Alveolar Space Research Articles

Complex treatment of destructive pulmonary tuberculosis using inhaled tauractant therapy

Introduction. Chemotherapy is the main component used in the treatment of tuberculosis. In addition to chemotherapy, pathogenetic treatment holds a special place in the complex treatment. The inhaled tauractant therapy restores phospholipid content on the surface of the alveolar epithelium, stimulates the involvement of additional lung parenchyma areas in breathing, facilitates elimination of toxic substances together with sputum from the alveolar space and protects the alveolar epithelium against injury caused by chemical and physical agents. Thereby it promotes acceleration of the lung parenchyma recovery processes.Aim. To study the experience of using Surfactant-BL in patients with destructive pulmonary tuberculosis receiving a standard chemotherapy regimen, taking into account the drug susceptibility for Mycobacterium tuberculosis.Materials and methods. A study was conducted involving 10 patients with destructive pulmonary tuberculosis who were diagnosed with it for the first time in their lives. They received treatment in Respiratory Tuberculosis Patients Department No. 4 of the Budgetary Healthcare Institution of Omsk Region – Clinical TB Dispensary in 2022–2023.Results. Tauractant showed a pronounced positive effect on the destructive tuberculosis process in patients who already received a standard chemotherapy regimen. Inhaled therapy promoted acceleration of the cavity closure.Conclusion. The addition of inhaled tauractant therapy to the standard chemotherapy regimen in patients with multidrug resistance (MDR) and pre-extensively drug-resistant (pre-XDR) respiratory TB significantly accelerated the TB cavity closure. The severity of intoxication and respiratory syndrome decreased in terms of clinical symptoms (relief of shortness of breath and cough). Spirography showed an increase in major indices of the pulmonary function test monitored at 2and 4-month follow-up.

Nonbronchoscopic Bronchoalveolar Lavage Improves Respiratory Culture Accuracy in Critically Ill Patients.

Diagnosis of pneumonia is challenging in critically ill, intubated patients due to limited diagnostic modalities. Endotracheal aspirate (EA) cultures are standard of care in many ICUs; however, frequent EA contamination leads to unnecessary antibiotic use. Nonbronchoscopic bronchoalveolar lavage (NBBL) obtains sterile, alveolar cultures, avoiding contamination. However, paired NBBL and EA sampling in the setting of a lack of gold standard for airway culture is a novel approach to improve culture accuracy and limit antibiotic use in the critically ill patients. We designed a pilot study to test respiratory culture accuracy between EA and NBBL. Adult, intubated patients with suspected pneumonia received concurrent EA and NBBL cultures by registered respiratory therapists. Respiratory culture microbiology, cell counts, and antibiotic prescribing practices were examined. We performed a prospective pilot study at the Cleveland Clinic Main Campus Medical ICU in Cleveland, Ohio for 22 months from May 2021 through March 2023. Three hundred forty mechanically ventilated patients with suspected pneumonia were screened. Two hundred fifty-seven patients were excluded for severe hypoxia (Fio2 ≥ 80% or positive end-expiratory pressure ≥ 12 cm H2O), coagulopathy, platelets less than 50,000, hemodynamic instability as determined by the treating team, and COVID-19 infection to prevent aerosolization of the virus. All 83 eligible patients were enrolled and underwent concurrent EA and NBBL. More EA cultures (42.17%) were positive than concurrent NBBL cultures (26.51%, p = 0.049), indicating EA contamination. The odds of EA contamination increased by eight-fold 24 hours after intubation. EA was also more likely to be contaminated with oral flora when compared with NBBL cultures. There was a trend toward decreased antibiotic use in patients with positive EA cultures if paired with a negative NBBL culture. Alveolar immune cell populations were recovered from NBBL samples, indicating successful alveolar sampling. There were no major complications from NBBL. NBBL is more accurate than EA for respiratory cultures in critically ill, intubated patients. NBBL provides a safe and effective technique to sample the alveolar space for both clinical and research purposes.

