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Lung infection is one of the leading causes of morbidity and mortality worldwide. Even with appropriate antibiotic and antiviral treatment, mortality in hospitalized patients often exceeds 10%, highlighting the need for the development of new therapeutic strategies. Of late, cystic fibrosis transmembrane conductance regulator (CFTR) is—in addition to its well-established roles in the lung airway and extrapulmonary organs—increasingly recognized as a key regulator of alveolar homeostasis and defense. In the alveolar epithelium, CFTR mediates alveolar fluid secretion and liquid homeostasis; in the microvascular endothelium, CFTR maintains vascular barrier function. CFTR also contributes to alveolar immunity. Yet, in lung infection, diverse molecular mechanisms reduce CFTR abundance and otherwise impair its function, promoting alveolar inflammation, edema, and cell death. Preservation or restoration of CFTR function by CFTR modulator drugs thus presents a promising avenue to combat lung infection in a pathogen-independent manner. [ABSTRACT FROM AUTHOR]

Background/Objectives: Pulmonary embolism (PE) is a potentially serious condition characterized by the blockage of blood vessels in the lungs, often presenting significant diagnostic challenges due to its non-specific symptoms. This study aimed to evaluate the utility of the alveolar–arterial (A-a) oxygen gradient as a diagnostic tool for PE, hypothesizing that it could enhance early detection when combined with other clinical markers. Methods: We retrospectively analyzed 168 patients at the University Hospital Center Split. This study correlated A-a gradients with PE confirmed by CT pulmonary angiography. Key clinical and biochemical markers, including heart rate, C-reactive protein (CRP), pro-brain natriuretic peptide (NT-proBNP), D-dimer, high-sensitivity troponin (hs-troponin), and arterial oxygen pressure (PaO2), were assessed. Results: Our findings revealed that patients with PE had significantly higher A-a gradients than those without PE. The observed-to-expected ratio for the A-a gradient was notably increased in the PE group. Additionally, patients with PE exhibited elevated heart rate, CRP, NT-proBNP, D-dimer, and hs-troponin levels, while PaO2 levels were notably lower. Conclusions: This study demonstrates that an elevated A-a gradient reflects the severity of gas exchange impairment in PE. The results suggest that early diagnosis of PE may be improved by incorporating A-a gradient analysis alongside other clinical markers, potentially leading to more effective and timely interventions. [ABSTRACT FROM AUTHOR]

The aim of this study was to test whether combined physical exercise training of moderate intensity executed during the development of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) hinders the progression of pulmonary and right heart harmful functional and structural remodeling in rats. Wistar rats were injected with MCT (60 mg/kg) and after 24 h were exposed to a combined exercise training program: aerobic exercise (treadmill running—60 min/day; 60% of maximum running speed); and resistance exercise (vertical ladder climbing—15 climbs; 60% of maximum carrying load), on alternate days, 5 days/wk, for ∼3 wk. After euthanasia, the lung and right ventricle (RV) were excised and processed for histological, single myocyte, and biochemical analyses. Combined exercise increased the tolerance to physical effort (time until fatigue and relative maximum load) and prevented increases in pulmonary artery resistance (acceleration time (TA)/ejection time (TE)] and reductions in RV function [tricuspid annular plane systolic excursion (TAPSE)]. Moreover, in myocytes isolated from the RV, combined exercise preserved contraction amplitude, as well as contraction and relaxation velocities, and inhibited reductions in the amplitude and maximum speeds to peak and to decay of the intracellular Ca2+ transient. Furthermore, combined exercise avoided RV (RV weight, cardiomyocyte, extracellular matrix, collagen, inflammatory infiltrate, and extracellular matrix) and lung (pulmonary alveoli and alveolar septum) harmful structural remodeling. In addition, combined exercise restricted RV [nitric oxide (NO) and carbonyl protein (CP)] and lung [catalase (CAT), glutathione S-transferase (GST), and NO] oxidative stress. In conclusion, the applied combined exercise regime hinders the progression of pulmonary and right heart functional and structural harmful remodeling in rats with MCT-induced PAH. NEW & NOTEWORTHY: This study reveals that combined exercise improves tolerance to physical effort, prevents increases in pulmonary artery resistance, and conserves the right heart function during the progression of pulmonary arterial hypertension. Our analyses show that combined exercise hinders harmful right ventricular and lung structural remodeling and oxidative stress, which reflects in the maintenance of right ventricular myocytes' contractile function by preserving the intracellular calcium cycling. An attenuated progression of the disease impacts positively on its prognosis. [ABSTRACT FROM AUTHOR]

As an important carrier of intercellular information transmission, exosomes regulate the physiological and pathological state of local or distant cells by carrying a variety of signal molecules such as microRNAs (miRNAs). Current research indicates that exosomes and miRNAs can serve as biomarkers and therapeutic targets for a variety of cardiovascular diseases (CVDs). This narrative review summarizes the research progress of exosomes and their miRNAs in CVDs, particularly in pulmonary valve diseases (PVDs), and, for the first time, explores their potential associations with transcatheter pulmonary valve replacement (TPVR). Currently, miRNAs play a crucial role in determining the optimal timing for TPVR intervention, and they demonstrate broad application prospects in post-TPVR right ventricular (RV) remodeling, treatment, and prognosis monitoring. However, the association between exosomes and miRNAs and the development of PVDs, particularly pulmonary regurgitation, remains unclear. The molecular mechanisms of exosomes and miRNAs in PVDs and RV remodeling after TPVR have not been fully elucidated, and their application in postoperative treatment following TPVR is still in its infancy. Future research must focus on advancing fundamental studies, validating biomarkers, and enhancing clinical applications to achieve significant breakthroughs. [ABSTRACT FROM AUTHOR]

Purpose: Lung injury associated with bronchopulmonary dysplasia (BPD) and its related neurodevelopmental disorders have garnered increasing attention in the context of premature infants. Establishing a reliable animal model is essential for delving into the underlying mechanisms of these conditions. Methods: Newborn rats were randomly assigned to two groups: the hyperoxia-induced BPD group and the normoxia (NO) group. For the BPD group, they were nurtured in a hyperoxic environment with a high oxygen inspired fraction (0.85) from birth until day 14 within 28 days postnatally. In contrast, the NO group consisted of newborn rats that were nurtured in a normoxic environment with a standard oxygen inspired fraction (0.21) for 28 days postnatally. Various pathological sections of both lung and brain tissues were examined. TUNEL staining, immunofluorescence assays, and functional tests were performed, and the results were meticulously analyzed to assess the impact of hyperoxia environments on the developing organs. Results: In the newborn rats of the BPD group, a significant reduction in alveolar number coupled with enlargement was observed, alongside severe fibrosis, collagen deposition, and constriction of bronchi and vascular lumens. This was accompanied by an accumulation of inflammatory cells and a marked deterioration in lung function compared to the NO group (P < 0.05). Additionally, a decrease in neuronal count, an increase in neuronal apoptosis, proliferation of neuroglia cells, and demyelination were noted, and poorer performance in the Morris water maze test within the BPD group (P < 0.05). Conclusion: The BPD-rats model was established successfully. Lung injury in the BPD group evident across the bronchi to the alveoli and pulmonary vessels, which was associated with deteriorated lung function at postnatal day 14. Concurrently, brain injury extended from the cerebral cortex to the hippocampus, which was associated with impaired performance in orientation navigation and spatial probe tests at postnatal day 28. [ABSTRACT FROM AUTHOR]

Airways, alveoli and the pulmonary tissues are the most vulnerable to the external environment including occasional deliberate or accidental exposure to highly toxic chemical gases. However, there are many effective protective mechanisms that maintain the integrity of the pulmonary tissues and preserve lung function. Alveolar macrophages form the first line of defense against any pathogen or chemical/reactant that crosses the airway mucociliary barrier and reaches the alveolar region. Resident alveolar macrophages are activated or circulating monocytes infiltrate the airspace to contribute towards inflammatory or reparative responses. Studies on response of alveolar macrophages to noxious stimuli are rapidly emerging and alveolar macrophage are also being sought as therapeutic target. Here such studies have been reviewed and put together for a better understanding of the role pulmonary macrophages in general and alveolar macrophage in particular play in the pathogenesis of disease caused by chemical induced acute lung injury. [ABSTRACT FROM AUTHOR]

