Lung Morphology Research Articles

Effects of Positive End-Expiratory Pressure on Lung Recruitment, Respiratory Mechanics, and Intracranial Pressure in Mechanically Ventilated Brain-Injured Patients.

Background: The pathophysiological effects of positive end-expiratory pressure (PEEP) on respiratory mechanics, lung recruitment, and intracranial pressure (ICP) in acute brain-injured patients have not been completely elucidated. The primary aim of this study was to assess the effects of PEEP augmentation on respiratory mechanics, quantitative computed lung tomography (qCT) findings, and its relationship with ICP modifications. Secondary aims included the assessment of the correlations between different factors (respiratory mechanics and qCT features) with the changes of ICP and how these factors at baseline may predict ICP response after greater PEEP levels.Methods: A prospective, observational study included mechanically ventilated patients with acute brain injury requiring invasive ICP and who underwent two-PEEP levels lung CT scan. Respiratory system compliance (Crs), arterial partial pressure of carbon dioxide (PaCO2), mean arterial pressure (MAP), data from qCT and ICP were obtained at PEEP 5 and 15 cmH2O.Results: Sixteen examinations (double PEEP lung CT and neuromonitoring) in 15 patients were analyzed. The median age of the patients was 54 years (interquartile range, IQR = 39–65) and 53% were men. The median Glasgow Coma Scale (GCS) at intensive care unit (ICU) admission was 8 (IQR = 3–12). Median alveolar recruitment was 2.5% of total lung weight (−1.5 to 4.7). PEEP from 5 to 15 cmH2O increased ICP [median values from 14.0 (11.2–17.5) to 23.5 (19.5–26.8) mmHg, p < 0.001, respectively]. The amount of recruited lung tissue on CT was inversely correlated with the change (Δ) in ICP (rho = −0.78; p = 0.0006). Additionally, ΔCrs (rho = −0.77, p = 0.008), ΔPaCO2 (rho = 0.81, p = 0.0003), and ΔMAP (rho = −0.64, p = 0.009) were correlated with ΔICP. Baseline Crs was not predictive of ICP response to PEEP.Conclusions: The main factors associated with increased ICP after PEEP augmentation included reduced Crs, lower MAP and lung recruitment, and increased PaCO2, but none of these factors was able to predict, at baseline, ICP response to PEEP. To assess the potential benefits of increased PEEP in patients with acute brain injury, hemodynamic status, respiratory mechanics, and lung morphology should be taken into account.

Assessment of Lung Structure and Regional Function Using 0.55 T MRI in Patients With Lymphangioleiomyomatosis.

Contemporary lower-field magnetic resonance imaging (MRI) may offer advantages for lung imaging by virtue of the improved field homogeneity. The aim of this study was to evaluate the utility of lower-field MRI for combined morphologic imaging and regional lung function assessment. We evaluate low-field MRI in patients with lymphangioleiomyomatosis (LAM), a rare lung disease associated with parenchymal cysts and respiratory failure. We performed lung imaging on a prototype low-field (0.55 T) MRI system in 65 patients with LAM. T2-weighted imaging was used for assessment of lung morphology and to derive cyst scores, the percent of lung parenchyma occupied by cysts. Regional lung function was assessed using oxygen-enhanced MRI with breath-held ultrashort echo time imaging and inhaled 100% oxygen as a T1-shortening MR contrast agent. Measurements of percent signal enhancement from oxygen inhalation and percentage of lung with low oxygen enhancement, indicating functional deficits, were correlated with global pulmonary function test measurements taken within 2 days. We were able to image cystic abnormalities using T2-weighted MRI in this patient population and calculate cyst score with strong correlation to computed tomography measurements (R = 0.86, P < 0.0001). Oxygen-enhancement maps demonstrated regional deficits in lung function of patients with LAM. Heterogeneity of oxygen enhancement between cysts was observed within individual patients. The percent low-enhancement regions showed modest, but significant, correlation with FEV1 (R = -0.37, P = 0.007), FEV1/FVC (R = -0.33, P = 0.02), and cyst score (R = 0.40, P = 0.02). The measured arterial blood ΔT1 between normoxia and hyperoxia, used as a surrogate for dissolved oxygen in blood, correlated with DLCO (R = -0.28, P = 0.03). Using high-performance 0.55 T MRI, we were able to perform simultaneous imaging of pulmonary structure and regional function in patients with LAM.