The anti-inflammatory effects of NaCl with KCl as a potent graphene exfoliator in a patients with interstitial pneumonia by epithelial-mesenchymal transition

A 72-year-old man with normal pressure hydrocephalus to our hospital with a history of productive cough, sputum, fever, dyspnea combined with nasal cannula oxygen therapy, chest radiography, vital signs: Total leukocyte count of 11800/cmm and Erythrocyte Sedimentation Rate (ESR) 53 mm in the first hour using Westergren method, C-reactive protein (CRP) 11.2 mg/dl [1]. The intravenous infusion of a solution consisting of 250mL normal saline with of potassium chloride (KCl) over 6 h , vitamin C intake with supportive care resulted in recovery, intramuscular injections of the graphene previously [2,3]. After the injection, ESR, CRP was 40-1.91 and segmental neutrophil was 79.6%. Alveolar epithelial cells underwent Epithelial-Mesenchymal Transition (EMT) in the progression of Acute Interstitial Pneumonia (AIP). AIP is characterized by acute respiratory prodrome including sore throat, headache, cough, dyspnea, and often fever with abrupt onset and short duration . AIP was defined Diffuse Alveolar Damage (DAD). The pathologic progress of DAD three phases: acute exudative phase, characterized by interstitial edema, hyaline membrane, and acute interstitial inflammation accumulation; proliferative phase,characterized by in alveolar spaces; and fibrotic phase,characterized by enlarged fibrotic septa and laminated intra-alveolar fibrosis. Epithelial-mesenchymal transition defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype [4].

Increased body condition score has a detrimental effect on arterial oxygen tension and increases the risk of hypoxaemia in anaesthetised horses

SummaryBackgroundImpaired oxygenation during anaesthesia can be detrimental. Bodyweight and body shape influence arterial oxygen tension (PaO2) but the effect of body condition score (BCS) has not been investigated.ObjectivesTo examine the effect of BCS on respiratory indices.Study designRetrospective.MethodsIn total, 524 anaesthetic records were reviewed. Records from healthy adult horses under isoflurane anaesthesia in dorsal recumbency, receiving controlled mechanical ventilation, with complete ventilation and arterial blood gas data and BCS assessment by one person (KL) were included in data analysis. Data were analysed using student's t‐test, Mann–Whitney U test, chi‐squared analysis and logistic regression.ResultsIn total, 135 records for 85 horses with BCS <6/9 (Group N) and 50 horses with BCS ≥6/9 (Group O) met the inclusion criteria. Overall, there was a strong negative correlation between BCS and PaO2 (Spearman's r = 0.72, p < 0.001). Group O had significantly lower PaO2 (112 [50–546 mmHg]) compared to Group N (380 [65–658 mmHg], p < 0.001) which remained when horses were further categorised by bodyweight >500 kg (118 mmHg vs. 390 mmHg, p < 0.001) and <500 kg (160 mmHg vs. 451 mmHg, p < 0.04). Group O were 34 times more likely to be hypoxaemic (PaO2 < 100 mmHg) compared to Group N (χ2 = 34.39, p = 0.03). Alveolar dead space fraction was greater in Group O (0.27 [0.10–0.41]) versus Group N (0.24 [0.12–0.35]), p < 0.001. Multivariate logistic regression analysis identified a significant association between PaO2 and bodyweight (p = 0.01), alveolar dead space fraction (p = 0.005) and BCS (p < 0.001).Main limitationsRetrospective design.ConclusionsBody condition score ≥6/9 has a detrimental effect on PaO2, alveolar dead space fraction and is a risk factor for hypoxaemia in healthy anaesthetised horses in dorsal recumbency.

Early time-course of respiratory mechanics, mechanical power and gas exchange in ARDS patients

PurposeTo describe the clinical course of ARDS during the first three days of mechanical ventilation, to compare ventilatory setting, respiratory mechanics and gas exchange variables collected during the first three days of mechanical ventilation between patients who survived and died during intensive care unit (ICU) stay and to investigate the variables associated with mortality at ICU admission and throughout the first three days of mechanical ventilation. Materials and methodsProspective observational study. Mechanically ventilated ARDS patients were studied at ICU admission and for the following three days. Univariate logistic regression models were performed for PaO2/FiO2 ratio, driving pressure and alveolar dead space fraction and for mechanical power and mechanical power ratio. ResultsMechanical power ratio was higher in non survivors at ICU admission and over time; PaO2/FiO2 ratio was higher in survivors with a similar behavior over time in the two groups while alveolar dead space fraction was similar at ICU admission and over time between groups. Mechanical power ratio was the only physiological variable which remained consistently associated with ICU mortality throughout the study. ConclusionsThe alteration in oxygenation, dead space, and mechanical power ratio should be assessed not at intensive care admission, but during the first days of mechanical ventilation to better predict outcome.