Pyrethrin and pyrethroid are a relatively new class of pesticides with potent insecticidal properties. Pyrethrins are naturally occurring pesticides obtained from the Chrysanthemum cinerariaefolium flower, while pyrethroids are their synthetic derivatives. They are widely used as the insecticides of choice in agriculture, veterinary medicine, public health programs, and household activities. Pyrethrin, being a broad-spectrum insecticide kills a wide range of pests, while pyrethroids last longer in the environment owing to low susceptibility to sunlight, and greater stability and efficacy than parent molecules. Humans can be exposed through inhalation, ingestion, and dermal routes. Indoor usage of an insecticide poses a serious risk to human health, especially to women, children, and stay-at-home people. Although pyrethrin and pyrethroid are generally considered safe, sustained skin or inhalation exposure or direct contact with open wounds results in higher toxicity to mammals. There is a paucity of data on the impact of pyrethrin and pyrethroid on overall pulmonary health. The respiratory system, from the nose, nasal passages, airways, and bronchi to the pulmonary alveoli, is vulnerable to environmental contaminants such as pesticides because of its anatomical location as well as being a highly blood profused organ. Under and over-functioning of the respiratory system triggers diverse pathologies such as serious infections, allergies, asthma, metastatic malignancies, and auto-immune conditions. While the association between workplace-related pesticide exposures and respiratory diseases and symptoms is well documented, it is important to understand the adverse health impact of pyrethrin and pyrethroid on the general population for awareness and also for better regulation and implementation of the law. [ABSTRACT FROM AUTHOR]

Objective: Avacopan, an activated complement factor 5 receptor antagonist, has been approved as adjunct therapy for severe active antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Current evidence supports the management of AAV presenting with diffuse alveolar hemorrhage (DAH) by administering glucocorticoids combined with either rituximab or cyclophosphamide in addition to supportive care. The role of avacopan in patients with DAH as a primary severe disease manifestation of AAV has not been well established. Furthermore, concerns remain regarding timely access to avacopan, the best glucocorticoid tapering regimen, and long‐term efficacy and safety of the drug. We sought to identify clinical features and outcomes of patients presenting with DAH secondary to AAV who received avacopan in addition to glucocorticoids and rituximab or cyclophosphamide. Methods: We performed a retrospective cohort study of all consecutive patients presenting with DAH as part of active severe granulomatosis with polyangiitis or microscopic polyangiitis. Demographic and clinical characteristics were collected at presentation and follow‐up. Results: Fifteen patients met inclusion criteria and were observed for a median time of 17 weeks (interquartile range [IQR] 6–37 weeks) after initiation of avacopan. Patients were predominantly female and White, had never smoked, and were a median age of 66 years (IQR 52–72 years) at diagnosis. The majority had newly diagnosed severe AAV with renal involvement. Three patients progressed to respiratory failure. The timing of avacopan introduction and patterns of glucocorticoid tapers varied widely in this cohort. Two serious adverse events related to infection were observed, including one opportunistic infection leading to the patient's death, although neither was directly attributed to avacopan administration. Conclusion: We describe the clinical course of patients who presented with the severe AAV disease manifestation of DAH and received avacopan as adjunct therapy. Most patients achieved remission during follow‐up, and adverse events, including infection, were observed. [ABSTRACT FROM AUTHOR]

Complement and extracellular vesicles (EVs) association with thrombogenic tendencies is acknowledged, but limited evidence exists for their link to COVID-19 venous thromboembolism. This study aims to examine the relationship between pulmonary embolism and the expression of complement and other proteins related to thrombogenesis in severe Covid-19 patients. We included prospectively 207 severe COVID-19 patients and retrospectively screened for pulmonary embolism (PE). This analysis comprises 20 confirmed PE cases and 20 matched patients without PE. Blood samples taken at the admission in the intensive care unit were analyzed for complement using ELISA. EVs derived from neutrophils, endothelium, or platelets, as well carrying complement or tissue factor were analyzed using flow cytometry. Complement levels were markedly elevated, with a notable increase in C3a and Terminal Complement Complex. The most prevalent EV population was identified as tissue factor (TF)-carrying EVs which peaked in patients with PE during ICU days 4–9. However, for both the complement and analyzed EV populations, no statistically significant differences were found between the patients who developed pulmonary embolism and those who did not. In conclusion, complement factors and EVs expressing tissue factor, along with EVs derived from endothelial cells and platelets, are elevated in severe COVID-19 patients, regardless of the presence of pulmonary embolism. However, the involvement of complement and procoagulant EVs in peripheral plasma in the development of pulmonary embolism is still unclear and requires further investigation. [ABSTRACT FROM AUTHOR]

This article presents a study conducted at Rouen University Hospital in France on the use of high-frequency ultrasound and color Doppler to diagnose congenital peripheral bronchial obstruction in fetuses. The study included 14 fetuses with an echogenic region in the lung and identified cases of extrinsic and intrinsic obstruction. Postnatal imaging was used to confirm the diagnosis and determine the need for surgery. The findings provide valuable insights into the prenatal diagnosis and management of congenital bronchial obstruction, emphasizing the importance of accurate diagnosis for prenatal counseling and further management. [Extracted from the article]

Background: The recruitment-to-inflation ratio (R/I) has been recently proposed to bedside assess response to PEEP. The impact of PEEP on ventilator-induced lung injury depends on the extent of dynamic strain reduction. We hypothesized that R/I may reflect the potential for lung recruitment (i.e. recruitability) and, consequently, estimate the impact of PEEP on dynamic lung strain, both assessed through computed tomography scan. Methods: Fourteen lung-damaged pigs (lipopolysaccharide infusion) underwent ventilation at low (5 cmH2O) and high PEEP (i.e., PEEP generating a plateau pressure of 28–30 cmH2O). R/I was measured through a one-breath derecruitment maneuver from high to low PEEP. PEEP-induced changes in dynamic lung strain, difference in nonaerated lung tissue weight (tissue recruitment) and amount of gas entering previously nonaerated lung units (gas recruitment) were assessed through computed tomography scan. Tissue and gas recruitment were normalized to the weight and gas volume of previously ventilated lung areas at low PEEP (normalized-tissue recruitment and normalized-gas recruitment, respectively). Results: Between high (median [interquartile range] 20 cmH2O [18–21]) and low PEEP, median R/I was 1.08 [0.88–1.82], indicating high lung recruitability. Compared to low PEEP, tissue and gas recruitment at high PEEP were 246 g [182–288] and 385 ml [318–668], respectively. R/I was linearly related to normalized-gas recruitment (r = 0.90; [95% CI 0.71 to 0.97) and normalized-tissue recruitment (r = 0.69; [95% CI 0.25 to 0.89]). Dynamic lung strain was 0.37 [0.29–0.44] at high PEEP and 0.59 [0.46–0.80] at low PEEP (p < 0.001). R/I was significantly related to PEEP-induced reduction in dynamic (r = − 0.93; [95% CI − 0.78 to − 0.98]) and global lung strain (r = − 0.57; [95% CI − 0.05 to − 0.84]). No correlation was found between R/I and and PEEP-induced changes in static lung strain (r = 0.34; [95% CI − 0.23 to 0.74]). Conclusions: In a highly recruitable ARDS model, R/I reflects the potential for lung recruitment and well estimates the extent of PEEP-induced reduction in dynamic lung strain. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explored how lung cancer spreads through air spaces in small tumors (up to 2 cm) and its impact on patient outcomes. Focusing on small-size and early-stage lung adenocarcinomas, the researchers analyzed medical records of patients treated between 2012 and 2022. We measured the distance of floating cancer cells spread from the main tumor through alveolar spaces and categorized patients based on whether this spread was present and its extent. Interestingly, while overall survival rates were similar across groups, patients with more extensive spread (2 mm or more) experienced a higher chance of cancer recurrence even in this very early cancer. This suggests that understanding the extent of spread through air spaces is crucial in predicting cancer recurrence in small lung tumors. Further research with a larger group of patients is needed to confirm these risk factors and improve treatment strategies. This study aimed to identify the clinical manifestation and implications according to the grading of tumor spread through air spaces in early-stage small (≤2 cm) pathological stage I non-mucinous lung adenocarcinomas. Medical records of patients with pathological stage I tumors sized ≤2 cm were retrospectively reviewed and analyzed. The furthest distance of the spread through air spaces from the tumor margin was measured on a standard-length scale (mm). Enrolled patients were categorized into spread through air spaces (STAS) (−) and STAS (+), and STAS (+) was subdivided according to its furthest distance as follows: STAS (+)-L (<2 mm) and STAS (+)-H (≥2 mm). Risk factors for STAS (+) included papillary predominant subtype (p = 0.027), presence of micropapillary patterns (p < 0.001), and EGFR (p = 0.039). The overall survival of the three groups did not differ significantly (p = 0.565). The recurrence-free survival of STAS (+)-H groups was significantly lower than those of STAS (−) and STAS (+)-L (p < 0.001 and p = 0.039, respectively). A number of alveolar spaces were definite risk factors for STAS (+)-H groups (p < 0.001), and male gender could be one (p = 0.054). In the patient group with small (≤2 cm) pathological stage I lung adenocarcinomas, the presence of STAS ≥ 2 mm was related to significantly lower recurrence-free survival. For identifying definite risk factors for the presence of farther STAS, more precise analysis from a larger study population should be undertaken. [ABSTRACT FROM AUTHOR]

