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Stem Cell Research & Therapy May 2024Bleomycin (BLM)-induced lung injury is characterized by mixed histopathologic changes with inflammation and fibrosis, such as observed in human patients with...
BACKGROUND
Bleomycin (BLM)-induced lung injury is characterized by mixed histopathologic changes with inflammation and fibrosis, such as observed in human patients with bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Although no curative therapies for these lung diseases exist, stem cell therapy has emerged as a potential therapeutic option. Multilineage-differentiating stress-enduring (Muse) cells are endogenous pluripotent- and macrophage-like stem cells distributed in various adult and fetal tissues as stage-specific embryonic antigen-3-positive cells. They selectively home to damaged tissue by sensing sphingosine-1-phosphate and replace the damaged/apoptotic cells by in vivo differentiation. Clinical trials for some human diseases suggest the safety and therapeutic efficacy of intravenously injected human leukocyte antigen-mismatched allogenic Muse cells from adult bone marrow (BM) without immunosuppressant. Here, we evaluated the therapeutic effects of human Muse cells from preterm and term umbilical cord (UC), and adult BM in a rat BLM-induced lung injury model.
METHODS
Rats were endotracheally administered BLM to induce lung injury on day 0. On day 3, human preterm UC-Muse, term UC-Muse, or adult BM-Muse cells were administered intravenously without immunosuppressants, and rats were subjected to histopathologic analysis on day 21. Body weight, serum surfactant protein D (SP-D) levels, and oxygen saturation (SpO) were monitored. Histopathologic lung injury scoring by the Ashcroft and modified American Thoracic Society document scales, quantitative characterization of engrafted Muse cells, RNA sequencing analysis, and in vitro migration assay of infused Muse cells were performed.
RESULTS
Rats administered preterm- and term-UC-Muse cells exhibited a significantly better recovery based on weight loss, serum SP-D levels, SpO, and histopathologic lung injury scores, and a significantly higher rate of both Muse cell homing to the lung and alveolar marker expression (podoplanin and prosurfactant protein-C) than rats administered BM-Muse cells. Rats receiving preterm-UC-Muse cells showed statistically superior results to those receiving term-UC-Muse cells in many of the measures. These findings are thought to be due to higher expression of genes related to cell migration, lung differentiation, and cell adhesion.
CONCLUSION
Preterm UC-Muse cells deliver more efficient therapeutic effects than term UC- and BM-Muse cells for treating BLM-induced lung injury in a rat model.
Topics: Animals; Humans; Rats; Bleomycin; Lung Injury; Umbilical Cord; Disease Models, Animal; Rats, Sprague-Dawley; Male; Cell Differentiation; Female
PubMed: 38773627
DOI: 10.1186/s13287-024-03763-8 -
American Journal of Cardiovascular... 2024The current traditional pathophysiologic concept of pulmonary edema of cardiogenic origin explains its development by a hydrostatic effect due to increased pulmonary... (Review)
Review
The current traditional pathophysiologic concept of pulmonary edema of cardiogenic origin explains its development by a hydrostatic effect due to increased pulmonary capillary pressure resulting in fluid flux to alveolar and interstitial areas from capillaries. However, several experimental studies and clinical data of poor response to hemodynamic and diuretic treatment in many scenarios provide further evidence of the involvement of several other contributing factors to the development of cardiogenic pulmonary edema. Several experimental and clinical studies have found that sympathetic overactivity with elevated plasma catecholamine concentrations may play an important role in the development of cardiovascular-associated pulmonary edema. Catecholamine-induced pulmonary injury may be one of the key mechanisms in acute cardiogenic pulmonary edema triggering proinflammatory cytokine overactivation, oxidative stress and myocardial injury. In the everyday treatment of acute heart failure, physicians should consider the possibility of other noncardiogenic mechanisms involved in the progression of acute pulmonary edema, particularly catecholamine overactivity, lymphatic drainage, inflammatory and oxidative stress, high surfactant protein. The classic, hemodynamic treatment approach in pulmonary edema with the coexistence of other contributing factors may not provide adequate clinical benefit during treatment.
PubMed: 38764545
DOI: 10.62347/YGQQ8696 -
Lung Jun 2024Pulmonary fibrosis is a characteristic of various interstitial lung diseases (ILDs) with differing etiologies. Clinical trials in progressive pulmonary fibrosis (PPF)...