Assessment of respiratory and reproductive impacts of artisanal refinery activities on male Albino Wistar rats: implications for environmental health

BackgroundArtisanal petroleum refining operations have been known to produce a significant volume of air pollutants. The highest concentration of pollutants is generated during the oven heating or crude boiling phase of the operation. The major pollutant is black carbon or soot. Although these operations are widespread, especially in developing countries, the impact of exposure to emissions from artisanal refinery on both respiratory and reproductive health remains poorly understood.ObjectiveThis study is aimed to examine the effects of controlled subacute exposure to carbon soot emissions generated during the oven heating phase of the refining process, on the respiratory and reproductive systems of male albino Wistar rats.MethodsTo simulate the exposure conditions found in artisanal refineries, we developed a replicable fabrication of an artisanal refinery combustion system fitted with an exposure chamber for in vivo studies. 6–8 weeks old adolescent albino Wistar rats were divided into four groups (A, B, C, & D), with group A acting as the general control group and was not exposed to any carbon soot particulate matter. Group B, C, and D were exposed subacutely for four hours each day for 3, 7, 14, 21, and 28 days to varying emission concentrations. Daily exposure measurements were determined using Aeroqual Series 300 Gas Monitor, and average exposure concentration of carbon soot particulate matter (PM2.5), for each exposed group were given as: (1.221 ± 0.169 mg/m3, 1.290 ± 0.214 mg/m3 1.282 ± 0.235 mg/m3). Animals from each group were euthanised on Day 3, 7, 14, 21, and Day 28, respectively. Tissue samples of the lungs and testis were collected for immunohistochemistry and oxidative stress analysis.Discussion/Conclusion: Cytoarchitecture of the lungs and testis via histology and immunohistochemistry, showed inflammatory cell infiltration, thickened alveolar walls, diminished alveolar spaces, hyperaemia, and bronchial epithelial hyperplasia in the lungs of Group B, C, and D animals that were exposed to soot. While cytoarchitecture of the testis revealed a distortion of the Leydig cells, vacuolations and mild vacuolations within the spermatid layer, loss of flagella, and some distortion of seminiferous tubule in the lumen.Notable increase in the mean expression and significant P-values determined by one-way analysis of variance (ANOVA), followed by Tukey’s post hoc test, were observed on Day 14–28 (P < 0.05) for tumour-necrosis-factor alpha (TNF-α), Day 21–28 (P < 0.001) for malondialdehyde (MDA), and Day 21 (P < 0.001) for superoxide dismutase (SOD) expression in the lungs of each of the experimental Group (B, C, D) when compared to the control Group A.Our study provides valuable insights into the health risks associated with exposure to carbon soot particulate matter, thus underscoring the urgent need for necessary control measures to curb air pollution as a result of artisanal refinery activities.

Cardiogenic Pulmonary Edema in Emergency Medicine.

Cardiogenic pulmonary edema (CPE) is characterized by the development of acute respiratory failure associated with the accumulation of fluid in the lung's alveolar spaces due to an elevated cardiac filling pressure. All cardiac diseases, characterized by an increasing pressure in the left side of the heart, can cause CPE. High capillary pressure for an extended period can also cause barrier disruption, which implies increased permeability and fluid transfer into the alveoli, leading to edema and atelectasis. The breakdown of the alveolar-epithelial barrier is a consequence of multiple factors that include dysregulated inflammation, intense leukocyte infiltration, activation of procoagulant processes, cell death, and mechanical stretch. Reactive oxygen and nitrogen species (RONS) can modify or damage ion channels, such as epithelial sodium channels, which alters fluid balance. Some studies claim that these patients may have higher levels of surfactant protein B in the bloodstream. The correct approach to patients with CPE should include a detailed medical history and a physical examination to evaluate signs and symptoms of CPE as well as potential causes. Second-level diagnostic tests, such as pulmonary ultrasound, natriuretic peptide level, chest radiograph, and echocardiogram, should occur in the meantime. The identification of the specific CPE phenotype is essential to set the most appropriate therapy for these patients. Non-invasive ventilation (NIV) should be considered early in the treatment of this disease. Diuretics and vasodilators are used for pulmonary congestion. Hypoperfusion requires treatment with inotropes and occasionally vasopressors. Patients with persistent symptoms and diuretic resistance might benefit from additional approaches (i.e., beta-agonists and pentoxifylline). This paper reviews the pathophysiology, clinical presentation, and management of CPE.

