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Premature infants with bronchopulmonary dysplasia (BPD) have impaired alveolar gas exchange due to alveolar simplification and dysmorphic pulmonary vasculature. Advances in clinical care have improved survival for infants with BPD, but the overall incidence of BPD remains unchanged because we lack specific therapies to prevent this disease. Recent work has suggested a role for increased transforming growth factor-beta (TGFβ) signaling and myofibroblast populations in BPD pathogenesis, but the functional significance of each remains unclear. Here, we utilize multiple murine models of alveolar simplification and comparative single-cell RNA sequencing to identify shared mechanisms that could contribute to BPD pathogenesis. Single-cell RNA sequencing reveals a profound loss of myofibroblasts in two models of BPD and identifies gene expression signatures of increased TGFβ signaling, cell cycle arrest, and impaired proliferation in myofibroblasts. Using pharmacologic and genetic approaches, we find no evidence that increased TGFβ signaling in the lung mesenchyme contributes to alveolar simplification. In contrast, this is likely a failed compensatory response, since none of our approaches to inhibit TGFβ signaling protect mice from alveolar simplification due to hyperoxia while several make simplification worse. In contrast, we find that impaired myofibroblast proliferation is a central feature in several murine models of BPD, and we show that inhibiting myofibroblast proliferation is sufficient to cause pathologic alveolar simplification. Our results underscore the importance of impaired myofibroblast proliferation as a central feature of alveolar simplification and suggest that efforts to reverse this process could have therapeutic value in BPD.

BACKGROUND: Chronic lung disease of prematurity, called bronchopulmonary dysplasia (BPD), lacks effective therapies, stressing the need for preclinical testing systems that reflect human pathology for identifying causal pathways and testing novel compounds. Alveolar organoids derived from human pluripotent stem cells (hPSC) are promising test platforms for studying distal airway diseases like BPD, but current protocols do not accurately replicate the distal niche environment of the native lung. Herein, we investigated the contributions of cellular constituents of the alveolus and fetal respiratory movements on hPSC-derived alveolar organoid formation. METHODS: Human PSCs were differentiated in 2D culture into lung progenitor cells (LPC) which were then further differentiated into alveolar organoids before and after removal of co-developing mesodermal cells. LPCs were also differentiated in Transwell® co-cultures with and without human fetal lung fibroblast. Forming organoids were subjected to phasic mechanical strain using a Flexcell® system. Differentiation within organoids and Transwell® cultures was assessed by flow cytometry, immunofluorescence, and qPCR for lung epithelial and alveolar markers of differentiation including GATA binding protein 6 (GATA 6), E-cadherin (CDH1), NK2 Homeobox 1 (NKX2-1), HT2-280, surfactant proteins B (SFTPB) and C (SFTPC). RESULTS: We observed that co-developing mesenchymal progenitors promote alveolar epithelial type 2 cell (AEC2) differentiation within hPSC-derived lung organoids. This mesenchymal effect on AEC2 differentiation was corroborated by co-culturing hPSC-NKX2-1+ lung progenitors with human embryonic lung fibroblasts. The stimulatory effect did not require direct contact between fibroblasts and NKX2-1+ lung progenitors. Additionally, we demonstrate that episodic mechanical deformation of hPSC-derived lung organoids, mimicking in situ fetal respiratory movements, increased AEC2 differentiation without affecting proximal epithelial differentiation. CONCLUSION: Our data suggest that biophysical and mesenchymal components promote AEC2 differentiation within hPSC-derived distal organoids in vitro.

Fibroblasts are present throughout the body and function to maintain tissue homeostasis. Recent studies have identified diverse fibroblast subsets in healthy and injured tissues1,2, but the origins and functional roles of injury-induced fibroblast lineages remain unclear. Here we show that lung-specialized alveolar fibroblasts take on multiple molecular states with distinct roles in facilitating responses to fibrotic lung injury. We generate a genetic tool that uniquely targets alveolar fibroblasts to demonstrate their role in providing niches for alveolar stem cells in homeostasis and show that loss of this niche leads to exaggerated responses to acute lung injury. Lineage tracing identifies alveolar fibroblasts as the dominant origin for multiple emergent fibroblast subsets sequentially driven by inflammatory and pro-fibrotic signals after injury. We identify similar, but not completely identical, fibroblast lineages in human pulmonary fibrosis. TGFβ negatively regulates an inflammatory fibroblast subset that emerges early after injury and stimulates the differentiation into fibrotic fibroblasts to elicit intra-alveolar fibrosis. Blocking the induction of fibrotic fibroblasts in the alveolar fibroblast lineage abrogates fibrosis but exacerbates lung inflammation. These results demonstrate the multifaceted roles of the alveolar fibroblast lineage in maintaining normal alveolar homeostasis and orchestrating sequential responses to lung injury.