INTRODUCTION
Pulmonary fibrosis is a characteristic of various interstitial lung diseases (ILDs) with differing etiologies. Clinical trials in progressive pulmonary fibrosis (PPF) enroll patients based on previously described clinical criteria for past progression, which include a clinical practice guideline for PPF classification and inclusion criteria from the INBUILD trial. In this study, we compared the ability of past FVC (forced vital capacity) progression and baseline biomarker levels to predict future progression in a cohort of patients from the PFF Patient Registry.
METHODS
Biomarkers previously associated with pathobiology and/or progression in pulmonary fibrosis were selected to reflect cellular senescence (telomere length), pulmonary epithelium (SP-D, RAGE), myeloid activation (CXCL13, YKL40, CCL18, OPN) and fibroblast activation (POSTN, COMP, PROC3).
RESULTS
PFF or INBUILD-like clinical criteria was used to separate patients into past progressor and non-past progressor groups, and neither clinical criterion appeared to enrich for patients with greater future lung function decline. All baseline biomarkers measured were differentially expressed in patient groups compared to healthy controls. Baseline levels of SP-D and POSTN showed the highest correlations with FVC slope over one year, though correlations were low.
CONCLUSIONS
Our findings provide further evidence that prior decline in lung function may not predict future disease progression for ILD patients, and elevate the need for molecular definitions of a progressive phenotype. Across ILD subtypes, certain shared pathobiologies may be present based on the molecular profile of certain biomarker groups observed. In particular, SP-D may be a common marker of pulmonary injury and future lung function decline across ILDs.
Topics: Humans; Disease Progression; Biomarkers; Registries; Male; Female; Middle Aged; Vital Capacity; Aged; Lung Diseases, Interstitial; Pulmonary Fibrosis; Pulmonary Surfactant-Associated Protein D; Lung; Predictive Value of Tests; Chitinase-3-Like Protein 1; Chemokines, CC; Osteopontin; Receptor for Advanced Glycation End Products; Idiopathic Pulmonary Fibrosis
PubMed: 38753183
DOI: 10.1007/s00408-024-00694-2 -
International Journal of Molecular... May 2024Nanoparticles (NPs) have shown significant potential for pulmonary administration of therapeutics for the treatment of chronic lung diseases in a localized and sustained...
Nanoparticles (NPs) have shown significant potential for pulmonary administration of therapeutics for the treatment of chronic lung diseases in a localized and sustained manner. Nebulization is a suitable method of NP delivery, particularly in patients whose ability to breathe is impaired due to lung diseases. However, there are limited studies evaluating the physicochemical properties of NPs after they are passed through a nebulizer. High shear stress generated during nebulization could potentially affect the surface properties of NPs, resulting in the loss of encapsulated drugs and alteration in the release kinetics. Herein, we thoroughly examined the physicochemical properties as well as the therapeutic effectiveness of Infasurf lung surfactant (IFS)-coated PLGA NPs previously developed by us after passing through a commercial Aeroneb vibrating-mesh nebulizer. Nebulization did not alter the size, surface charge, IFS coating and bi-phasic release pattern exhibited by the NPs. However, there was a temporary reduction in the initial release of encapsulated therapeutics in the nebulized compared to non-nebulized NPs. This underscores the importance of evaluating the drug release kinetics of NPs using the inhalation method of choice to ensure suitability for the intended medical application. The cellular uptake studies demonstrated that both nebulized and non-nebulized NPs were less readily taken up by alveolar macrophages compared to lung cancer cells, confirming the IFS coating retention. Overall, nebulization did not significantly compromise the physicochemical properties as well as therapeutic efficacy of the prepared nanotherapeutics.
Topics: Nanoparticles; Humans; Nebulizers and Vaporizers; Administration, Inhalation; Drug Delivery Systems; Lipids; Drug Liberation; Lung; Polymers; Pulmonary Surfactants; Drug Carriers; Macrophages, Alveolar; Particle Size; A549 Cells; Animals; Surface Properties
PubMed: 38732246
DOI: 10.3390/ijms25095028 -
STAR Protocols Jun 2024Human alveolar macrophages are a unique myeloid subset critical for understanding pulmonary diseases and are difficult to access. Here, we present a protocol to generate...
Human alveolar macrophages are a unique myeloid subset critical for understanding pulmonary diseases and are difficult to access. Here, we present a protocol to generate human alveolar macrophage-like (AML) cells from fresh peripheral blood mononuclear cells or purified monocytes. We describe steps for cell isolation, incubation in a defined cocktail of pulmonary surfactant and lung-associated cytokines, phenotype analysis, and validation with human alveolar macrophages. We then detail procedures for quality control and technical readouts for monitoring microbial response. For complete details on the use and execution of this protocol, please refer to Pahari et al. and Neehus et al..