Chronic toxicity assessment of nano-formulated Bischofia javanica leaves: Implications for pharmacological use

This study explores the chronic toxicity of nano-formulated Bischofia javanica leaves, a plant with pharmacological significance in Indonesia, following OECD guidelines 452. Graded doses (2, 4, 6, and 8 g/kg BW) of nano-formulated Bischofia javanica were administered to the treatment groups for 60 days, while the control group (K-) received only water. On the 61st day, the mice were euthanized, and samples for biochemical, hematological, and histopathological analysis were collected. Statistical analysis involved one-way ANOVA and Tukey’s post hoc tests. Graded doses of nano-formulated Bischofia javanica leaves caused significant alterations in liver function. Doses between 2 and 4 g/kg BW improved liver histology and physiological markers. Higher doses (6 to 8 g/kg BW) led to liver dysfunction and histological degeneration, characterized by substantial fatty alterations, intracellular fat accumulation in hepatocytes, and compromised central blood vessels and sinusoids. The lungs showed signs of alveolar inflammation, epithelial exfoliation, debris, and the accumulation of inflammatory cells in alveolar spaces. Lower doses showed uniformly distributed cardiac blood vessels, while higher doses resulted in heart hemorrhages and amorphous exudates. Except for high doses, which significantly elevated specific liver damage indicators, no other levels of Bischofia javanica caused treatment-related mortality or significant alterations in hematological and biochemical parameters. Blood sugar levels remained stable across the dose range. In conclusion, moderate doses of nano-formulated Bischofia javanica leaf extracts can enhance physiological functions positively. However, caution is necessary when contemplating high doses, as they can cause dysfunction or damage vital organ systems.

Type 1 diabetes contributes to combined pulmonary fibrosis and emphysema in male alpha 1 antitrypsin deficient mice.

Type 1 diabetes (T1D) is a metabolic disease characterized by hyperglycemia and can affect multiple organs, leading to life-threatening complications. Increased prevalence of pulmonary disease is observed in T1D patients, and diabetes is a leading cause of comorbidity in several lung pathologies. A deficiency of alpha-1 antitrypsin (AAT) can lead to the development of emphysema. Decreased AAT plasma concentrations and anti-protease activity are documented in T1D patients. The objective of this study was to determine whether T1D exacerbates the progression of lung damage in AAT deficiency. First, pulmonary function testing (PFT) and histopathological changes in the lungs of C57BL/6J streptozotocin (STZ)-induced T1D mice were investigated 3 and 6 months after the onset of hyperglycemia. PFT demonstrated a restrictive pulmonary pattern in the lungs of STZ-injected mice, along with upregulation of mRNA expression of pro-fibrotic markers Acta2, Ccn2, and Fn1. Increased collagen deposition was observed 6 months after the onset of hyperglycemia. To study the effect of T1D on the progression of lung damage in AAT deficiency background, C57BL/6J AAT knockout (KO) mice were used. Control and STZ-challenged AAT KO mice did not show significant changes in lung function 3 months after the onset of hyperglycemia. However, histological examination of the lung demonstrated increased collagen accumulation and alveolar space enlargement in STZ-induced AAT KO mice. AAT pretreatment on TGF-β-stimulated primary lung fibroblasts reduced mRNA expression of pro-fibrotic markers ACTA2, CCN2, and FN1. Induction of T1D in AAT deficiency leads to a combined pulmonary fibrosis and emphysema (CPFE) phenotype in male mice.