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]

The article comments on a study which examined difficulties of striking a balance between gaining potential benefits and minimizing the hazards associated with lung unit recruitment involving patients with acute respiratory distress syndrome (ARDS). It discusses the potential consequences of higher mean airway pressure, methods for recruitment that include raising positive end-expiratory pressure (PEEP), and the important effects of body positioning and initial baseline PEEP conditions.

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]

Identification of the breathing cycle forms the basis of any breath-by-breath gas exchange analysis. Classically, the breathing cycle is defined as the time interval between the beginning of two consecutive inspiration phases. Based on this definition, several research groups have developed algorithms designed to estimate the volume and rate of gas transferred across the alveolar membrane ("alveolar gas exchange"); however, most algorithms require measurement of lung volume at the beginning of the ith breath (VLi-1; i.e., the end-expiratory lung volume of the preceding ith breath). The main limitation of these algorithms is that direct measurement of VLi-1 is challenging and often unavailable. Two solutions avoid the requirement to measure VLi-1 by redefining the breathing cycle. One method defines the breathing cycle as the time between two equal fractional concentrations of lung expired oxygen (Fo2) (or carbon dioxide; Fco2), typically in the alveolar phase, whereas the other uses the time between equal values of the Fo2/Fn2 (or Fco2/Fn2) ratios [i.e., the ratio of fractional concentrations of lung expired O2 (or CO2) and nitrogen (N2)]. Thus, these methods identify the breathing cycle by analyzing the gas fraction traces rather than the gas flow signal. In this review, we define the traditional approach and two alternative definitions of the human breathing cycle and present the rationale for redefining this term. We also explore the strengths and limitations of the available approaches and provide implications for future studies.