Topics: Humans; Macrophages, Alveolar; Monocytes; Leukocytes, Mononuclear; Cell Culture Techniques; Cytokines; Cell Separation; Cells, Cultured
PubMed: 38722740
DOI: 10.1016/j.xpro.2024.103061 -
EBioMedicine Jun 2024Interstitial lung diseases (ILDs) in adults and children (chILD) are a heterogeneous group of lung disorders leading to inflammation, abnormal tissue repair and scarring... (Review)
Review
Interstitial lung diseases (ILDs) in adults and children (chILD) are a heterogeneous group of lung disorders leading to inflammation, abnormal tissue repair and scarring of the lung parenchyma often resulting in respiratory failure and death. Inherited factors directly cause, or contribute significantly to the risk of developing ILD, so called familial pulmonary fibrosis (FPF), and monogenic forms may have a poor prognosis and respond poorly to current treatments. Specific, variant-targeted or precision treatments are lacking. Clinical trials of repurposed drugs, anti-fibrotic medications and specific treatments are emerging but for many patients no interventions exist. We convened an expert working group to develop an overarching framework to address the existing research gaps in basic, translational, and clinical research and identified areas for future development of preclinical models, candidate medications and innovative clinical trials. In this Position Paper, we summarise working group discussions, recommendations, and unresolved questions concerning precision treatments for FPF.
Topics: Humans; Precision Medicine; Animals; Disease Management; Pulmonary Fibrosis; Clinical Trials as Topic
PubMed: 38718684
DOI: 10.1016/j.ebiom.2024.105135 -
PloS One 2024Transcriptional response to changes in oxygen concentration is mainly controlled by hypoxia-inducible transcription factors (HIFs). Besides regulation of...
Transcriptional response to changes in oxygen concentration is mainly controlled by hypoxia-inducible transcription factors (HIFs). Besides regulation of hypoxia-responsible gene expression, HIF-3α has recently been shown to be involved in lung development and in the metabolic process of fat tissue. However, the precise mechanism for such properties of HIF-3α is still largely unknown. To this end, we generated HIF3A gene-disrupted mice by means of genome editing technology to explore the pleiotropic role of HIF-3α in development and physiology. We obtained adult mice carrying homozygous HIF3A gene mutations with comparable body weight and height to wild-type mice. However, the number of litters and ratio of homozygous mutation carriers born from the mating between homozygous mutant mice was lower than expected due to sporadic deaths on postnatal day 1. HIF3A gene-disrupted mice exhibited abnormal configuration of the lung such as a reduced number of alveoli and thickened alveolar walls. Transcriptome analysis showed, as well as genes associated with lung development, an upregulation of stearoyl-Coenzyme A desaturase 1, a pivotal enzyme for fatty acid metabolism. Analysis of fatty acid composition in the lung employing gas chromatography indicated an elevation in palmitoleic acid and a reduction in oleic acid, suggesting an imbalance in distribution of fatty acid, a constituent of lung surfactant. Accordingly, administration of glucocorticoid injections during pregnancy resulted in a restoration of normal alveolar counts and a decrease in neonatal mortality. In conclusion, these observations provide novel insights into a pivotal role of HIF-3α in the preservation of critically important structure and function of alveoli beyond the regulation of hypoxia-mediated gene expression.
Topics: Animals; Female; Male; Mice; Animals, Newborn; Apoptosis Regulatory Proteins; Aryl Hydrocarbon Receptor Nuclear Translocator; Fatty Acids; Pulmonary Alveoli; Repressor Proteins; Stearoyl-CoA Desaturase
PubMed: 38717999
DOI: 10.1371/journal.pone.0300751 -
AJP Reports Apr 2024Giant pulmonary cyst in extremely low birth weight (ELBW) infants has been described as one of severe pulmonary diseases. Any definitive therapy for refractory cases,...
Giant pulmonary cyst in extremely low birth weight (ELBW) infants has been described as one of severe pulmonary diseases. Any definitive therapy for refractory cases, where conservative methods of treatments are not effective, has not been established as a standard. Herein, we report an ELBW infant with a giant pulmonary cyst cured by percutaneous drainage without any adverse events. A female infant was born with a birth weight of 327 g. Surfactant was administered on days 1 and 2 of life to treat respiratory distress syndrome. Tracheal intubation was performed and synchronized intermittent mandatory ventilation was promptly initiated following birth. On the course, right giant pulmonary cyst developed on day 9 after birth. Although we started conservative therapy, including right lateral decubitus positioning, high-frequency oscillatory ventilation, and systemic corticosteroid administration, the diameter of the cyst had reached 34 mm, and mediastinal displacement was observed on day 28 after birth when she weighed 393 g. She recovered by percutaneous drainage followed by suction with a pressure of -10 cm H O under mild sedation for 3 days. We believe that percutaneous drainage can be one of the available options for unilateral pulmonary interstitial emphysema.
