ABSTRACT
BACKGROUND: The Coronavirus (COVID-19) pandemic has exacerbated the risk for poor physical and mental health outcomes among vulnerable older adults. Multicomponent interventions could potentially prevent or reduce the risk of becoming frail; however, there is limited evidence about utilizing alternative modes of delivery where access to in-person care may be challenging. This randomized feasibility trial aimed to understand how a multicomponent rehabilitation program can be delivered remotely to vulnerable older adults with frailty during the pandemic. METHODS: Participants were randomized to either a multimodal or socialization arm. Over a 12-week intervention period, the multimodal group received virtual care at home, which included twice-weekly exercise in small group physiotherapy-led live-streamed sessions, nutrition counselling and protein supplementation, medication consultation via a videoconference app, and once-weekly phone calls from student volunteers, while the socialization group received only once-weekly phone calls from the volunteers. The RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) framework was used to evaluate the feasibility of the program. The main clinical outcomes were change in the 5-times sit-to-stand test (5 × STS) and Depression, Anxiety and Stress Scale (DASS-21) scores. The feasibility outcomes were analyzed using descriptive statistics and expressed as frequencies and mean percent with corresponding confidence intervals (CI). Analysis of covariance (ANCOVA) was used for the effectiveness component. RESULTS: The program enrolled 33% (n = 72) of referrals to the study (n = 220), of whom 70 were randomized. Adoption rates from different referral sources were community self-referrals (60%), community organizations (33%), and healthcare providers (25%). At the provider level, implementation rates varied from 75 to 100% for different aspects of program delivery. Participant's adherence levels included virtual exercise sessions 81% (95% CI: 75-88%), home-based exercise 50% (95% CI: 38-62%), protein supplements consumption 68% (95% CI: 55-80%), and medication optimization 38% (95% CI: 21-59%). Most participants (85%) were satisfied with the program. There were no significant changes in clinical outcomes between the two arms. CONCLUSION: The GERAS virtual frailty rehabilitation study for community-dwelling older adults living with frailty was feasible in terms of reach of participants, adoption across referral settings, adherence to implementation, and participant's intention to maintain the program. This program could be feasibly delivered to improve access to socially isolated older adults where barriers to in-person participation exist. However, trials with larger samples and longer follow-up are required to demonstrate effectiveness and sustained behavior change. TRIAL REGISTRATION: ClinicalTrials.gov NCT04500366. Registered August 5, 2020, https://clinicaltrials.gov/ct2/show/NCT04500366.
ABSTRACT
BACKGROUND: Current protocols for detection of circulating fibrocytes (CFs) in peripheral blood described in various pulmonary and nonpulmonary disorders involve complex and time consuming, non standardized techniques. OBJECTIVE: Testing a method to rapidly detect and quantify CFs using whole blood lysis flow cytometry-based assay in patients with idiopathic pulmonary fibrosis (IPF) and healthy controls. METHODS: One milliliter of venous blood sample in ethylenediaminetetraacetic acid (EDTA) from 33 IPF patients and 35 healthy control subjects was collected. Using whole blood lysis method peripheral blood leukocytes were labeled with monoclonal antibodies for cell surface (CD34 and CD45) and intracellular markers (collagen-1) for flow cytometric analysis. CFs were defined as CD45(+) cells coexpressing collagen-I and CD34 molecules. RESULTS: In 29 (87.8%) IPF patients and 10 (28.5%) control subjects, a well-defined highly granular CD45(+) cell population was detected in dot plots generated by side scatter properties of CD45(+) cells. These CD45(+) cells were identified as CFs on the basis of coexpression of collagen-I and CD34; none of the other cell types in the peripheral blood were labeled with these monoclonal antibodies. In IPF patients the percentage of CFs was significantly higher compared to healthy controls (median (range): 1.37% (0.52-5.65) and 1.04% (0.1-1.84), respectively; P = 0.03). CONCLUSIONS: Whole blood lysis method combined with fluorescence-activated cell sorting (FACS) allows detecting a well-defined homogeneous population of CFs. This method is simple, reproducible, and provides an accurate and rapid estimation of CFs.
ABSTRACT
Fibrocytes are bone marrow-derived, circulating mesenchymal progenitor cells that play a role in several fibrotic disorders, including lung fibrosis. They are attracted to injured tissue by various chemokines. It is likely that fibrocytes play a detrimental role in tissue homeostasis and promote fibrosis, although this paradigm needs further confirmation. This would make fibrocytes a possible novel treatment target for fibrotic disorders. Fibrocytes also have some potential as a biomarker for idiopathic pulmonary fibrosis (IPF) and other diseases, but the promising preliminary data from single centre studies still require independent validation. Despite several, as yet, unresolved issues, it has become clear that fibrocytes are more than an incidental finding in lung injury and repair, and may hold great promise for the future of IPF management.
