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The European Respiratory Journal Apr 2024There is an unmet need for new therapeutic strategies that target alternative pathways to improve the prognosis of patients with pulmonary arterial hypertension (PAH).... (Review)
Review
There is an unmet need for new therapeutic strategies that target alternative pathways to improve the prognosis of patients with pulmonary arterial hypertension (PAH). As immunity has been involved in the development and progression of vascular lesions in PAH, we review the potential contribution of B-cells in its pathogenesis and evaluate the relevance of B-cell-targeted therapies. Circulating B-cell homeostasis is altered in PAH patients, with total B-cell lymphopenia, abnormal subset distribution (expansion of naïve and antibody-secreting cells, reduction of memory B-cells) and chronic activation. B-cells are recruited to the lungs through local chemokine secretion, and activated by several mechanisms: 1) interaction with lung vascular autoantigens through cognate B-cell receptors; 2) costimulatory signals provided by T follicular helper cells (interleukin (IL)-21), type 2 T helper cells and mast cells (IL-4, IL-6 and IL-13); and 3) increased survival signals provided by B-cell activating factor pathways. This activity results in the formation of germinal centres within perivascular tertiary lymphoid organs and in the local production of pathogenic autoantibodies that target the pulmonary vasculature and vascular stabilisation factors (including angiotensin-II/endothelin-1 receptors and bone morphogenetic protein receptors). B-cells also mediate their effects through enhanced production of pro-inflammatory cytokines, reduced anti-inflammatory properties by regulatory B-cells, immunoglobulin (Ig)G-induced complement activation, and IgE-induced mast cell activation. Precision-medicine approaches targeting B-cell immunity are a promising direction for select PAH conditions, as suggested by the efficacy of anti-CD20 therapy in experimental models and a trial of rituximab in systemic sclerosis-associated PAH.
Topics: Humans; B-Lymphocytes; Pulmonary Arterial Hypertension; Animals; Lung; Autoantibodies; Hypertension, Pulmonary
PubMed: 38485150
DOI: 10.1183/13993003.01949-2023 -
Viruses Aug 2023Critical COVID-19 has been associated with altered patterns of cytokines. Distinct inflammatory processes in systemic and pulmonary sites have been reported, but studies...
Critical COVID-19 has been associated with altered patterns of cytokines. Distinct inflammatory processes in systemic and pulmonary sites have been reported, but studies comparing these two sites are still scarce. We aimed to evaluate the profile of pulmonary and systemic cytokines and chemokines in critically ill COVID-19 patients. Levels of cytokines and chemokines were measured in plasma samples and minibronchoalveolar lavage of critical COVID-19 patients within 48 h and 5-8 days after intubation. Distinct inflammatory processes were observed in the lungs and blood, which were regulated separately. Survivor patients showed higher lung cytokine levels including IFN-γ, IL-2, IL-4, G-CSF, and CCL4, while nonsurvivors displayed higher levels in the blood, which included IL-6, CXCL8, CXCL10, CCL2, and CCL4. Furthermore, our findings indicate that high TNF and CXCL8 levels in the mini-BAL were associated with better lung oxygen exchange capacity, whereas high levels of IFN-γ in plasma were associated with worse lung function, as measured using the PaO/FiO ratio. These results suggest that a robust and localized inflammatory response in the lungs is protective and associated with survival, whereas a systemic inflammatory response is detrimental and associated with mortality in critical COVID-19.
Topics: Humans; COVID-19; Cytokines; Plasma; Inflammation; Lung
PubMed: 37632046
DOI: 10.3390/v15081704 -
Respiratory Research Nov 2023Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 (ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2).
METHODS
In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis.
RESULTS
Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-β upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion.
CONCLUSIONS
These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.