Introduction: Endurance exercise at altitude can increase cardiac output and pulmonary vascular pressure to levels that may exceed the stress tolerability of the alveolar--capillary unit. This study examined the effect of ultramarathon trail racing at different altitudes (ranging from <1000 m to between 1500 and 2700 m) on alveolar--capillary recruitment and lung diffusion. Methods: Cardiac and lung function were examined before and after an ultramarathon in 67 runners (age: 41 ± 9 yr, bodymass index: 23 ± 2 kg⋅m-2, 10 females), and following 12-24 h of recovery in a subset (n = 27). Cardiac biomarkers (cTnI and BNP) were assessed from whole blood, whereas lung fluid accumulation (comet tails), stroke volume (SV), and cardiac output (Q)were quantified via echocardiography. Lung diffusing capacity for carbonmonoxide (DLco) and its components, alveolar membrane conductance (Dm) and capillary blood volume (Vc), were determined via a single-breath method at rest and during three stages of submaximal semirecumbent cycling (20, 30, and 40W). Results:Average race time was 25 ± 12 h. From pre- to post-race, there was an increase in cardiac biomarkers (cTnI: 0.04 ± 0.02 vs 0.13 ± 0.03 ng⋅mL-1,BNP: 20 ± 2 vs 112 ± 21 pg⋅mL-1; P < 0.01) and lung comet tails (2 ± 1 vs 7 ± 6, P < 0.01), a decrease in resting and exercise SV (76 ± 2 vs 69 ± 2 mL, 40 W: 93 ± 2 vs 88 ± 2 mL; P < 0.01), and an elevation in Q at rest (4.1 ± 0.1 vs 4.6 ± 0.2 L⋅min-1, P < 0.01; 40 W: 7.3 ± 0.2 vs 7.4 ± 0.3 L⋅min-1, P = 0.899). Resting DLco and Vc decreased after the race ( P < 0.01), whereas Dm was unchanged ( P = 0.465); however, during the three stages of exercise, DLco, Vc, and Dm were all reduced from pre- to post-race (40 W: 36.3 ± 0.9 vs 33.0 ± 0.8 mL⋅min-1⋅mm Hg-1, 83 ± 3 vs 73 ± 2 mL, 186 ± 6 vs 170 ± 7 mL⋅min-1⋅mm Hg-1, respectively; P < 0.01). When corrected for alveolar volume and Q, DLco decreased from pre- to post-race ( P < 0.01), and changes in DLco were similar for all ultramarathon events ( P > 0.05). Conclusions: Competing in an ultramarathon leads to a transient increase in cardiac injury biomarkers, mild lung-fluid accumulation, and impairments in lung diffusion. Reductions in DLco are predominantly caused by a reduced Vc and possible pulmonary capillary de-recruitment at rest. However, impairments in alveolar--capillary recruitment and Dm both contribute to a fall in exertional DLco following an ultramarathon. Perturbations in lung diffusion were evident across a range of event distances and varying environmental exposures. [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 bag-valve-mask (BVM) or manual resuscitator bag is used as a first-line technique to ventilate patients with respiratory failure. Volume-restricted manual resuscitator bags (eg, pediatric bags) have been suggested to minimize overventilation and associated complications. There are studies that both support and caution against the use of a pediatric resuscitator bag to ventilate an adult patient. In this study, we evaluated the ability of pre-hospital clinicians to adequately ventilate an adult manikin with both an adult- and pediatric-size manual resuscitator bag without the assistance of an advanced airway or airway adjunct device. METHODS: This study was conducted at an international conference in 2022. Conference attendees with pre-hospital health care experience were recruited to ventilate an adult manikin using a BVM for 1 min with both an adult and pediatric resuscitator bag, without the use of adjunct airway devices, while 6 ventilatory variables were collected or calculated: tidal volume (VT), breathing frequency, adequate breaths (VT > 150 mL), proportion of adequate breaths, peak inspiratory pressure (PIP), and estimated alveolar ventilation (EAV). RESULTS: A total of 208 participants completed the study. Ventilation with the adult-sized BVM delivered an average VT of 290.4 mL compared to 197.1 mL (P < .001) when using the pediatric BVM. PIP with the adult BVM was higher than with the pediatric BVM (10.6 cm H2O vs 8.6 cm H2O, P < .001). The median EAV with the adult bag (1,138.1 [interquartile range [IQR] 194.0-2,869.9] mL/min) was markedly greater than with the pediatric BVM (67.7 [IQR 0-467.3] mL/min, P < .001). CONCLUSIONS: Both pediatric- and adult-sized BVM provided lower ventilation volumes than those recommended by professional guidelines for an adult. Ventilation with the pediatric BVM was significantly worse than with the adult bag when ventilating a simulated adult subject. [ABSTRACT FROM AUTHOR]

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]

Objective To investigate the role of macrophages in the process of fine particulate matter (PM2.5) exposure induced damage to pulmonary blood-air barrier. Methods Eighteen male BALB/C mice (aged of 10 weeks, weighing 24~27 g) were randomly divided into control group and low- and high-dose PM2.5 exposure groups (receiving 1.8 and 16.2 mg/kg, respectively), with 6 mice in each group. The control group received tracheal instillations of normal saline on days 1, 4, and 7, whereas the exposure groups were administered corresponding dose of PM2.5 exposure at the same time points. In 24 h after last exposure, pathological changes in the lung tissues were observed, and the contents of total protein (TP), lactate dehydrogenase (LDH), and alkaline phosphatase (AKP) in bronchoalveolar lavage fluid (BALF), and F4/80 protein level in lung tissue were measured to evaluate the blood-air barrier damage and macrophage infiltration within the lung tissues. Additionally, an in vitro model of the blood-air barrier was established using A549 alveolar epithelial cells and EA.hy926 vascular endothelial cells. In combination with a THP-1 macrophage model, the supernatant PM2.5 supernatant, macrophage supernatant, and PM2.5-macrophage supernatant were incubated with the barrier model for 24 h, respectively. Transmembrane electrical resistance (TEER), sodium fluorescein permeability of the barrier model, and LDH release from the barrier cells were measured to ascertain the extent of macrophage-mediated enhancement in barrier damage induced by PM2.5 exposure. Furthermore, the expression of inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-8 in the macrophages after PM2.5 exposure was analyzed with quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA). Results PM2.5 exposure induced lung tissue damage in mice in a dose-dependent manner, significantly elevated the contents of TP, LDH and AKP in the BALF and caused marked infiltration of macrophages into the lung tissue, especially the high-dose exposure when compared with the mice from the control group (P