PubMed: 38707264
DOI: 10.1055/s-0044-1786713 -
Respiratory Research May 2024Influenza A virus (IAV) infection is a significant risk factor for respiratory diseases, but the host defense mechanisms against IAV remain to be defined. Immune...
BACKGROUND
Influenza A virus (IAV) infection is a significant risk factor for respiratory diseases, but the host defense mechanisms against IAV remain to be defined. Immune regulators such as surfactant protein A (SP-A) and Toll-interacting protein (Tollip) have been shown to be involved in IAV infection, but whether SP-A and Tollip cooperate in more effective host defense against IAV infection has not been investigated.
METHODS
Wild-type (WT), Tollip knockout (KO), SP-A KO, and Tollip/SP-A double KO (dKO) mice were infected with IAV for four days. Lung macrophages were isolated for bulk RNA sequencing. Precision-cut lung slices (PCLS) from WT and dKO mice were pre-treated with SP-A and then infected with IAV for 48 h.
RESULTS
Viral load was significantly increased in bronchoalveolar lavage (BAL) fluid of dKO mice compared to all other strains of mice. dKO mice had significantly less recruitment of neutrophils into the lung compared to Tollip KO mice. SP-A treatment of PCLS enhanced expression of TNF and reduced viral load in dKO mouse lung tissue. Pathway analysis of bulk RNA sequencing data suggests that macrophages from IAV-infected dKO mice reduced expression of genes involved in neutrophil recruitment, IL-17 signaling, and Toll-like receptor signaling.
CONCLUSIONS
Our data suggests that both Tollip and SP-A are essential for the lung to exert more effective innate defense against IAV infection.
Topics: Animals; Mice, Knockout; Pulmonary Surfactant-Associated Protein A; Mice; Orthomyxoviridae Infections; Influenza A virus; Mice, Inbred C57BL; Intracellular Signaling Peptides and Proteins; Lung
PubMed: 38702733
DOI: 10.1186/s12931-024-02820-3 -
The Cochrane Database of Systematic... May 2024Respiratory distress occurs in up to 7% of newborns, with respiratory support (RS) provided invasively via an endotracheal (ET) tube or non-invasively via a nasal... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Respiratory distress occurs in up to 7% of newborns, with respiratory support (RS) provided invasively via an endotracheal (ET) tube or non-invasively via a nasal interface. Invasive ventilation increases the risk of lung injury and chronic lung disease (CLD). Using non-invasive strategies, with or without minimally invasive surfactant, may reduce the need for mechanical ventilation and the risk of lung damage in newborn infants with respiratory distress.
OBJECTIVES
To evaluate the benefits and harms of nasal high-frequency ventilation (nHFV) compared to invasive ventilation via an ET tube or other non-invasive ventilation methods on morbidity and mortality in preterm and term infants with or at risk of respiratory distress.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, CINAHL and three trial registries in April 2023.
SELECTION CRITERIA
Randomised controlled trials (RCTs), cluster- or quasi-RCTs of nHFV in newborn infants with respiratory distress compared to invasive or non-invasive ventilation.
DATA COLLECTION AND ANALYSIS
Two authors independently selected the trials for inclusion, extracted data, assessed the risk of bias, and undertook GRADE assessment.