Topics: Mice; Humans; Animals; Leukocytes, Mononuclear; Antibodies, Monoclonal; Endothelial Cells; Fibrinolysin; Lung; Fibrosis; Idiopathic Pulmonary Fibrosis; Pneumonia; Collagen; Bleomycin; Fibroblasts; Phosphopyruvate Hydratase; Mice, Inbred C57BL
PubMed: 37964270
DOI: 10.1186/s12931-023-02583-3 -
Allergology International : Official... Oct 2023Cryptococcus neoformans and Cryptococcus gattii are pathogenic fungi that infect the human respiratory system and cause life-threatening pulmonary cryptococcosis. The... (Review)
Review
Cryptococcus neoformans and Cryptococcus gattii are pathogenic fungi that infect the human respiratory system and cause life-threatening pulmonary cryptococcosis. The immunopathology of cryptococcosis is completely different from that of other fungal allergies. In murine cryptococcal infection models, cryptococcal cells are usually injected via nasal or intratracheal routes. After the infection, the alveolar epithelial cells are impaired and release IL-33, an IL-1 family cytokine that functions as an alarmin. This cytokine detrimentally amplifies allergic responses, and also induces a protective immune response against parasitic infection. In the pulmonary cryptococcosis model, type-II alveolar epithelial cells are the major source of IL-33, and the alveolar epithelial cells, ILC2, and Th2 cells express the IL-33 receptor (ST2). In IL-33- or ST2-deficient mice, allergy-like immune responses are attenuated after the C. neoformans infection. The numbers of ILC2 and Th2 cells and the levels of type 2 cytokines, including IL-4, IL-5, and IL-13, are decreased in the mouse lungs in both models. In association with these changes, total blood IgE, bronchus mucus production, and the number of eosinophils are decreased. Conversely, lung neutrophils and M1-type macrophages are increased. These are protective immune subsets suppressing cryptococcal growth. As a result, the lung fungal burden of IL-33- and ST2-deficient mice is decreased post-infection, and both deficient mice show significantly improved mortality. This pathogenesis varies depending on the cryptococcal and murine strains used in the animal experiments. Here, we overview and discuss the itmmunopathology of the IL-33/ST2 axis in a murine lethal cryptococcal infection model.
Topics: Animals; Humans; Mice; Cryptococcosis; Cryptococcus neoformans; Cytokines; Disease Models, Animal; Immunity, Innate; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Lung; Lymphocytes
PubMed: 37482531
DOI: 10.1016/j.alit.2023.07.002 -
Frontiers in Immunology 2023Up to 30% of hospitalized COVID-19 patients experience persistent sequelae, including pulmonary fibrosis (PF).
INTRODUCTION
Up to 30% of hospitalized COVID-19 patients experience persistent sequelae, including pulmonary fibrosis (PF).
METHODS
We examined COVID-19 survivors with impaired lung function and imaging worrisome for developing PF and found within six months, symptoms, restriction and PF improved in some (Early-Resolving COVID-PF), but persisted in others (Late-Resolving COVID-PF). To evaluate immune mechanisms associated with recovery versus persistent PF, we performed single-cell RNA-sequencing and multiplex immunostaining on peripheral blood mononuclear cells from patients with Early- and Late-Resolving COVID-PF and compared them to age-matched controls without respiratory disease.
RESULTS AND DISCUSSION
Our analysis showed circulating monocytes were significantly reduced in Late-Resolving COVID-PF patients compared to Early-Resolving COVID-PF and non-diseased controls. Monocyte abundance correlated with pulmonary function forced vital capacity and diffusion capacity. Differential expression analysis revealed MHC-II class molecules were upregulated on the CD8 T cells of Late-Resolving COVID-PF patients but downregulated in monocytes. To determine whether these immune signatures resembled other interstitial lung diseases, we analyzed samples from Idiopathic Pulmonary Fibrosis (IPF) patients. IPF patients had a similar marked decrease in monocyte HLA-DR protein expression compared to Late-Resolving COVID-PF patients. Our findings indicate decreased circulating monocytes are associated with decreased lung function and uniquely distinguish Late-Resolving COVID-PF from Early-Resolving COVID-PF, IPF, and non-diseased controls.
Topics: Humans; Monocytes; Leukocytes, Mononuclear; COVID-19; Idiopathic Pulmonary Fibrosis; Lung
PubMed: 38292490
DOI: 10.3389/fimmu.2023.1308594 -
Journal of Medical Genetics Nov 2023Pulmonary disease is the major cause of morbidity and mortality in osteogenesis imperfecta (OI). We investigated the contribution of intrinsic lung factors to impaired...