BULLOUS LUNG DISEASE COMPLICATING COVID-19 PNEUMONIA

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: The long-term pulmonary sequelae and mechanism of lung injury seen in COVID-19 pneumonia are still under investigation, but have consistently been characterized by tissue destruction due to a hyperinflammatory state [1]. We discuss a case of bullous disease as a consequence of severe COVID 19 infection. CASE PRESENTATION: 71-year-old never smoker male presented with dyspnea, fevers and myalgias diagnosed with COVID-19 infection and admitted to the intensive care unit for acute hypoxemic respiratory failure due to acute respiratory distress syndrome (ARDS). On examination, he was noted to be in respiratory distress, with decreased breath sounds and crackles noted at the lung bases. Commuted Tomography (CT) chest revealed ground glass opacities (GGO), peripheral consolidative opacities affecting all five lobes, intralobular septal thickening in upper lobes, and traction bronchiectasis (Figure 1). His inflammatory markers were significantly elevated: C-reactive protein 384.8 mg/L, ferritin 2803 ng/mL, and D-dimer >20,000 ng/mL. His persistent hypoxemia due to COVID-19 infection was managed with high flow nasal cannula, prolonged course of corticosteroids, convalescent plasma and remdesivir. Follow up CT chest without IV contrast one month after hospitalization showed a new 8 cm bulla at the apex of the right lung with new focal emphysematous-type changes in the upper lobes, improved GGOs, traction bronchiectasis and subpleural fibrosis (Figure 2). Unfortunately, his recovery was complicated by readmission to the hospital for large right sided pneumothorax which required definitive management with surgical pleurodesis. DISCUSSION: Biopsies of lung tissue affected by severe COVID-19 pneumonia have shown interstitial inflammatory infiltrates and predominant findings consistent with diffuse alveolar damage, which is the primary histopathology of acute respiratory distress syndrome [2]. The formation of bullae after disruption of normal lung morphology is an established complication of ARDS and this underlying pattern of acute lung injury [3]. This case is unique in its description of development and recognition of significant bullous disease in a patient with COVID-19 infection without prior history of lung disease. To our knowledge, this is only the second reported case of bulla formation prior to observed pneumothorax in COVID-19 infection. There are otherwise an increasing number of cases reporting incidental bullous lung disease seen on CT imaging after readmission for spontaneous pneumothorax following index hospitalization for COVID-19 pneumonia. CONCLUSIONS: Although the precise etiologic mechanism is unclear, development of bullous lung disease as a consequence of COVID-19 infection is important to recognize and could represent an interval finding prior to presentation with spontaneous pneumothorax. REFERENCE #1: Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020;383(23):2255-2273. REFERENCE #2: Hariri LP, North CM, Shih AR, et al. Lung Histopathology in Coronavirus Disease 2019 as Compared With Severe Acute Respiratory Sydrome and H1N1 Influenza: A Systematic Review. Chest. 2021;159(1):73-84. REFERENCE #3: Gattinoni L, Caironi P, Pelosi P, Goodman LR. What has computed tomography taught us about the acute respiratory distress syndrome?. Am J Respir Crit Care Med. 2001;164(9):1701-1711. DISCLOSURES: No relevant relationships by Raymond Foley, source=Web Response No relevant relationships by Ashita Mittal, source=Web Response No relevant relationships by Simrina Sabharwal, source=Web Response

Lung Ultrasound Assessment of Focal and Non-focal Lung Morphology in Patients With Acute Respiratory Distress Syndrome.