Respiratory coronaviruses (RCoVs) significantly threaten human health, necessitating the development of an ex vivo respiratory culture system for investigating RCoVs infection. Here, we successfully generated a porcine precision-cut lung slices (PCLSs) culture system, containing all resident lung cell types in their natural arrangement. Next, this culture system was inoculated with a porcine respiratory coronavirus (PRCV), exhibiting clinical features akin to humans who were infected by SARS-CoV-2. The results demonstrated that PRCV efficiently infected and replicated within PCLSs, targeting ciliated cells in the bronchioles, terminal bronchioles, respiratory bronchioles, and pulmonary alveoli. Additionally, through RNA-Seq analysis of the innate immune response in PCLSs following PRCV infection, expression levels of interferons, inflammatory cytokines and IFN stimulated genes were significantly upregulated. This ex vivo model may not only offer new insights into PRCV infection in the porcine respiratory tract but also serve as a valuable tool for studying human respiratory CoVs infection. [ABSTRACT FROM AUTHOR]

Background: People with alcohol use disorder (AUD) have an increased risk of developing pneumonia and pulmonary diseases. Alveolar macrophages (AMs) are immune cells of the lower respiratory tract that are necessary for clearance of pathogens. However, alcohol causes AM oxidative stress, mitochondrial damage and dysfunction, and diminished phagocytic capacity, leading to lung injury and immune suppression. Methods: AMs were isolated by bronchoalveolar lavage from people with AUD and male and female C57BL/6J mice given chronic ethanol (20% w/v, 12 weeks) in drinking water. The peroxisome proliferator‐activated receptor γ ligand, pioglitazone, was used to treat human AMs ex vivo (10 μM, 24 h) and mice in vivo by oral gavage (10 mg/kg/day). Levels of AM mitochondrial superoxide and hypoxia‐inducible factor‐1 alpha (HIF‐1α) mRNA, a marker of oxidative stress, were measured by fluorescence microscopy and RT‐qPCR, respectively. Mouse AM phagocytic ability was determined by internalized Staphylococcus aureus, and mitochondrial capacity, dependency, and flexibility for glucose, long‐chain fatty acid, and glutamine oxidation were measured using an extracellular flux analyzer. In vitro studies used a murine AM cell line, MH‐S (±0.08% ethanol, 72 h) to investigate mitochondrial fuel oxidation and ATP‐linked respiration. Results: Pioglitazone treatment decreased mitochondrial superoxide in AMs from people with AUD and ethanol‐fed mice and HIF‐1α mRNA in ethanol‐fed mouse lungs. Pioglitazone also reversed mouse AM glutamine oxidation and glucose or long‐chain fatty acid flexibility to meet basal oxidation needs. In vitro, ethanol decreased the rate of AM mitochondrial and total ATP production, and pioglitazone improved changes in glucose and glutamine oxidation. Conclusions: Pioglitazone reversed chronic alcohol‐induced oxidative stress in human AM and mitochondrial substrate oxidation flexibility and superoxide levels in mouse AM. Decreased ethanol‐induced AM HIF‐1α mRNA with pioglitazone suggests that this pathway may be a focus for metabolic‐targeted therapeutics to improve morbidity and mortality in people with AUD. [ABSTRACT FROM AUTHOR]

Introduction and Objective.The tracheobronchial tree consists of the pathways through which air reaches the pulmonary alveoli. Anomalies in the tracheobronchial tree can be both congenital and acquired. Congenital anomalies include tracheal bronchus, accessory cardiac bronchus, lung aplasia, hypoplasia, or agenesis. The aim of this review is to summarise knowledge about the most common congenital anomalies in the tracheobronchial tree, and associated symptoms. Review Methods. The review was created based on 19 papers found in PubMed and PubMedCentral databases after searching for: 'tracheobronchial branches abnormality', 'tracheal bronchus', and 'accessory cardiac bronchus', published between 2001--2023. Brief description of the state of knowledge. Accessory cardiac bronchus (ACB) and tracheal bronchus (TB) are the 2 most common congenital anomalies of the tracheobronchial tree. The incidence of ACB ranges from 0.07% -- 0.5%, and TB between 0.9% -- 3% There are 3 types of ACB, with type I being the most common. TB is most frequently detected on the right side. Both anomalies are often asymptomatic; however, diagnosing them may be crucial in cases of recurrent symptoms of unknown origin, such as cough, haemoptysis or recurrent pneumonia. They may also contribute to complications in surgical procedures conducted on the respiratory tract or within the chest cavity. Summary. Understanding the occurrence of anatomical anomalies in the branching of the tracheobronchial tree can facilitate the diagnosis of atypical respiratory symptoms and clarify the cause of procedural failures, such as bronchoscopy, intubation or thoracic surgery. [ABSTRACT FROM AUTHOR]

Community-acquired pneumonia is reported as one of the infectious diseases that leads to the development of acute respiratory distress syndrome. The innate immune system is the first line of defence against microbial invasion; however, its dysregulation during infection, resulting in an increased pathogen load, stimulates the over-secretion of chemokines and pro-inflammatory cytokines. This phenomenon causes damage to the epithelial–endothelial barrier of the pulmonary alveoli and the leakage of the intravascular protein into the alveolar lumen. Fluoroquinolones are synthetic antimicrobial agents with immunomodulatory properties that can inhibit bacterial proliferation as well as exhibit anti-inflammatory activities. It has been demonstrated that the structure of fluoroquinolones, particularly those with a cyclopropyl group, exerts immunomodulatory effects. Its capability to inhibit phosphodiesterase activity leads to the accumulation of intracellular cAMP, which subsequently enhances PKA activity, resulting in the inhibition of transcriptional factor NF-κB and the activation of CREB. Another mechanism reported is the inhibition of TLR and ERK signalling pathways. Although the sequence of events has not been completely understood, significant progress has been made in comprehending the specific mechanisms underlying the immunomodulatory effects of fluoroquinolones. Here, we review the indirect immunomodulatory effects of FQs as an alternative to empirical therapy in patients diagnosed with community-acquired pneumonia. [ABSTRACT FROM AUTHOR]

Air pollution, especially fine particulate matter (PM2.5, with an aerodynamic diameter of less than 2.5 μm), represents a risk factor for human health. Many studies, regarding cancer onset and progression, correlated with the short and/or long exposition to PM2.5. This is mainly mediated by the ability of PM2.5 to reach the pulmonary alveoli by penetrating into the blood circulation. This review recapitulates the methodologies used to study PM2.5 in cellular models and the downstream effects on the main molecular pathways implicated in cancer. We report a set of data from the literature, that describe the involvement of miRNAs or long noncoding RNAs on the main biological processes involved in oxidative stress, inflammation, autophagy (PI3K), cell proliferation (NFkB, STAT3), and EMT (Notch, AKT, Wnt/β-catenin) pathways. microRNAs, as well as gene expression profile, responds to air pollution environment modulating some key genes involved in epigenetic modification or in key mediators of the biological processes described below. In this review, we provide some scientific evidences about the thigh correlation between miRNAs dysregulation, PM2.5 exposition, and gene pathways involved in cancer progression. [ABSTRACT FROM AUTHOR]