MAIN RESULTS
We identified 33 studies, mostly in low- to middle-income settings, that investigated this therapy in 5068 preterm and 46 term infants. nHFV compared to invasive respiratory therapy for initial RS We are very uncertain whether nHFV reduces mortality before hospital discharge (RR 0.67, 95% CI 0.20 to 2.18; 1 study, 80 infants) or the incidence of CLD (RR 0.38, 95% CI 0.09 to 1.59; 2 studies, 180 infants), both very low-certainty. ET intubation, death or CLD, severe intraventricular haemorrhage (IVH) and neurodevelopmental disability (ND) were not reported. nHFV vs nasal continuous positive airway pressure (nCPAP) used for initial RS We are very uncertain whether nHFV reduces mortality before hospital discharge (RR 1.00, 95% CI 0.41 to 2.41; 4 studies, 531 infants; very low-certainty). nHFV may reduce ET intubation (RR 0.52, 95% CI 0.33 to 0.82; 5 studies, 571 infants), but there may be little or no difference in CLD (RR 1.35, 95% CI 0.80 to 2.27; 4 studies, 481 infants); death or CLD (RR 2.50, 95% CI 0.52 to 12.01; 1 study, 68 participants); or severe IVH (RR 1.17, 95% CI 0.36 to 3.78; 4 studies, 531 infants), all low-certainty evidence. ND was not reported. nHFV vs nasal intermittent positive-pressure ventilation (nIPPV) used for initial RS nHFV may result in little to no difference in mortality before hospital discharge (RR 1.86, 95% CI 0.90 to 3.83; 2 studies, 84 infants; low-certainty). nHFV may have little or no effect in reducing ET intubation (RR 1.33, 95% CI 0.76 to 2.34; 5 studies, 228 infants; low-certainty). There may be a reduction in CLD (RR 0.63, 95% CI 0.42 to 0.95; 5 studies, 307 infants; low-certainty). A single study (36 infants) reported no events for severe IVH. Death or CLD and ND were not reported. nHFV vs high-flow nasal cannula (HFNC) used for initial RS We are very uncertain whether nHFV reduces ET intubation (RR 2.94, 95% CI 0.65 to 13.27; 1 study, 37 infants) or reduces CLD (RR 1.18, 95% CI 0.46 to 2.98; 1 study, 37 participants), both very low-certainty. There were no mortality events before hospital discharge or severe IVH. Other deaths, CLD and ND, were not reported. nHFV vs nCPAP used for RS following planned extubation nHFV probably results in little or no difference in mortality before hospital discharge (RR 0.92, 95% CI 0.52 to 1.64; 6 studies, 1472 infants; moderate-certainty). nHFV may result in a reduction in ET reintubation (RR 0.42, 95% CI 0.35 to 0.51; 11 studies, 1897 infants) and CLD (RR 0.78, 95% CI 0.67 to 0.91; 10 studies, 1829 infants), both low-certainty. nHFV probably has little or no effect on death or CLD (RR 0.90, 95% CI 0.77 to 1.06; 2 studies, 966 infants) and severe IVH (RR 0.80, 95% CI 0.57 to 1.13; 3 studies, 1117 infants), both moderate-certainty. We are very uncertain whether nHFV reduces ND (RR 0.92, 95% CI 0.37 to 2.29; 1 study, 74 infants; very low-certainty). nHFV versus nIPPV used for RS following planned extubation nHFV may have little or no effect on mortality before hospital discharge (RR 1.83, 95% CI 0.70 to 4.79; 2 studies, 984 infants; low-certainty). There is probably a reduction in ET reintubation (RR 0.69, 95% CI 0.54 to 0.89; 6 studies, 1364 infants), but little or no effect on CLD (RR 0.88, 95% CI 0.75 to 1.04; 4 studies, 1236 infants); death or CLD (RR 0.92, 95% CI 0.79 to 1.08; 3 studies, 1070 infants); or severe IVH (RR 0.78, 95% CI 0.55 to 1.10; 4 studies, 1162 infants), all moderate-certainty. One study reported there might be no difference in ND (RR 0.88, 95% CI 0.35 to 2.16; 1 study, 72 infants; low-certainty). nHFV versus nIPPV following initial non-invasive RS failure nHFV may have little or no effect on mortality before hospital discharge (RR 1.44, 95% CI 0.10 to 21.33); or ET intubation (RR 1.23, 95% CI 0.51 to 2.98); or CLD (RR 1.01, 95% CI 0.70 to 1.47); or severe IVH (RR 0.47, 95% CI 0.02 to 10.87); 1 study, 39 participants, all low- or very low-certainty. Other deaths or CLD and ND were not reported.
AUTHORS' CONCLUSIONS
For initial RS, we are very uncertain if using nHFV compared to invasive respiratory therapy affects clinical outcomes. However, nHFV may reduce intubation when compared to nCPAP. For planned extubation, nHFV may reduce the risk of reintubation compared to nCPAP and nIPPV. nHFV may reduce the risk of CLD when compared to nCPAP. Following initial non-invasive respiratory support failure, nHFV when compared to nIPPV may result in little to no difference in intubation. Large trials, particularly in high-income settings, are needed to determine the role of nHFV in initial RS and following the failure of other non-invasive respiratory support. Also, the optimal settings of nHVF require further investigation.
Topics: Humans; Infant, Newborn; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome, Newborn; Noninvasive Ventilation; High-Frequency Ventilation; Infant, Premature; Bias; Intubation, Intratracheal; Pulmonary Surfactants
PubMed: 38695628
DOI: 10.1002/14651858.CD012712.pub2