PURPOSE
Pulmonary disease is the major cause of morbidity and mortality in osteogenesis imperfecta (OI). We investigated the contribution of intrinsic lung factors to impaired pulmonary function in children and young adults with OI types III, IV, VI.
METHODS
Patients with type III (n=8), IV (n=21), VI (n=5), VII (n=2) or XIV (n=1) OI (mean age 23.6 years) prospectively underwent pulmonary function tests (PFTs) and thoracic CT and radiographs.
RESULTS
PFT results were similar using arm span or ulnar length as height surrogates. PFTs were significantly lower in type III than type IV or VI OI. All patients with type III and half of type IV OI had lung restriction; 90% of patients with OI had reduced gas exchange. Patients with variants had significantly lower forced expiratory flow (FEF)25%-75% compared with those with variants. PFTs correlated negatively with Cobb angle or age. CT scans revealed small airways bronchial thickening (100%, 86%, 100%), atelectasis (88%, 43%, 40%), reticulations (50%, 29%, 20%), ground glass opacities (75%, 5%, 0%), pleural thickening (63%, 48%, 20%) or emphysema (13%, 19%, 20%) in type III, IV or VI OI, respectively.
CONCLUSION
Both lung intrinsic and extrinsic skeletal abnormalities contribute to OI pulmonary dysfunction. Most young adult patients have restrictive disease and abnormal gas exchange; impairment is greater in type III than type IV OI. Decreased FEF25%-75% and thickening of small bronchi walls indicate a critical role for small airways. Lung parenchymal abnormalities (atelectasis, reticulations) and pleural thickening were also detected. Clinical interventions to mitigate these impairments are warranted.
TRIAL REGISTRATION NUMBER
NCT03575221.
Topics: Humans; Osteogenesis Imperfecta; Male; Female; Respiratory Function Tests; Adolescent; Young Adult; Adult; Child; Lung; Tomography, X-Ray Computed; Lung Diseases; Child, Preschool; Collagen Type I
PubMed: 37197785
DOI: 10.1136/jmg-2022-109009 -
Respiratory Medicine Dec 2023The pulmonary manifestations of Systemic Lupus Erythematosus (SLE) in pediatric patients are poorly understood and the pulmonary manifestations reported from the adult...
The pulmonary manifestations of Systemic Lupus Erythematosus (SLE) in pediatric patients are poorly understood and the pulmonary manifestations reported from the adult population are generally extrapolated to the pediatric population. In the present work, the review of 228 files was carried out, in which the pulmonary manifestations, symptoms and antibody levels of the patients treated at the Hospital Regional de Alta Especialidad de Ixtapaluca (HRAEI), State of Mexico, Mexico, were identified. Statistical significance between groups was estimated using the Chi-square and Mann-Whitney U test. The main pulmonary manifestations identified were pleurisy (14 %), pulmonary hemorrhage (3.9 %), pulmonary thromboembolism (0.9 %), acute lupus pneumonitis (0.4 %), pulmonary arterial hypertension (0.4 %), and small lung syndrome (0.4 %). While the initial symptomatology was dyspnea with an incidence of 9.6 %, the mean oxygen saturation in the population was 96.87 %. Pleural effusion was identified as the most frequent pulmonary manifestation in radiographic changes. No statistically significant difference was found in antibody levels when comparing the groups. The most common pulmonary manifestation associated with SLE is pleurisy, however, the range of pulmonary manifestations in this type of patient can be very varied, as well as the presentation of each of them.
Topics: Adult; Humans; Child; Lupus Erythematosus, Systemic; Lung Diseases; Lung; Pleurisy; Pleural Effusion
PubMed: 37926179
DOI: 10.1016/j.rmed.2023.107456 -
Nature Communications Mar 2024Hospital-acquired pneumonia (HAP) is associated with high mortality and costs, and frequently caused by multidrug-resistant (MDR) bacteria. Although prior antimicrobial...