Allergic asthma (AA) is a common breathing disorder clinically characterized by the high occurrence of acute and continuous inflammation. However, the current treatment options for AA are lacking in effectiveness and diversity. In this study, we determined that the cell membrane receptor of gamma-glutamyl transferase (GGT) was highly overexpressed on the inflammatory cells that infiltrate the pulmonary tissues in AA cases. Therefore, we developed a GGT-specific dendrimer-dexamethasone conjugate (GSHDDC) that could be administered via aerosol inhalation to treat AA in a rapid and sustained manner. The GSHDDC was fabricated by the covalent attachment of 6-hydroxyhexyl acrylate-modified dexamethasone to polyamidoamine dendrimers via a carbonic ester linkage and the amino Michael addition, followed by the surface modification of the dendrimers with the GGT substrate of glutathione. After aerosol inhalation by the AA mice, the small particle-sized GSHDDC could easily diffuse into pulmonary alveoli and touch with the inflammatory cells via the glutathione ligand/GGT receptor-mediated recognition. The overexpressed GGT on the surface of inflammatory cells then triggers the gamma-glutamyl transfer reactions of glutathione to generate positively charged primary amines, thereby inducing rapid cationization-mediated cellular endocytosis into the inflammatory cells. The dexamethasone was gradually released by the intracellular enzyme hydrolysis, enabling sustained anti-inflammatory effects (e.g., reducing eosinophil infiltration, decreasing the levels of inflammatory factors) in the ovalbumin-induced AA mice. This study demonstrates the effectiveness of an inhalational and active inflammatory cells-targeted dendrimer-dexamethasone conjugate for efficient AA therapy. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a severe respiratory disease with a high mortality rate. The integrity of the pulmonary endothelial barrier influences the development and prognosis of ALI. Therefore, it has become an important target for ALI treatment. Extracellular vesicles (EVs) are promising nanotherapeutic agents against ALI. Herein, endothelium‐derived engineered extracellular vesicles (eEVs) that deliver microRNA‐125b‐5p (miRNA‐125b) to lung tissues exerting a protective effect on endothelial barrier integrity are reported. eEVs that are modified with lung microvascular endothelial cell‐targeting peptides (LET) exhibit a prolonged retention time in lung tissues and targeted lung microvascular endothelial cells in vivo and in vitro. To improve the efficacy of the EVs, miRNA‐125b is loaded into EVs. Finally, LET‐EVs‐miRNA‐125b is constructed. The results show that compared to the EVs, miRNA‐125b, and EVs‐miRNA‐125b, LET‐EVs‐miRNA‐125b exhibit the most significant treatment efficacy in ALI. Moreover, LET‐EVs‐miRNA‐125b is found to have an important protective effect on endothelial barrier integrity by inhibiting cell apoptosis, promoting angiogenesis, and protecting intercellular junctions. Sequencing analysis reveals that LET‐EVs‐miRNA‐125b downregulates early growth response‐1 (EGR1) levels, which may be a potential mechanism of action. Taken together, these findings suggest that LET‐EVs‐miRNA‐125b can treat ALI by protecting the endothelial barrier integrity. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is caused by a bacterium called Mycobacterium tuberculosis (Mtb). When Mtb enters inside the pulmonary alveolus, it is phagocytosed by the alveolar macrophages, followed by a cascade of immune responses. This leads to the recruitment and accumulation of additional macrophages and T cells in the pulmonary tissues. A key outcome of this is the formation of granuloma, the hallmark of TB infection. In this paper, we develop a mathematical model of the evolution of granuloma by a system of partial differential equations that is based on the classical Keller–Segel chemotaxis equation. We investigate the effect of different parameters on the formation of granuloma. We present numerical simulation results that illustrate the impact of different parameters. The implication of our result on the disease progression is also discussed. [ABSTRACT FROM AUTHOR]

Newly formed particles and their growth contribute significantly to cloud condensation nuclei. However, the effect of rain on new particle formation (NPF) is poorly understood. Rainfall removes the pre‐existing large particles by below‐cloud scavenging to reduce condensation and coagulation sinks by 4.0 × 10−2 and 1.5 × 10−4 s−1. The scavenging effect largely depends on the amount and duration of rain and the surface area concentration of the raindrops. NPF events can be facilitated by a combination of fewer condensation sinks and favorable meteorological conditions, contributing 3%–47% of PM2.5 (particulate matter smaller than 2.5 μm). The physical mechanism was confirmed by theoretical analysis. The results help elucidate the NPF process from a physical perspective, which can improve the prediction of the occurrence and duration of haze events. Until precursors are reduced, significant reductions in particulate matter (PM) may be difficult because NPF and its growth recharge the atmosphere with PM. Plain Language Summary: New particle formation (NPF) significantly contributes to the ultrafine particle number and thus impacts the cloud properties. Newly formed particles may also be inhaled into the pulmonary alveoli and blood systems, harming human health. However, compared with the chemical mechanism, the underlying physical mechanism of NPF events is poorly understood, especially the relationship between rainfall and subsequent NPF. NPF events will be more frequent owing to the combination of warmer and wetter climates and fewer coagulation sinks in response to clean air action. This study deepens our understanding of the interaction between NPF and meteorology. A reduction in precursor emissions for NPF should be imposed to further reduce particulate matter. Key Points: Positive correlation between N13‒25 and rainfall was showed in spring and summerNew particle formation (NPF) was facilitated by reduced condensation sinks and favorable meteorology in response to rainfallSurface area concentration of the raindrops is a key parameter for modulating NPF [ABSTRACT FROM AUTHOR]

Objective: Sulfur mustard (SM) is an important chemical warfare agent. The mechanisms underlying SM toxicity have not been completely elucidated. However, oxidative stress and the subsequent damage to macromolecules have been considered ascrucial steps in SM toxicity. In this study, a rat model of SM-induced acute pulmonary injury was established using an equal toxicity dose (1LD50). This study employed two methods to directly compare oxidative stress indices in serum enzymes and the epithelial cells of the alveolar septa. Methods: Male Sprague-Dawley rats were randomly divided into intraperitoneal SM, intraperitoneal propylene glycol control, tracheal SM, tracheal propylene glycol control, and control groups. SM-induced serum enzyme levels and protein expression in the epithelial cells of the alveolar septa were measured using enzyme-linked immunosorbent assay and immunohistochemistry. Results: Serum levels of superoxide dismutase, catalase, and glutathione peroxidase were upregulated in the intraperitoneal SM group compared with those in the tracheal SM group. Positive expression ratios of CuZn-superoxide dismutase, Mn-superoxide dismutase, paraoxonase-1, and apolipoprotein-1 proteins in the epithelial cells of the alveolar septa in the intraperitoneal SM group were elevated compared with those in the tracheal SM group. Conclusion: Under SM (1LD50) exposure, there were significantly higher serum enzyme levels and protein expressions in the epithelial cells of the alveolar septa of rats injected with SM intraperitoneally compared with SM administered by intratracheal instillation. The results demonstrated that the differences in oxidative stress indices at the molecular level in SM-induced pulmonary injury were dependent on the route of exposure. [ABSTRACT FROM AUTHOR]

Background: Clinical studies have shown that diffuse chorioamniotic hemosiderosis (DCH) is a risk factor for bronchopulmonary dysplasia (BPD). However, the details of the underlying mechanism are unknown. We focused on iron, one of the blood components that diffuses within the amniotic cavity in DCH. Specifically, we conducted a histological evaluation of its effects on fetal lung development. Methods: Iron dextran 10 mg (Fe group) or physiological saline (control group) was injected into the individual amniotic cavities of pregnant Sprague Dawley rats on gestational day 19. The pups were born naturally, and the placentas and lungs collected on postnatal days 1, 14, and 60 were subjected to histological analysis. Results: The placenta and lungs of the Fe group on day 14 contained significantly larger numbers of iron‐positive granules. Morphological analysis of the lungs showed that on day 60, the total number of alveoli was significantly lower in the Fe group (p = 0.015). Immunohistochemical staining of the lung tissue for 8‐hydroxy‐2′‐deoxyguanosine showed that, on day 1, there were significantly more positive cells in the Fe group (p = 0.003). The number of ectodermal dysplasia 1 positive cells on day 14 was significantly increased in the Fe group (p = 0.001). Conclusions: These results suggest that diffuse iron deposition in immature fetal lungs increases oxidative stress and decreases the number of postnatal alveoli associated with impaired lung development. [ABSTRACT FROM AUTHOR]