Fusobacterium nucleatum putatively affects the alveoli by disrupting the alveolar epithelial cell tight junction, enlarging the alveolar space, and increasing paracellular permeability

Fusobacterium nucleatum (Fn) is abundant in the human oral cavity and has been associated with periodontal disease, which in-turn has been linked to respiratory disease development. Tight junctions (TJs) line the airway and alveoli surfaces serving as a first line of defense against multiple pathogens. Fn has already been linked to respiratory diseases, however, how Fn affects the alveolar TJ was not fully elucidated. Here, we designed and analyzed a TJ network, grew Fn cells and inoculated it in vitro (16HBE and primary cells) and in vivo (mice lung), measured transepithelial electrical resistance, performed RT-PCR, checked for in vitro cell and mice lung permeability, and determined air space size through morphometric measurements. We found that Fn can potentially affect TJs proteins that are directly exposed to the alveolar surface. Additionally, Fn could possibly cause neutrophil accumulation and an increase in alveolar space. Moreover, Fn putatively may cause an increase in paracellular permeability in the alveoli.

PECAM-1 mediates temsirolimus-induced increase in neutrophil transendothelial migration that leads to lung injury

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.

THU551 Glycoprotein-NMB (GPNMB) Is A Potential Lymphangioleiomyomatosis (LAM) Therapeutic Target And Biomarker

Abstract Disclosure: E. Gibbons: None. S.R. Hammes: None. Lymphangioleiomyomatosis (LAM) is a rare, progressive, destructive cystic lung disease affecting almost exclusively female-sexed individuals. Mutations in the tuberous sclerosis (TSC1 or TSC2) genes constitutively activate the mTORC1 pathway, promoting hyperproliferation of smooth muscle cells, creating small tumors throughout the lungs. These tumors, through largely unknown mechanisms, result in the formation of large cysts that replace normal alveolar space. Inhibition of mTORC1 with Sirolimus slows but does not stop LAM progression; therefore, there is a need for new LAM treatment options and biomarkers. Due to LAM’s estrogen sensitivity, female specificity, and metastatic nature, we previously proposed LAM cells originate from the uterine myometrium. We therefore designed a uterine-specific TSC2-null mouse model where all the mice generate uterine tumors characteristic of LAM and half develop lung metastases, suggesting that indeed LAM tumors may be derived from the uterus. Using bulk RNASeq analysis of uterine tissue from our mouse model, when focusing on genes regulated by estrogen and TSC2, we discovered increased expression of melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB), a known oncogenic protein in other cancers. GPNMB was not only highly expressed in our mouse model; it was also expressed intracellularly and on the cell surface of TSC2-null cell lines and in LAM tumor cells from patient lungs and uteri. Notably, the extracellular domain of GPNMB was released from the surface of TSC2-null cell lines, suggesting that the ectodomain may also be released from TSC2-null cells in LAM patients. Here we show that, GPNMB protein and mRNA expression increased when the cells were serum starved, mimicking conditions of a tumor microenvironment. This increase was dependent on mTORC1 signaling and mRNA transcription. Knocking down GPNMB expression by siRNA had minimal effects on TSC2-null cells pro-tumorigenic functions in vitro aside from decreasing invasion. However, knocking out GPNMB in TSC2-null cells using CRISPR/Cas9 significantly decreased mouse xenograft tumor growth. Additionally, treating mice with a GPNMB antibody drug conjugate abrogated xenograft growth, highlighting GPNMB’s potential as a therapeutic target. Also, GPNMB’s ectodomain was released from the cell surface of TSC2-null cells by the proteases Adam10 and 17. Of note, the ectodomain is implicated in mediating GPNMB’s effects on tumor growth, suggesting that Adam10/17 inhibition may mitigate TSC2-null tumor growth. Importantly, the GPNMB ectodomain is a potential serum biomarker of LAM, as there was a significant increase in GPNMB ectodomain levels in patient serum as compared with healthy controls. Furthermore, serum GPNMB levels decreased in most patients after Sirolimus treatment, implicating GPNMB as a potential marker for responsiveness to treatment. Presentation: Thursday, June 15, 2023

Alveolar macrophages in tissue homeostasis, inflammation, and infection: evolving concepts of therapeutic targeting.