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]

Alveolar formation increases the surface area for gas exchange. A molecular understanding of alveologenesis remains incomplete. Here, we show that the autonomic nerve and alveolar myofibroblast form a functional unit in mice. Myofibroblasts secrete neurotrophins to promote neurite extension/survival, whereas neurotransmitters released from autonomic terminals are necessary for myofibroblast proliferation and migration, a key step in alveologenesis. This establishes a functional link between autonomic innervation and alveolar formation. We also discover that planar cell polarity (PCP) signaling employs a Wnt-Fz/Ror-Vangl cascade to regulate the cytoskeleton and neurotransmitter trafficking/release from the terminals of autonomic nerves. This represents a new aspect of PCP signaling in conferring cellular properties. Together, these studies offer molecular insight into how autonomic activity controls alveolar formation. Our work also illustrates the fundamental principle of how two tissues (e.g., nerves and lungs) interact to build alveoli at the organismal level.

The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways. Organoid modelling reveals that these respiratory airway secretory (RAS) cells act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RAS cell lineage differentiation into alveolar type 2 cells is regulated by Notch and Wnt signalling. In chronic obstructive pulmonary disease, RAS cells are altered transcriptionally, corresponding to abnormal alveolar type 2 cell states, which are associated with smoking exposure in both humans and ferrets. These data identify a distinct progenitor in a region of the human lung that is not found in mouse that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease.

Alveolar formation requires coordinated movement and interaction between alveolar epithelial cells, mesenchymal myofibroblasts, and endothelial cells/pericytes to produce secondary septa. These processes rely on the acquisition of distinct cellular properties to enable ligand secretion for cell-cell signaling and initiate morphogenesis through cellular contraction, cell migration, and cell shape change. In this study, we showed that mitochondrial activity and distribution play a key role in bestowing cellular functions on both alveolar epithelial cells and mesenchymal myofibroblasts for generating secondary septa to form alveoli in mice. These results suggest that mitochondrial function is tightly regulated to empower cellular machineries in a spatially specific manner. Indeed, such regulation via mitochondria is required for secretion of ligands, such as platelet-derived growth factor, from alveolar epithelial cells to influence myofibroblast proliferation and contraction/migration. Moreover, mitochondrial function enables myofibroblast contraction/migration during alveolar formation. Together, these findings yield novel mechanistic insights into how mitochondria regulate pivotal steps of alveologenesis. They highlight selective utilization of energy in cells and diverse energy demands in different cellular processes during development. Our work serves as a paradigm for studying how mitochondria control tissue patterning.

Loss of alveolar type 2 cells (AEC2s) and the ectopic appearance of basal cells in the alveoli characterize severe lung injuries such as idiopathic pulmonary fibrosis (IPF). Here we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, transdifferentiate into basal cells in response to fibrotic signalling in the lung mesenchyme, in vitro and in vivo. Single-cell analysis of normal hAEC2s and mesenchymal cells in organoid co-cultures revealed the emergence of pathologic fibroblasts and basaloid cells previously described in IPF. Transforming growth factor-β1 and anti-bone morphogenic protein signalling in the organoids promoted transdifferentiation. Trajectory and histologic analyses of both hAEC2-derived organoids and IPF epithelium indicated that hAEC2s transdifferentiate into basal cells through alveolar-basal intermediates that accumulate in proximity to pathologic CTHRC1hi/TGFB1hi fibroblasts. Our study indicates that hAEC2 loss and expansion of alveolar metaplastic basal cells in severe human lung injuries are causally connected through an hAEC2-basal cell lineage trajectory driven by aberrant mesenchyme.