Purpose: Acute lung injury (ALI) is a severe pulmonary disease characterized by damage to the alveoli and pulmonary blood vessels, leading to severe impairment of lung function. Studies on the effect of capsaicin (8-methyl-N-geranyl-6-nonamide, CAP) on lipopolysaccharide (LPS)-induced ALI in bronchial epithelial cells transformed with Ad12-SV40 2B (BEAS-2B) are still limited. This study aimed to investigate the effect and specific mechanism by which CAP improves LPS-induced ALI.Methods: The present study investigated the effect of CAP and the potential underlying mechanisms in LPS-induced ALI in vitro and vivo via RNA sequencing, Western blotting (WB), quantitative real-time reverse transcription PCR (qRT‒PCR), enzyme-linked immunosorbent assay (ELISA), and transmission electron microscopy (TEM). The TRPV1 inhibitor AMG9810 and the AKT agonist SC79 were used to confirm the protective effect of the TRPV1/AKT axis against ALI. The autophagy agonist rapamycin (Rapa) and the autophagy inhibitors 3-methyladenine (3-MA) and bafilomycin A1 (Baf-A1) were used to clarify the characteristics of LPS-induced autophagy.Results: Our findings demonstrated that CAP effectively suppressed inflammation and autophagy in LPS-induced ALI, both in vivo and in vitro. This mechanism involves regulation by the TRPV1/AKT signaling pathway. By activating TRPV1, CAP reduces the expression of P-AKT, thereby exerting its anti-inflammatory and inhibitory effects on pro-death autophagy. Furthermore, prior administration of CAP provided substantial protection to mice against ALI induced by LPS, reduced the lung wet/dry ratio, decreased proinflammatory cytokine expression, and downregulated LC3 expression.Conclusion: Taken together, our results indicate that CAP protects against LPS-induced ALI by inhibiting inflammatory responses and autophagic death through the TRPV1/AKT signaling pathway, presenting a novel strategy for ALI therapy. [ABSTRACT FROM AUTHOR]

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Specialists in the professional fields where the staff is exposed to dust have studied, found and differentiate the different effects depending on the type of dust, both in terms of mineral and organic dust. These studies have led to regulations that differentiate mineralogical (amorphic silica, silica, crystalline, marble, etc.) and organic (wood essence, cellulose, tobacco, etc.). The granulometric fractions that differentiate the inhaled components that reach the pulmonary alveolus were also analyzed. A distinction is required between dust type to assess public health risk based on experience gained in the professional environment, in particular mining, where it was well studied and later regulated. For România, especially in Baia Mare and its surroundings, it seems that this professional experience was ignored when the decision to close and green the mining perimeters was taken, the tailing ponds. [ABSTRACT FROM AUTHOR]

This article discusses a case of a 24-year-old female patient with HIV infection who initially presented with symptoms resembling tuberculosis. However, further examination revealed that she had Cryptococcus neoformans, a fungus that commonly affects immunocompromised individuals. Cryptococcosis, caused by inhaling spores, can be life-threatening and prompt diagnosis is crucial. The article highlights the importance of considering cryptococcosis as a diagnostic possibility, especially in immunocompromised individuals. It also discusses the diagnosis and treatment of cryptococcal lymphadenitis in HIV patients, emphasizing the importance of early detection and treatment for better patient outcomes. [Extracted from the article]

The results of the use of terahertz (THz) irradiation generated by a silicon nanosandwich under conditions of a stabilized source-drain current in the treatment of covid complications are presented. THz irradiation was used in addition to drug therapy for the treatment of patients with COVID-19, which made it possible to reduce the patient's stay in the intensive care unit, reduce the time of patient intubation and stay on mechanical ventilation, and reduce the radiological and pharmacological burden on the patient. An idea was obtained about the resonant response of a living biological tissue to THz irradiation, which made it possible to formulate requirements for irradiation parameters depending on the characteristics of the biological tissue under study. The characteristics of resonant frequencies for the pulmonary alveoli were determined, which made it possible to develop and use the proposed treatment method for the treatment of pneumonia caused by COVID-19. [ABSTRACT FROM AUTHOR]

Long‐term abuse of methamphetamine (MA) can cause lung toxicity. Intercellular communication between macrophages and alveolar epithelial cells (AECs) is critical for maintaining lung homeostasis. Microvesicles (MVs) are an important medium of intercellular communication. However, the mechanism of macrophage MVs (MMVs) in MA‐induced chronic lung injury remains unclear. This study aimed to investigate if MA can augment the activity of MMVs and if circ_YTHDF2 is a key factor in MMV‐mediated macrophage–AEC communication, and to explore the mechanism of MMV‐derived circ_YTHDF2 in MA‐induced chronic lung injury. MA elevated peak velocity of the pulmonary artery and pulmonary artery accelerate time, reduced the number of alveolar sacs, thickened the alveolar septum, and accelerated the release of MMVs and the uptake of MMVs by AECs. Circ_YTHDF2 was downregulated in lung and MMVs induced by MA. The immune factors in MMVs were increased by si‐circ_YTHDF. Circ_YTHDF2 knockdown in MMVs induced inflammation and remodelling in the internalised AECs by MMVs, which was reversed by circ_YTHDF2 overexpression in MMVs. Circ_YTHDF2 bound specifically to and sponged miRNA‐145‐5p. Runt‐related transcription factor 3 (RUNX3) was identified as potential target of miR‐145‐5p. RUNX3 targeted zinc finger E‐box‐binding homeobox 1 (ZEB1)‐related inflammation and EMT of AECs. In vivo, circ_YTHDF2 overexpression‐MMVs attenuated MA‐induced lung inflammation and remodelling by the circ_YTHDF2–miRNA‐145‐5p–RUNX3 axis. Therefore, MA abuse can induce pulmonary dysfunction and alveolus injury. The immunoactivity of MMVs is regulated by circ_YTHDF2. Circ_YTHDF2 in MMVs is the key to communication between macrophages and AECs. Circ_YTHDF2 sponges miR‐145‐5p targeting RUNX3 to participate in ZEB1‐related inflammation and remodelling of AECs. MMV‐derived circ_YTHDF2 would be an important therapeutic target for MA‐induced chronic lung injury. Key points: Methamphetamine (MA) abuse induces pulmonary dysfunction and alveoli injury.The immunoactivity of macrophage microvesicles (MMVs) is regulated by circ_YTHDF2.Circ_YTHDF2 in MMVs is the key to MMV‐mediated intercellular communication between macrophages and alveolar epithelial cells.Circ_YTHDF2 sponges miR‐145‐5p targeting runt‐related transcription factor 3 (RUNX3) to participate in zinc finger E‐box‐binding homeobox 1 (ZEB1)‐related inflammation and remodelling.MMV‐derived circ_YTHDF2 would be an important therapeutic target for MA‐induced chronic lung injury. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a common condition, particularly in the COVID-19 pandemic, which is distinguished by sudden onset of respiratory insufficiency with tachypnea, oxygen-refractory cyanosis, reduced lung compliance and diffuse infiltration of pulmonary alveoli. It is well-established that increasing activity of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling axis and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation are associated with the pathogenesis of ALI. Since ALI poses a huge challenge to human health, it is urgent to tackle this affliction with therapeutic intervention. Qinhuo Shanggan oral solution (QHSG), a traditional Chinese herbal formula, is clinically used for effective medication of various lung diseases including ALI, with the action mechanism obscure. In the present study, with the rat model of lipopolysaccharide (LPS)-induced ALI, QHSG was unveiled to ameliorate ALI by alleviating the pathological features, reversing the alteration in white blood cell profile and impeding the production of inflammatory cytokines through down-regulation of TLR4/NF-κB signaling cascade and inhibition of NLRP3 inflammasome activation. In LPS-stimulated RAW264.7 mouse macrophages, QHSG was discovered to hinder the generation of inflammatory cytokines by lessening TLR4/NF-κB signaling pathway activity and weakening NLRP3 inflammasome activation. Taken together, QHSG may resolve acute lung injury, attributed to its anti-inflammation and immunoregulation by attenuation of TLR4/NF-κB signaling cascade and inhibition of NLRP3 inflammasome activation. Our findings provide a novel insight into the action mechanism of QHSG and lay a mechanistic foundation for therapeutic intervention in acute lung injury with QHSG in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Optimization of pulmonary to systemic blood flow (Qp:Qs) is the key to postoperative care of children with a single-ventricular heart. The ratio of end tidal CO2 to partial pressure of CO2 called alveolar functional fraction (AFF) has shown a strong relationship with Qp:Qs in the catheterization lab in this population (with Qp:Qs of 1 correlating with AFF of 0.7). As there are no studies to understand the relationship between AFF and clinical outcomes in the postoperative care of these children, this study was carried out. Methodology and Results: This retrospective cohort study included 29 postoperative periods of children who underwent surgery for a single-ventricular heart. The average AFF was calculated for each early postoperative period. The primary clinical outcome was time in hours to normalize lactate. Other clinical outcomes included duration of mechanical ventilation, duration of milrinone infusion; presence of acute kidney injury (AKI), seizures and necrotizing enterocolitis (NEC); need for tracheostomy, need for extra-corporeal support, and mortality in the first 60 days postoperatively. The study population was divided into Group 1 with AFF ≤0.7 and Group 2 with AFF >0.7, to compare the outcome differences between the groups. Time to normalize the lactate had a modest negative correlation with the AFF, with Pearson's r = -0.49 (P = 0.007) for the entire cohort. The clinical outcomes were not statistically different for groups with AFF ≤0.7 and with AFF >0.7, although the group with AFF ≤0.7 had a higher incidence of NEC and higher mortality, whereas the group with AFF >0.7 had a higher incidence of AKI. Conclusions: In this small study, the AFF showed a modest negative correlation with the time to normalize lactate in postoperative care after surgery for a single ventricle heart. There were the trends with some other important clinical outcomes but not statistically significant. A larger, multi center study is needed to delineate these relationships further. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite advancements in the field, lung malignancies are the primary cause of cancer-attributable morbidity and mortality on a global scale. Recently, therapeutic agents have demonstrated improved efficacy when combined with nanocarriers to improve their delivery, bioavailability, and efficacy. Accordingly, the aim of this study is to evaluate the effects and mechanisms of action of naringin–dextrin nanocomposites (Nar-Dx-NCs) against diethylnitrosamine (DEN)/2-acetylaminofluorene (2AAF)-induced lung carcinogenesis in male Wistar rats. Naringin's preventive action against DEN/2AAF-induced lung cancer was amplified using Nar-Dx-NCs, which exerted heightened anti-carcinogenic effects by suppressing oxidative stress, inflammation, and cell proliferation and activating apoptosis. Nanotechnology has proven advantageous in numerous scientific applications, one being to enhance the delivery of chemotherapeutic agents. This present study aims to evaluate the mechanisms underlying the chemopreventive action of naringin–dextrin nanocomposites (Nar-Dx-NCs) against diethylnitrosamine (DEN)/2-acetylaminofluorene (2AAF)-induced lung carcinogenesis in male Wistar rats. DEN was administered intraperitoneally (i.p.) (150 mg/kg/week) for two weeks, followed by the oral administration of 2AAF (20 mg/kg) four times a week for three weeks. Rats receiving DEN/2AAF were concurrently treated with naringin or Nar-Dx-NCs orally at a dose of 10 mg/kg every other day for 24 weeks. Naringin and Nar-Dx-NCs treatments prevented the formation of tumorigenic cells within the alveoli of rats exposed to DEN/2AAF. These findings were associated with a significant decrease in lipid peroxidation, upregulation of antioxidant enzyme (glutathione peroxidase and superoxide dismutase) activity, and enhanced glutathione and nuclear factor erythroid 2–related factor 2 expression in the lungs. Naringin and Nar-Dx-NCs exerted anti-inflammatory actions manifested by a decrease in lung protein expression of tumor necrosis factor-α and interleukin-1β and mRNA expression of interleukin-6, interferon-γ, nuclear factor-κB, and inducible nitric oxide synthase, with a concurrent increase in interleukin-10 expression. The anti-inflammatory effect of Nar-Dx-NCs was more potent than naringin. Regarding the effect on apoptosis, both naringin and Nar-Dx-NCs significantly reduced Bcl-2 and increased Bax and P53 expressions. Moreover, naringin or Nar-Dx-NCs induced a significant decrease in the expression of the proliferator marker, Ki-67, and the effect of Nar-Dx-NCs was more marked. In conclusion, Nar-Dx-NCs improved naringin's preventive action against DEN/2AAF-induced lung cancer and exerted anticarcinogenic effects by suppressing oxidative stress and inflammation and improving apoptotic signal induction and propagation. [ABSTRACT FROM AUTHOR]