Alveolar macrophages (AMs) are the sentinel cells of the alveolar space, maintaining homeostasis, fending off pathogens, and controlling lung inflammation. During acute lung injury, AMs orchestrate the initiation and resolution of inflammation in order to ultimately restore homeostasis. This central role in acute lung inflammation makes AMs attractive targets for therapeutic interventions. Single-cell RNA-Seq and spatial omics approaches, together with methodological advances such as the generation of human macrophages from pluripotent stem cells, have increased understanding of the ontogeny, function, and plasticity of AMs during infectious and sterile lung inflammation, which could move the field closer to clinical application. However, proresolution phenotypes might conflict with proinflammatory and antibacterial responses. Therefore, therapeutic targeting of AMs at vulnerable time points over the course of infectious lung injury might harbor the risk of serious side effects, such as loss of antibacterial host defense capacity. Thus, the identification of key signaling hubs that determine functional fate decisions in AMs is of the utmost importance to harness their therapeutic potential.

Increased intrapulmonary shunt and alveolar dead space post-COVID-19.

Increased intrapulmonary shunt (QS/Qt) and alveolar dead space (VD/VT) are present in early recovery from 2019 Novel Coronavirus (COVID-19). We hypothesized patients recovering from severe critical acute illness (NIH category 3-5) would have greater and longer lasting increased QS/Qt and VD/VT than patients with mild-moderate acute illness (NIH 1-2). Fifty-nine unvaccinated patients (33 males, aged 52 [38-61] yr, body mass index [BMI] 28.8 [25.3-33.6] kg/m2; median [IQR], 44 previous mild-moderate COVID-19, and 15 severe-critical disease) were studied 15-403 days postacute severe acute respiratory syndrome coronavirus infection. Breathing ambient air, steady-state mean alveolar Pco2, and Po2 were recorded simultaneously with arterial Po2/Pco2 yielding aAPco2, AaPo2, and from these, QS/Qt%, VD/VT%, and relative alveolar ventilation (40 mmHg/[Formula: see text], VArel) were calculated. Median [Formula: see text] was 39.4 [35.6-41.1] mmHg, [Formula: see text] 92.3 [87.1-98.2] mmHg; [Formula: see text] 32.8 [28.6-35.3] mmHg, [Formula: see text] 112.9 [109.4-117.0] mmHg, AaPo2 18.8 [12.6-26.8] mmHg, aAPco2 5.9 [4.3-8.0] mmHg, QS/Qt 4.3 [2.1-5.9] %, and VD/VT16.6 [12.6-24.4]%. Only 14% of patients had normal QS/Qt and VD/VT; 1% increased QS/Qt but normal VD/VT; 49% normal QS/Qt and elevated VD/VT; 36% both abnormal QS/Qt and VD/VT. Previous severe critical COVID-19 predicted increased QS/Qt (2.69 [0.82-4.57]% per category severity [95% CI], P < 0.01), but not VD/VT. Increasing age weakly predicted increased VD/VT (1.6 [0.1-3.2]% per decade, P < 0.04). Time since infection, BMI, and comorbidities were not predictors (all P > 0.11). VArel was increased in most patients. In our population, recovery from COVID-19 was associated with increased QS/Qt in 37% of patients, increased VD/VT in 86%, and increased alveolar ventilation up to ∼13 mo postinfection. NIH severity predicted QS/Qt but not elevated VD/VT. Increased VD/VT suggests pulmonary microvascular pathology persists post-COVID-19 in most patients.NEW & NOTEWORTHY Using novel methodology quantifying intrapulmonary shunt and alveolar dead space in COVID-19 patients up to 403 days after acute illness, 37% had increased intrapulmonary shunt and 86% had elevated alveolar dead space likely due to independent pathology. Elevated shunt was partially related to severe acute illness, and increased alveolar dead space was weakly related to increasing age. Ventilation was increased in the majority of patients regardless of previous disease severity. These results demonstrate persisting gas exchange abnormalities after recovery.