Pulmonary alveolar microlithiasis (PAM) is a rare genetic disorder that causes calcium phosphate microliths to form in the alveoli. Symptoms usually appear in a person's third or fourth decade of life. A definitive diagnosis does not always demand a lung biopsy but can be achieved in families with more than one member with PAM and compatible chest imaging. We present the case of a 47-year-old woman referred to us for shortness of breath. Chest imaging revealed bilateral diffuse ground-glass opacities, interlobar fissure calcification, and subpleural linear calcifications, leading to a diagnosis of PAM. Although there is no specific treatment for this condition, early diagnosis can help prevent it from progressing rapidly by avoiding exposure to risk factors. [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]

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]

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]

Recent studies have demonstrated the feasibility of islet implantation into the alveoli. However, until today, there are no data on islet behavior and morphology at their transplant site. This study is the first to investigate islet distribution as well insulin production at the implant site. Using an ex vivo postmortem swine model, porcine pancreatic islets were isolated and aerosolized into the lung using an endoscopic spray-catheter. Lung tissue was explanted and bronchial airways were surgically isolated and connected to a perfusor. Correct implantation was confirmed via histology. The purpose of using this new lung perfusion model was to measure static as well as dynamic insulin excretions following glucose stimulation. Alveolar islet implantation was confirmed after aerosolization. Over 82% of islets were correctly implanted into the intra-alveolar space. The medium contact area to the alveolar surface was estimated at 60 +/- 3% of the total islet surface. The new constructed lung perfusion model was technically feasible. Following static glucose stimulation, insulin secretion was detected, and dynamic glucose stimulation revealed a biphasic insulin secretion capacity during perfusion. Our data indicate that islets secrete insulin following implantation into the alveoli and display an adapted response to dynamic changes in glucose. These preliminary results are encouraging and mark a first step toward endoscopically assisted islet implantation in the lung.

BackgroundSARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear.MethodsWe present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19.ResultsInfected ALO monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection, whereas distal alveolar differentiation (AT2→AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both.ConclusionsFindings validate a human lung model of COVID-19, which can be immediately utilized to investigate COVID-19 pathogenesis and vet new therapies and vaccines.FundingThis work was supported by the National Institutes for Health (NIH) grants 1R01DK107585-01A1, 3R01DK107585-05S1 (to SD); R01-AI141630, CA100768 and CA160911 (to PG) and R01-AI 155696 (to PG, DS and SD); R00-CA151673 and R01-GM138385 (to DS), R01- HL32225 (to PT), UCOP-R00RG2642 (to SD and PG), UCOP-R01RG3780 (to P.G. and D.S) and a pilot award from the Sanford Stem Cell Clinical Center at UC San Diego Health (P.G, S.D, D.S). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. L.C.A's salary was supported in part by the VA San Diego Healthcare System. This manuscript includes data generated at the UC San Diego Institute of Genomic Medicine (IGC) using an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).

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]

Temsirolimus is a first-generation mTOR inhibitor commonly used in the clinical treatment of cancers that is associated with lung injury. However, the mechanism underlying this adverse effect remains elusive. Endothelial barrier dysfunction plays a pivotal role in the infiltration of neutrophils into the pulmonary alveoli, which eventually induces lung injury. The present study demonstrates that temsirolimus induces the aberrant expression of adhesion molecules in endothelial cells, leading to enhanced neutrophil infiltration and subsequent lung injury. Results of a mouse model revealed that temsirolimus disrupted capillary–alveolar barrier function and facilitated neutrophil transmigration across the endothelium within the alveolar space. Consistent with our in vivo observations, temsirolimus impaired intercellular barrier function within monolayers of human lung endothelial cells, resulting in increased neutrophil infiltration. Furthermore, we demonstrated that temsirolimus-induced neutrophil transendothelial migration was mediated by platelet endothelial cell adhesion molecule-1 (PECAM-1) in both in vitro and in vivo experiments. Collectively, these findings highlight that temsirolimus induces endothelial barrier dysfunction via PECAM-1-dependent pathway both in vitro and in vivo , ultimately leading to neutrophil infiltration and subsequent pulmonary injury. • Temsirolimus induces transendothelial migration of neutrophils in mice. • Temsirolimus treatment promoted pulmonary endothelial barrier dysfunction. • The neutrophil trafficking induced by temsirolimus in a PECAM-1-dependent manner. [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]