Simple Summary: Proper development of the fetal lung is vital to the survival and healthy growth of pigs after birth, but many factors can disturb the normal growth of the fetal pig lung. In the previous study, we found that the Hoxa1 mutation of g.50111251 G > TC resulted in the congestion and edema of fetal lungs, and all neonatal Hoxa1−/− piglets died of respiratory failure during the suckling period. The results of this study showed that supplementing all-trans retinoic acid (ATRA) to pregnant sows alleviated the dyspnea of neonatal Hoxa1−/− piglets by increasing the IFN-γ concentration (p < 0.05), airspace area (p < 0.01) and pulmonary microvessel density (p < 0.01); increasing the expression of VEGFD (p < 0.01), PDGFD (p < 0.01), KDR (p < 0.01), ID1 (p < 0.01), and NEDD4 (p < 0.01); and decreasing the septal wall thickness (p < 0.01) and the expression of SFTPC (p < 0.01) and FOXO3 (p < 0.01). Neonatal Hoxa1−/− piglets were characterized by dyspnea owing to the Hoxa1 mutation, and maternal administration with ATRA alleviated the dyspnea of neonatal Hoxa1−/− piglets. The purpose of this experiment was to explore how maternal ATRA administration rescued the abnormal fetal lungs of Hoxa1−/− piglets. Samples of the lungs were collected from neonatal Hoxa1−/− and non-Hoxa1−/− piglets delivered by sows in the control group, and from neonatal Hoxa1−/− piglets born by sows administered with ATRA at 4 mg/kg body weight on dpc 12, 13, or 14, respectively. These were used for the analysis of ELISA, histological morphology, immunofluorescence staining, immunohistochemistry staining, and quantitative real-time PCR. The results indicate that the Hoxa1 mutation had adverse impacts on the development of the alveoli and pulmonary microvessels of Hoxa1−/− piglets. Maternal administration with ATRA at 4 mg/kg body weight on dpc 14 rescued the abnormal lung development of Hoxa1−/− piglets by increasing the IFN-γ concentration (p < 0.05), airspace area (p < 0.01) and pulmonary microvessel density (p < 0.01); increasing the expression of VEGFD (p < 0.01), PDGFD (p < 0.01), KDR (p < 0.01), ID1 (p < 0.01), and NEDD4 (p < 0.01); and decreasing the septal wall thickness (p < 0.01) and the expression of SFTPC (p < 0.01) and FOXO3 (p < 0.01). Maternal administration with ATRA plays a vital role in rescuing the abnormal development of lung of Hoxa1−/− fetal piglets. [ABSTRACT FROM AUTHOR]

Pulmonary involvement due to SARS-CoV-2 infection can lead to acute respiratory distress syndrome in patients with COVID-19. Consequently, pulmonary imaging is crucial for management of COVID-19. This study aimed to evaluate the prognostic value of lung ultrasound (LUS) with a handheld ultrasound device (HHUD) in patients with COVID-19 treated with extracorporeal membrane oxygenation (ECMO). Therefore, patients underwent LUS with a HHUD every two days until they were either discharged from the intensive care unit or died. The study was conducted at the University Hospital of Bonn's anesthesiological intensive care ward from December 2020 to August 2021. A total of 33 patients (median [IQR]: 56.0 [53–60.5] years) were included. A high LUS score was associated with a decreased P/F ratio (repeated measures correlation [rmcorr]: −0.26; 95% CI: −0.34, −0.15; p < 0.001), increased extravascular lung water, defined as fluid accumulation in the pulmonary interstitium and alveoli (rmcorr: 0.11; 95% CI: 0.01, 0.20; p = 0.030), deteriorated electrolyte status (base excess: rmcorr: 0.14; 95% CI: 0.05, 0.24; p = 0.004; pH: rmcorr: 0.12; 95% CI: 0.03, 0.21; p = 0.001), and decreased pulmonary compliance (rmcorr: −0.10; 95% CI: −0.20, −0.01; p = 0.034). The maximum LUS score was lower in survivors (median difference [md]: −0.35; 95% CI: −0.55, −0.06; p = 0.006). A cutoff value for non-survival was calculated at a LUS score of 2.63. At the time of maximum LUS score, P/F ratio (md: 1.97; 95% CI: 1.12, 2.76; p < 0.001) and pulmonary compliance (md: 18.67; 95% CI: 3.33, 37.15; p = 0.018) were higher in surviving patients. In conclusion, LUS with a HHUD enables continuous evaluation of cardiopulmonary function in COVID-19 patients receiving ECMO support therapy and provides prognostic value in determining the patients' likelihood of survival. [ABSTRACT FROM AUTHOR]