Subject(s)
Fibroblasts/pathology , Lung/pathology , Mesenchymal Stem Cells/pathology , Pulmonary Fibrosis/pathology , Animals , Biomarkers/metabolism , Chemokines/metabolism , Chemotaxis , Fibroblasts/metabolism , Humans , Lung/metabolism , Mesenchymal Stem Cells/metabolism , Pulmonary Fibrosis/metabolism , Wound HealingABSTRACT
Fibrocytes are bone marrow-derived mesenchymal cell precursors, defined primarily by their ability to co-express markers of both haematopoietic (e.g. CD45 or CXCR4) and stromal (e.g. collagen) lineages. Fibrocytes in culture also have ultrastructural cell surface features that distinguish them from other leukocytes. Extensive efforts have helped to characterise fibrocytes phenotypically and functionally, but it is still unclear exactly how these cells contribute to tissue repair and/or pathologic fibrosis. Nevertheless, the varied levels of fibrocytes in blood have raised considerable interest as a biomarker of disease activity, such as chronic lung diseases, including pulmonary fibrosis, asthma and pulmonary hypertension. These cells also may become a novel therapeutic target for these difficult to treat disorders. This review will briefly summarize the current knowledge about fibrocytes in human lung disease and in animal disease models and highlight areas of consensus as well as issues that remain controversial to date.
Subject(s)
Fibroblasts/metabolism , Lung Diseases/physiopathology , Asthma/physiopathology , Biomarkers , Cell Differentiation , Chronic Disease , Humans , Hypertension, Pulmonary/physiopathology , Lung/metabolism , Mesenchymal Stem Cells , Monocytes/metabolismABSTRACT
The growth factor GM-CSF has an important role in pulmonary surfactant metabolism and the regulation of antibacterial activities of lung sentinel cells. However, the potential of intra-alveolar GM-CSF to augment lung protective immunity against inhaled bacterial pathogens has not been defined in preclinical infection models. We hypothesized that transient overexpression of GM-CSF in the lungs of mice by adenoviral gene transfer (Ad-GM-CSF) would protect mice from subsequent lethal pneumococcal pneumonia. Our data show that intra-alveolar delivery of Ad-GM-CSF led to sustained increased pSTAT5 expression and PU.1 protein expression in alveolar macrophages during a 28-d observation period. Pulmonary Ad-GM-CSF delivery 2-4 wk prior to infection of mice with Streptococcus pneumoniae significantly reduced mortality rates relative to control vector-treated mice. This increased survival was accompanied by increased inducible NO synthase expression, antibacterial activity, and a significant reduction in caspase-3-dependent apoptosis and secondary necrosis of lung sentinel cells. Importantly, therapeutic treatment of mice with rGM-CSF improved lung protective immunity and accelerated bacterial clearance after pneumococcal challenge. We conclude that prophylactic delivery of GM-CSF triggers long-lasting immunostimulatory effects in the lung in vivo and rescues mice from lethal pneumococcal pneumonia by improving antibacterial immunity. These data support use of novel antibiotic-independent immunostimulatory therapies to protect patients against bacterial pneumonias.
Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Pneumonia, Pneumococcal/immunology , Pneumonia, Pneumococcal/prevention & control , Adenoviridae/genetics , Animals , Bronchoalveolar Lavage Fluid/immunology , Bronchoalveolar Lavage Fluid/microbiology , Gene Transfer Techniques , Genetic Vectors/administration & dosage , Genetic Vectors/immunology , Genetic Vectors/therapeutic use , Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis , Intubation, Intratracheal , Lung/immunology , Lung/microbiology , Lung/virology , Mice , Mice, Inbred C57BL , Pneumonia, Pneumococcal/mortality , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic useABSTRACT
Oxidative stress with reactive oxygen species (ROS) can contribute to the pathogenesis of idiopathic pulmonary fibrosis. Antioxidant enzymes, such as extracellular superoxide dismutase (ECSOD), may modulate the injury and repair components of the fibrogenic response. Here we determined whether ECSOD could attenuate experimental TGF-ß1-induced persistent lung fibrosis. In this study, primary human lung fibroblasts, MRC-5 fibroblasts and A549 epithelial cells were exposed to recombinant active TGF-ß1. An adenovirus vector that expresses human ECSOD (AdECSOD) was constructed and rats were endotracheally intubated with an adenoviral vector encoding active TGF-ß1 (AdTGF-ß1), AdECSOD or a control vector (AdDL70) alone or in combinations AdTGF-ß1/AdDL70 or AdTGF-ß1/AdECSOD. TGF-ß1 alone induced fibrotic responses and significantly down-regulated endogenous ECSOD gene expression both in vitro and in vivo and caused oxidative stress in rat lung, associated with increased levels of activated TGF-ß1 in lung fluid and tissue. ECSOD protein was markedly reduced in the interstitium and fibrotic foci in TGF-ß1 induced experimental lung fibrosis. The fibrotic response caused by AdTGF-ß1 was markedly attenuated by concomitant gene transfer using AdECSOD, detected by lung function measurements, histologic and morphometric analysis, hydroxyproline content and fibrosis-related gene expression. In addition, the oxidative stress and increased presence of activated TGF-ß1 in rat lung induced by AdTGF-ß1 was significantly reduced by ECSOD gene transfer. These findings suggest a substantial role for oxidative stress in the pathogenesis of TGF-ß1 driven persistent pulmonary fibrosis and enhanced presence of ECSOD can inhibit latent TGF-ß1 activation by ROS and diminish subsequent fibrotic responses.