contribution of the chemokine receptors CCR4, CCR8, and CXCR3 to antigen-specific T(H)2 cell trafficking in a murine model of allergic pulmonary inflammation.
We used adoptive transfer experiments to compare the trafficking of wild-type antigen-specific T(H)2 cells with antigen-specific T(H)2 cells deficient in CCR4, CCR8, or CXCR3.
CCR4-deficient antigen-specific T(H)2 cells failed to traffic efficiently into the lung and the airways. In contrast, CCR8-deficient antigen-specific T(H)2 cells accumulated in these sites. Trafficking of CXCR3-deficient antigen-specific T(H)2 cells and CCR4-deficient and CCR8-deficient antigen-specific T(H)1 cells were comparable to their wild-type counterparts. Approximately 60% of IL-4-producing antigen-specific T cells expressed CCR4. Disruption of CCR4-mediated antigen-specific T(H)2 cell trafficking decreased the levels of T(H)2-type cytokines in the airways and reduced airway eosinophilia and mucus production.
Our study demonstrates that CCR4 is required for the efficient entry of antigen-specific T(H)2 cells into the lung and the airways in a murine model of allergic pulmonary inflammation.
Background
The aim of this study was to characterize severe immune‐related adverse events (irAEs) seen among hospitalized patients and to examine risk factors for irAE admissions and clinically ...relevant outcomes, including length of stay, immune checkpoint inhibitor (ICI) discontinuation, readmission, and death.
Methods
Patients who received ICI therapy (ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or any ICI combination) at Massachusetts General Hospital (MGH) and were hospitalized at MGH following ICI initiation between January 1, 2011, and October 24, 2018, were identified using pharmacy and hospital admission databases. Medical records of all irAE admissions were reviewed, and specialist review with defined criteria was performed. Demographic data, relevant clinical history (malignancy type and most recent ICI regimen), and key admission characteristics, including dates of admission and discharge, immunosuppressive management, ICI discontinuation, readmission, and death, were collected.
Results
In total, 450 admissions were classified as irAE admissions and represent the study's cohort. Alongside the increasing use of ICIs at our institution, the number of patients admitted to MGH for irAEs has gradually increased every year from 9 in 2011 to 92 in 2018. The hospitalization rate per ICI recipient has declined over that same time period (25.0% in 2011 to 8.5% in 2018). The most common toxicities leading to hospitalization in our cohort were gastrointestinal (30.7%; n = 138), pulmonary (15.8%; n = 71), hepatic (14.2%; n = 64), endocrine (12.2%; n = 55), neurologic (8.4%; n = 38), cardiac (6.7%; n = 30), and dermatologic (4.4%; n = 20). Multivariable logistic regression revealed statistically significant increases in irAE admission risk for CTLA‐4 monotherapy recipients (odds ratio OR, 2.02; p < .001) and CTLA‐4 plus PD‐1 combination therapy recipients (OR, 1.88; p < .001), relative to PD‐1/PD‐L1 monotherapy recipients, and patients with multiple toxicity had a 5‐fold increase in inpatient mortality.
Conclusion
This study illustrates that cancer centers must be prepared to manage a wide variety of irAE types and that CTLA‐4 and combination ICI regimens are more likely to cause irAE admissions, and earlier. In addition, admissions for patients with multi‐organ involvement is common and those patients are at highest risk of inpatient mortality.
Implications for Practice
The number of patients admitted to Massachusetts General Hospital for immune‐related adverse events (irAEs) has gradually increased every year and the most common admissions are for gastrointestinal (30.7%), pulmonary (15/8%), and hepatic (14.2%) events. Readmission rates are high (29% at 30 days, 49% at 180 days) and 64.2% have to permanently discontinue immune checkpoint inhibitor therapy. Importantly, multiple concurrent toxicities were seen in 21.6% (97/450) of irAE admissions and these patients have a fivefold increased risk of inpatient death.
Real‐world immune‐related adverse events (irAE) studies have been hampered by the relatively recent introduction of immune checkpoint inhibitor therapy. This article characterizes severe irAEs among hospitalized patients and examines risk factors for irAE admissions and clinically relevant outcomes.
Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma ...phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits.
We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes.
We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen.
Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10−7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10−6) and PIK3R6 with eosinophil count (P = 4.10 × 10−5) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge.
We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.
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