Aims: Fibroadipose vascular anomaly (FAVA) is a complex vascular malformation that is likely to be under‐recognised. In this study we aimed to report the pathological features and somatic PIK3CA mutations associated with the most common clinicopathological features. Methods and results: Cases were identified by reviewing the lesions resected from patients with FAVA registered at our Haemangioma Surgery Centre and unusual intramuscular vascular anomalies in our pathology database. There were 23 males and 52 females, who ranged in age from 1 to 51 years. Most cases occurred in the lower extremities (n = 62). The majority of the lesions were intramuscular, with a few disrupting the overlying fascia and involving subcutaneous fat (19 of 75), and a minority of the cases had cutaneous vascular stains (13 of 75). Histopathologically, the lesion was composed of anomalous vascular components that were intertwined with mature adipocytic and dense fibrous tissues and vascular components with: (a) clusters of thin‐walled channels, some with blood‐filled nodules and others with thin walls resembling pulmonary alveoli; (b) numerous small vessels (arteries, veins and indeterminate channels) – proliferative small blood vessels were often mixed with adipose tissue; (c) larger abnormal venous channels usually irregularly and sometimes excessively muscularised; (d) lymphoid aggregates or lymphoplasmacytic aggregates were usually observed; and (e) lymphatic malformations were sometimes seen as minor elements. All patients had their lessons subjected to PCR, and 53 patients had somatic PIK3CA mutations (53 of 75). Conclusions: FAVA is a slow‐flow vascular malformation with specific clinicopathological and molecular characteristics. Its recognition is fundamental for its clinical/prognostic implications and for targeted therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This review discusses the role of extracellular vesicles in pulmonary hypertension a serious and progressive lung disease characterized by high blood pressure and increased vascular resistance in pulmonary arteries. Extracellular vesicles are released by cells upon different stimuli, contain various molecules like proteins and genetic material derived from the parental cell and are involved in intercellular communication, both for homeostatic processes and in pathologic conditions. They seem to play a harmful role in pulmonary hypertension by carrying and transferring molecules that contribute to the progression of the disease. This review highlights how understanding the mechanisms involving extracellular vesicles in pulmonary hypertension could provide insights into the comprehension of the pathogenesis and in developing new therapies to manage this disease. The term pulmonary hypertension (PH) refers to different conditions, all characterized by increased pressure and resistance in the pulmonary arterial bed. PH has a wide range of causes (essentially, cardiovascular, pulmonary, or connective tissue disorders); however, idiopathic (i.e., without a clear cause) PH exists. This chronic, progressive, and sometimes devastating disease can finally lead to right heart failure and eventually death, through pulmonary vascular remodeling and dysfunction. The exact nature of PH pathophysiology is sometimes still unclear. Extracellular vesicles (EVs), previously known as apoptotic bodies, microvesicles, and exosomes, are small membrane-bound vesicles that are generated by almost all cell types and can be detected in a variety of physiological fluids. EVs are involved in intercellular communication, thus influencing immunological response, inflammation, embryogenesis, aging, and regenerative processes. Indeed, they transport chemokines, cytokines, lipids, RNA and miRNA, and other biologically active molecules. Although the precise functions of EVs are still not fully known, there is mounting evidence that they can play a significant role in the pathophysiology of PH. In this review, after briefly recapping the key stages of PH pathogenesis, we discuss the current evidence on the functions of EVs both as PH biomarkers and potential participants in the distinct pathways of disease progression. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (M.tb) infections remain one of the most significant causes of mortality worldwide. The current situation shows an emergence of new antibiotic-resistant strains making it difficult to control the tuberculosis (TB) disease. A large part of its success as a pathogen is due to its ability to persist for years or even decades without causing evident clinical manifestations. M.tb is highly successful in evading the host-defense by manipulating hostsignalling pathways. Although macrophages are generally viewed as the key cell type involved in harboring M.tb, growing evidence shows that neutrophils also play a fundamental role. Both cells are known to act in multiple ways when encountering an invading pathogen, including phagocytosis, release of cytokines and chemokines, and oxidative burst. In addition, the formation of neutrophil extracellular traps (NETs) and macrophage extracellular traps (METs) has been described to contribute to M. tb infections. NETs/METs are extracellular DNA fibers with associated granule components, which are released upon activation of the cells by the pathogen or by pro-inflammatory mediators. On one hand, they can lead to a protective immune response by entrapment and killing of pathogens. However, on the other hand, they can also play a severe pathological role by inducing tissue damage. Extracellular traps (ETs) produced in the pulmonary alveoli can expand easily and expose tissue-damaging factors with detrimental effects. Since host-directed therapies offer a complementary strategy in TB, the knowledge of NET/MET formation is important for understanding potential protective versus detrimental pathways during innate immune signaling. In this review, we summarize the progress made in understanding the role of NETs/METs in the pathogenesis of TB. [ABSTRACT FROM AUTHOR]

Background: In patients undergoing high-risk surgery, it is recommended to titrate fluid administration using stroke volume or a dynamic variable of fluid responsiveness (FR). However, this strategy usually requires the use of a hemodynamic monitor and/or an arterial catheter. Recently, it has been shown that variations of central venous pressure (ΔCVP) during an alveolar recruitment maneuver (ARM) can predict FR and that there is a correlation between CVP and peripheral venous pressure (PVP). This prospective study tested the hypothesis that variations of PVP (ΔPVP) induced by an ARM could predict FR. Methods: We studied 60 consecutive patients scheduled for high-risk abdominal surgery, excluding those with preoperative cardiac arrhythmias or right ventricular dysfunction. All patients had a peripheral venous catheter, a central venous catheter and a radial arterial catheter linked to a pulse contour monitoring device. PVP was always measured via an 18-gauge catheter inserted at the antecubital fossa. Then an ARM consisting of a standardized gas insufflation to reach a plateau of 30 cmH2O for 30 s was performed before skin incision. Invasive mean arterial pressure (MAP), pulse pressure, heart rate, CVP, PVP, pulse pressure variation (PPV), and stroke volume index (SVI) were recorded before ARM (T1), at the end of ARM (T2), before volume expansion (T3), and one minute after volume expansion (T4). Receiver-operating curves (ROC) analysis with the corresponding grey zone approach were performed to assess the ability of ∆PVP (index test) to predict FR, defined as an ≥ 10% increase in SVI following the administration of a 4 ml/kg balanced crystalloid solution over 5 min. Results: ∆PVP during ARM predicted FR with an area under the ROC curve of 0.76 (95%CI, 0.63 to 0.86). The optimal threshold determined by the Youden Index was a ∆PVP value of 5 mmHg (95%CI, 4 to 6) with a sensitivity of 66% (95%CI, 47 to 81) and a specificity of 82% (95%CI, 63 to 94). The AUC's for predicting FR were not different between ΔPVP, ΔCVP, and PPV. Conclusion: During high-risk abdominal surgery, ∆PVP induced by an ARM can moderately predict FR. Nevertheless, other hemodynamic variables did not perform better. [ABSTRACT FROM AUTHOR]

A hemorrhagic aortopulmonary artery sheath (HAPS) is an infrequent and critical complication of aortic dissection (AD), which is caused by a hematoma extending through the ruptured aortic wall into the aortopulmonary artery sheath. The adventitial hematoma might narrow or even occlude the lumen of the pulmonary arteries and extend into the pulmonary interstitium and alveoli. The prompt and accurate recognition of HAPS on computed tomography (CT) is crucial and might assist in the diagnosis of unidentifiable AD. HAPS was manifested as high attenuation areas surrounded the pulmonary arteries without enhancement on CT; even thickened bronchovascular sheath and ground-glass consolidations surrounded bronchovascular distribution, which might be associated with the prognosis. Aggressive and effective surgical treatment is the primary determinant of short-term survival. [ABSTRACT FROM AUTHOR]

The article explores the role of Notch signaling in rheumatoid arthritis (RA) and highlights the correlation of specific ligands (JAG1, JAG2, DLL1) and receptors (Notch1, Notch3) with early disease activity. Topics discussed include the impact of disease-modifying antirheumatic drugs on Notch expression, the relationship between Notch ligands and anti-tumor necrosis factor therapy responsiveness, and the influence of Toll-like receptor activation on Notch expression.