Single-cell transcriptomics delineates the immune cell landscape in equine lower airways and reveals upregulation of FKBP5 in horses with asthma

Equine asthma (EA) is a heterogenous, complex disease, with a significant negative impact on horse welfare and performance. EA and human asthma share fundamental similarities, making EA a useful model for studying the disease. One relevant sample type for investigating chronic lung inflammation is bronchoalveolar lavage fluid (BALF), which provides a snapshot of the immune cells present in the alveolar space. To investigate the immune cell landscape of the respiratory tract in horses with mild-to-moderate equine asthma (mEA) and healthy controls, single-cell RNA sequencing was conducted on equine BALF cells. We characterized the major immune cell populations present in equine BALF, as well as subtypes thereof. Interestingly, the most significantly upregulated gene discovered in cases of mEA was FKBP5, a chaperone protein involved in regulating the activity of the glucocorticoid receptor.

BATF2 enhances proinflammatory cytokine responses in macrophages and improves early host defense against pulmonary Klebsiella pneumoniae infection.

Basic leucine zipper transcription factor ATF-like 2 (BATF2) is a transcription factor that is emerging as an important regulator of the innate immune system. BATF2 is among the top upregulated genes in human alveolar macrophages treated with LPS, but the signaling pathways that induce BATF2 expression in response to Gram-negative stimuli are incompletely understood. In addition, the role of BATF2 in the host response to pulmonary infection with a Gram-negative pathogen like Klebsiella pneumoniae (Kp) is not known. We show that induction of Batf2 gene expression in macrophages in response to Kp in vitro requires TRIF and type I interferon (IFN) signaling, but not MyD88 signaling. Analysis of the impact of BATF2 deficiency on macrophage effector functions in vitro showed that BATF2 does not directly impact macrophage phagocytic uptake and intracellular killing of Kp. However, BATF2 markedly enhanced macrophage proinflammatory gene expression and Kp-induced cytokine responses. In vivo, Batf2 gene expression was elevated in lung tissue of wild-type (WT) mice 24 h after pulmonary Kp infection, and Kp-infected BATF2-deficient (Batf2-/-) mice displayed an increase in bacterial burden in the lung, spleen, and liver compared with WT mice. WT and Batf2-/- mice showed similar recruitment of leukocytes following infection, but in line with in vitro observations, proinflammatory cytokine levels in the alveolar space were reduced in Batf2-/- mice. Altogether, these results suggest that BATF2 enhances proinflammatory cytokine responses in macrophages in response to Kp and contributes to the early host defense against pulmonary Kp infection.NEW & NOTEWORTHY This study investigates the signaling pathways that mediate induction of BATF2 expression downstream of TLR4 and also the impact of BATF2 on the host defense against pulmonary Kp infection. We demonstrate that Kp-induced upregulation of BATF2 in macrophages requires TRIF and type I IFN signaling. We also show that BATF2 enhances Kp-induced macrophage cytokine responses and that BATF2 contributes to the early host defense against pulmonary Kp infection.

Evidence of non-invasive ventilation in Acute Pulmonary Edema: an integrative review

Introduction: Acute pulmonary edema is a multifactorial clinical syndrome in which there is accumulation of fluid in the pulmonary interstitium and alveolar spaces. It is considered a clinical emergency and one of the main causes of hospitalization, represents one of the main causes of hypoxemic acute respiratory failure, and its severity will depend on the amount of fluid accumulated in the lungs. Initially, when the individual has lower accumulations, he/she will present aquidyspnea, shorthand, and bilateral basal stumour in pulmonary auscultation. Objective: To verify in the literature the existence of evidence of the use of non-invasive mechanical ventilation in the reversibility of acute pulmonary edema. Metodhology: Through the 6 phases of the integrative review, we were able to organize the research in a way that is understandable and accessible so that the data are used as evidence in clinical practice. In order to answer the question presented for the review, bibliographic research of publications indexed in the following databases was performed: MEDLINE/PubMed, Web of Science and Scopus. Results: A total of 1,584 studies were found in the databases, with only 3 articles being included in the discussion because they better answered the research question. Conclusion: On the available literature, it is suggested that therapy may benefit patients with cardiogenic pulmonary edema, and that a greater number of studies may elucidate the best treatment of individuals affected by the disease using non-invasive ventilation as a more assertive resource.

Functional characterization of small and large alveolar macrophages in sarcoidosis and idiopathic pulmonary fibrosis compared with non-fibrosis interstitial lung diseases.