Hospital-acquired pneumonia (HAP) is associated with high mortality and costs, and frequently caused by multidrug-resistant (MDR) bacteria. Although prior antimicrobial therapy is a major risk factor for HAP, the underlying mechanism remains incompletely understood. Here, we demonstrate that antibiotic therapy in hospitalized patients is associated with decreased diversity of the gut microbiome and depletion of short-chain fatty acid (SCFA) producers. Infection experiments with mice transplanted with patient fecal material reveal that these antibiotic-induced microbiota perturbations impair pulmonary defense against MDR Klebsiella pneumoniae. This is dependent on inflammatory monocytes (IMs), whose fatty acid receptor (FFAR)2/3-controlled and phagolysosome-dependent antibacterial activity is compromized in mice transplanted with antibiotic-associated patient microbiota. Collectively, we characterize how clinically relevant antibiotics affect antimicrobial defense in the context of human microbiota, and reveal a critical impairment of IM´s antimicrobial activity. Our study provides additional arguments for the rational use of antibiotics and offers mechanistic insights for the development of novel prophylactic strategies to protect high-risk patients from HAP.
Topics: Humans; Mice; Animals; Anti-Bacterial Agents; Monocytes; Anti-Infective Agents; Klebsiella pneumoniae; Lung
PubMed: 38555356
DOI: 10.1038/s41467-024-47149-z -
European Respiratory Review : An... Sep 2023Asthma is a chronic inflammatory airway disorder whose pathophysiological and immunological mechanisms are not completely understood. Asthma exacerbations are mostly... (Review)
Review
Asthma is a chronic inflammatory airway disorder whose pathophysiological and immunological mechanisms are not completely understood. Asthma exacerbations are mostly driven by respiratory viral infections and characterised by worsening of symptoms. Despite current therapies, asthma exacerbations can still be life-threatening. Natural killer (NK) cells are innate lymphoid cells well known for their antiviral activity and are present in the lung as circulating and resident cells. However, their functions in asthma and its exacerbations are still unclear. In this review, we will address NK cell activation and functions, which are particularly relevant for asthma and virus-induced asthma exacerbations. Then, the role of NK cells in the lungs at homeostasis in healthy individuals will be described, as well as their functions during pulmonary viral infections, with an emphasis on those associated with asthma exacerbations. Finally, we will discuss the involvement of NK cells in asthma and virus-induced exacerbations and examine the effect of asthma treatments on NK cells.
Topics: Humans; Immunity, Innate; Asthma; Killer Cells, Natural; Lung
PubMed: 37437915
DOI: 10.1183/16000617.0036-2023 -
Respiratory Research Feb 2024Currently, there are no reliable clinical tools that allow non-invasive therapeutic support for patients with pulmonary arterial hypertension. This study aims to propose...
BACKGROUND
Currently, there are no reliable clinical tools that allow non-invasive therapeutic support for patients with pulmonary arterial hypertension. This study aims to propose a low-frequency ultrasound device for pulmonary hypertension therapy and to demonstrate its potential.
METHODS
A novel low-frequency ultrasound transducer has been developed. Due to its structural properties, it is excited by higher vibrational modes, which generate a signal capable of deeply penetrating biological tissues. A methodology for the artificial induction of pulmonary hypertension in sheep and for the assessment of lung physiological parameters such as blood oxygen concentration, pulse rate, and pulmonary blood pressure has been proposed.
RESULTS
The results showed that exposure of the lungs to low-frequency ultrasound changed physiological parameters such as blood oxygen concentration, pulse rate and blood pressure. These parameters are most closely related to indicators of pulmonary hypertension (PH). The ultrasound exposure increased blood oxygen concentration over a 7-min period, while pulse rate and pulmonary blood pressure decreased over the same period. In anaesthetised sheep exposed to low-frequency ultrasound, a 10% increase in SpO, a 10% decrease in pulse rate and an approximate 13% decrease in blood pressure were observed within 7 min.
CONCLUSIONS
The research findings demonstrate the therapeutic efficiency of low-frequency ultrasound on hypertensive lungs, while also revealing insights into the physiological aspects of gas exchange within the pulmonary system.
Topics: Humans; Animals; Sheep; Hypertension, Pulmonary; Lung; Ultrasonography; Blood Pressure; Oxygen
PubMed: 38317182
DOI: 10.1186/s12931-024-02713-5