Adeno‐associated virus (AAV) vector has shown multiple clinical breakthroughs, but its clinical implementation in inhaled gene therapy remains elusive due to difficulty in transducing lung airway cells. We demonstrate here AAV serotype 6 (AAV6) associated with extracellular vesicles (EVs) and secreted from vector‐producing HEK‐293 cells during vector preparation (EVAAV6) as a safe and highly efficacious gene delivery platform for inhaled gene therapy applications. Specifically, we discovered that EVAAV6 provided markedly enhanced reporter transgene expression in mucus‐covered air‐liquid interface (ALI) cultures of primary human bronchial and nasal epithelial cells as well as in mouse lung airways compared to standard preparations of AAV6 alone. Of note, AAV6 has been previously shown to outperform other clinically tested AAV serotypes, including those approved by the FDA for treating non‐lung diseases, in transducing ALI cultures of primary human airway cells. We provide compelling experimental evidence that the superior performance of EVAAV6 is attributed to the ability of EV to facilitate mucus penetration and cellular entry/transduction of AAV6. The tight and stable linkage between AAV6 and EVs appears essential to exploit the benefits of EVs given that a physical mixture of individually prepared EVs and AAV6 failed to mediate EV‐AAV6 interactions or to enhance gene transfer efficacy. [ABSTRACT FROM AUTHOR]

The rapid and non-invasive pulmonary drug delivery (PDD) has attracted great attention compared to the other routes. However, nanoparticle platforms, like liposomes (LPs) and extracellular vesicles (EVs), require extensive reformulation to suit the requirements of PDD. LPs are artificial vesicles composed of lipid bilayers capable of encapsulating hydrophilic and hydrophobic substances, whereas EVs are natural vesicles secreted by cells. Additionally, novel LPs-EVs hybrid vesicles may confer the best of both. The preparation methods of EVs are distinguished from LPs since they rely mainly on extraction and purification, whereas the LPs are synthesized from their basic ingredients. Similarly, drug loading methods into/onto EVs are distinguished whereby they are cell- or non-cell-based, whereas LPs are loaded via passive or active approaches. This review discusses the progress in LPs and EVs as well as hybrid vesicles with a special focus on PDD. It also provides a perspective comparison between LPs and EVs from various aspects (composition, preparation/extraction, drug loading, and large-scale manufacturing) as well as the future prospects for inhaled therapeutics. In addition, it discusses the challenges that may be encountered in scaling up the production and presents our view regarding the clinical translation of the laboratory findings into commercial products. [ABSTRACT FROM AUTHOR]

Background: Angiotensin-converting enzyme 2 (ACE2) is not only the entry route of SARS-CoV-2 infection but also triggers a major mechanism of COVID-19 aggravation by promoting a hyperinflammatory state, leading to lung injury, hematological and immunological dysregulation. The impact of ACE2 inhibitors on the course of COVID-19 is still unclear. The effect of ACE2 inhibitors on the course of acute respiratory distress syndrome (ARDS) during COVID-19 and other severe respiratory infections in conditions of hyperferritinemia (HF) was investigated. Methods: A cohort study of critically ill patients with COVID-19 and other respiratory diseases (widespread infection, pneumonia) who underwent treatment in The Critical Care Unit of the First University Clinic (Tbilisi, Georgia) during the 2020–2021 years was conducted. The impact of the ACE2 inhibitors on the course of the ARDS developed during COVID-19 and other severe respiratory infections in conditions of different severity of HF was evaluated. Results: In COVID-19-infected (I) and uninfected (II) patients with ARDS, ACE2 inhibitors reduce the levels of Ang II, C reactive protein (CRP) and D-dimer (I: from 1508.07 ± 26.68 to 48.51 ± 24.35, from 233.92 ± 13.02 to 198.12 ± 11.88, from 7.88 ± 0.47 to 6.28 ± 0.43; II: from 1000.14 ± 149.49 to 46.23 ± 88.21, 226.48 ± 13.81 to 183.52 ± 17.32, from 6.39 ± 0.58 to 5.48 ± 0.69) at moderate HF and Ang II, CRP levels (I: from 1845.89 ± 89.37 to 49.64 ± 51.05, from 209.28 ± 14.41 to 175.37 ± 9.84; II: from 1753.29 ± 65.95 to 49.76 ± 55.74, 287.10 ± 20.50 to 214.71 ± 17.32) at severe HF, reduce interleukin-6 (IL-6) expression at moderate HF (I: from 1977.23 ± 354.66 to 899.36 ± 323.76) and cause reduction of pCO2 index at severe HF (I: from 69.80 ± 3.22 to 60.44 ± 2.20) in COVID-19-infected patients. Conclusion: Study results show that the ACE2 inhibitors play an important role in the regulation of inflammatory processes in both COVID-19-infected and uninfected patients with ARDS. ACE2 inhibitors decrease immunological disorders, inflammation, and lung alveoli dysfunction, especially in COVID-19-infected patients. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a type of clinical pathophysiological syndrome characterized by a progressive increase in pulmonary vascular resistance and subsequent progressive failure of the right heart function, and is a common complication of many diseases. Mesenchymal stem cells (MSCs) autonomously home to sites damaged by disease, repair damaged tissues, and participate in the regulation of systemic inflammation and immune responses, which have good clinical application prospects. Extracellular vesicles (EVs), such as exosomes and microvesicles, participate in various biological activities by regulating intercellular communication. Exosomes secreted into the extracellular environment also affect the host immune system. MSC-derived extracellular vesicles (MSC-EVs), as a mediator in the paracrine processes of MSCs, carry biologically active substances such as proteins, lipids, mRNA, and micro-RNA. MSC-EVs therapies, safer than cell-based treatments, have been shown to be effective in modulating macrophages to support anti-inflammatory phenotypes, which are strongly related to histological and functional benefits in preclinical models of pulmonary hypertension. The main effects of active substances and their potential medical value have attracted wide attention from researchers. This article reviews the role and relevant mechanisms of MSC-EVs in the treatment of pulmonary hypertension in recent studies and provides a basis for their future clinical applications. [ABSTRACT FROM AUTHOR]

With the recent aging of society, the prevention of frailty has become an important issue because people desire both a long and healthy lifespan. Klotho-hypomorphic (kl/kl) mice are known to show phenotypes of premature aging. Ninjin'yoeito (NYT) is a traditional Japanese Kampo medicine used to treat patients with vulnerable constitution, fatigue or physical exhaustion caused by aging and illness. Recent studies have reported the potential efficacy of NYT against frailty. We therefore evaluated the effect of NYT on the gait function, activity, the histopathological status of organs and survival using kl/kl mice as a model of aging-related frailty. Two sets of 28-day-old male kl/kl mice were assigned to the vehicle (non-treated; NT), 3% or 5% NYT dietary groups. One set of groups (NT, n = 18; 3% NYT, n = 11; 5% NYT, n = 11) was subjected to the analysis of free walking, rotarod, and spontaneous activity tests at approximately 58 days old. Thereafter, we measured triceps surae muscles weight and myofiber cross-sectional area (CSA), and quantified its telomere content. In addition, we evaluated bone strength and performed histopathological examinations of organs. Survival was measured in the second set of groups (NT, 3% NYT and 5% NYT group, n = 8 each). In the walking test, several indicators such as gait velocity were improved in the NYT 3% group. Similar results were obtained for the latency to fall in the rotarod test and spontaneous motor activity. Triceps muscle mass, CSA and its telomere content were significantly improved in the NYT 3% group. Bone density, pulmonary alveolus destruction and testicular atrophy were also significantly improved in the NYT 3% group. Survival rate and body weight were both significantly improved in the NYT3% group compared with those in the NT group. Continuous administration of NYT from the early stage of aging improved not only gait performance, but also the survival in the agingrelated frailty model. This effect may be associated with the improvements in aging-related organ changes such as muscle atrophy. Intervention with NYT against the progression of frailty may contribute to a longer, healthier life span among the elderly individuals. [ABSTRACT FROM AUTHOR]