Sarcoidosis is a granulomatous disease that mostly affects the lungs. Advanced tissue injury caused by this disease can progress to pulmonary fibrosis with similar characteristics shared with idiopathic pulmonary fibrosis (IPF). The initial presentations of both sarcoidosis and IPF may be shared with other interstitial lung diseases (ILDs). Two populations of macrophages have been described in the alveolar space: small alveolar macrophages (AMs) and large alveolar macrophages. Despite their protective function, these cells may also play a role in the initiation and maintenance of inflammation leading to fibrosis. The aim of this study was the functional characterization of small and large AM subpopulations in sarcoidosis and IPF as a pathology with respectively mild and advanced tissue injury causing fibrosis, in comparison with non-fibrosis ILDs. Activation and adhesion surface markers as well as functions of small and large AMs isolated from bronchoalveolar lavage (BAL) were assessed by Flow Cytometry within patients with confirmed sarcoidosis (n= 14), IPF (n= 6), and non-fibrosis ILDs (n= 9). Our results showed that small AMs are immunologically more active, which may be important for airway inflammation. They are also proportionally more abundant in IPF, and therefore they may be more involved in a fibrosis process associated with the down-regulation of HLA-DR, LeuCAM, and CD62L expression. In Sarcoidosis, the inflammatory process appears to be associated with up-regulation of CD38 expression and oxidative burst activity. A relevant potential of the activation and adhesion markers as well as oxidative burst activity expressed on small and large AMs, in the perspective of differential diagnosis of sarcoidosis and IPF.

Lung regeneration with rat fetal lung implantation and promotion of alveolar stem cell differentiation by corticosteroids

IntroductionThe lung is a difficult organ to regenerate, and the development of functional lungs has still not been achieved. In this study, we investigated lung regeneration using a rat fetal lung tissue-implanted model. This study aimed to evaluate the functioning of the implanted fetal lung tissue and investigate the graft differentiation and maturation mechanism, focusing on alveolar stem cells. MethodsFetal lung tissue fragments were obtained from Lewis rats on day 17 and implanted into adult lungs. Animals were divided into the following three groups: group 1, injection into the adult left lung parenchyma; group 2, injection with post-caval lobectomy; and group 3, injection with post-caval lobectomy and corticosteroid administration. Computed tomography was performed on weeks 1, 2, 4, and 8. The presence of alveolar pore, CD31 expression, and bipotential progenitor cell (podoplanin+/surfactant protein C+) localization were histologically evaluated. MiRNA expression was comprehensively compared among the three groups. ResultsThe grafts comprised type I and type II alveolar cells connected to the recipient lungs with alveolar pores and capillary networks in the interstitial tissue. The alveolar space was the largest and the computed tomography value was the lowest in the grafts of the corticosteroid-administered group. The number of bipotential progenitor cells was the lowest in the corticosteroid administration group on day 7. Moreover, microRNA-487-3p, 374-5p, and 20b-5p expression was changed by more than 2-fold between the post-caval lobectomy and corticosteroid administration groups. ConclusionsImplanted fetal lung tissues established airway and capillary communication with the recipient lungs, and corticosteroids accelerated their maturation by promoting the differentiation of progenitor cells. The study findings provide new insights into lung regeneration research.

Circulating Surfactant Protein D: A Biomarker for Acute Lung Injury?

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening lung diseases in critically ill patients. The lack of prognostic biomarkers has halted detection methods and effective therapy development. Quantitative biomarker-based approaches in the systemic circulation have been proposed as a means of enhancing diagnostic strategies as well as pharmacotherapy in a patient-specific manner. Pulmonary surfactants are complex mixtures made up of lipids and proteins, which are secreted into the alveolar space by epithelial type II cells under normal and pathological conditions. In this review, we summarize the current knowledge of SP-D in lung injury from both preclinical and clinical studies. Among surfactant proteins, surfactant protein-D (SP-D) has been more widely studied in ALI and ARDS. Recent studies have reported that SP-D has a superior discriminatory ability compared to other lung epithelial proteins for the diagnosis of ARDS, which could reflect the severity of lung injury. Furthermore, we shed light on recombinant SP-D treatment and its benefits as a potential drug for ALI, and we encourage further studies to translate SP-D into clinical use for diagnosis and treatment.