Background: The identification of phenotypes based on lung morphology can be helpful to better target mechanical ventilation of individual patients with acute respiratory distress syndrome (ARDS). We aimed to assess the accuracy of lung ultrasound (LUS) methods for classification of lung morphology in critically ill ARDS patients under mechanical ventilation.Methods: This was a post hoc analysis on two prospective studies that performed LUS and chest computed tomography (CT) scanning at the same time. Expert panels from the two participating centers separately developed two LUS methods for classifying lung morphology based on LUS aeration scores from a 12-region exam (Amsterdam and Lombardy method). Moreover, a previously developed LUS method based on anterior LUS scores was tested (Piedmont method). Sensitivity and specificity of all three LUS methods was assessed in the cohort of the other center(s) by using CT as the gold standard for classification of lung morphology.Results: The Amsterdam and Lombardy cohorts consisted of 32 and 19 ARDS patients, respectively. From these patients, 23 (45%) had focal lung morphology while others had non-focal lung morphology. The Amsterdam method could classify focal lung morphology with a sensitivity of 77% and a specificity of 100%, while the Lombardy method had a sensitivity and specificity of 100 and 61%. The Piedmont method had a sensitivity and specificity of 91 and 75% when tested on both cohorts. With both the Amsterdam and Lombardy method, most patients could be classified based on the anterior regions alone.Conclusion: LUS-based methods can accurately classify lung morphology in invasively ventilated ARDS patients compared to gold standard chest CT. The anterior LUS regions showed to be the most discriminant between focal and non-focal lung morphology, although accuracy increased moderately when lateral and posterior LUS regions were integrated in the method.

Prenatal Molecular Hydrogen Administration Ameliorates Several Findings in Nitrofen-Induced Congenital Diaphragmatic Hernia.

Oxidative stress plays a pathological role in pulmonary hypoplasia and pulmonary hypertension in congenital diaphragmatic hernia (CDH). This study investigated the effect of molecular hydrogen (H2), an antioxidant, on CDH pathology induced by nitrofen. Sprague-Dawley rats were divided into three groups: control, CDH, and CDH + hydrogen-rich water (HW). Pregnant dams of CDH + HW pups were orally administered HW from embryonic day 10 until parturition. Gasometric evaluation and histological, immunohistochemical, and real-time polymerase chain reaction analyses were performed. Gasometric results (pH, pO2, and pCO2 levels) were better in the CDH + HW group than in the CDH group. The CDH + HW group showed amelioration of alveolarization and pulmonary artery remodeling compared with the CDH group. Oxidative stress (8-hydroxy-2′-deoxyguanosine-positive-cell score) in the pulmonary arteries and mRNA levels of protein-containing pulmonary surfactant that protects against pulmonary collapse (surfactant protein A) were significantly attenuated in the CDH + HW group compared with the CDH group. Overall, prenatal H2 administration improved respiratory function by attenuating lung morphology and pulmonary artery thickening in CDH rat models. Thus, H2 administration in pregnant women with diagnosed fetal CDH might be a novel antenatal intervention strategy to reduce newborn mortality due to CDH.

Isoforskolin, an adenylyl cyclase activator, attenuates cigarette smoke-induced COPD in rats

BackgroundChronic obstructive pulmonary disease (COPD) is characterized by limited airflow due to pulmonary and alveolar abnormalities from exposure to cigarette smoke (CS). Current therapeutic drugs are limited and the development of novel treatments to prevent disease progression is challenging. Isoforskolin (ISOF) from the plant Coleus forskohlii is an effective activator of adenylyl cyclase (AC) isoforms. Previously we found ISOF could attenuate acute lung injury in animal models, while the effect of ISOF on COPD has not been elucidated. PurposeIn this study, we aimed to evaluate the efficacy of ISOF on COPD and reveal its potential mechanisms. MethodsA rat model of COPD was established by long-term exposure to CS, then the rats were orally administered with ISOF (0.5, 1 and 2 mg/kg). The pulmonary function, lung morphology, inflammatory cells and cytokines in serum or bronchoalveolar lavage fluid (BALF) were evaluated. Transcriptomics, proteomics and network pharmacology analysis were utilized to identify potential mechanisms of ISOF. Droplet digital PCR was used to detect the mRNA expression of AC1-10 in donor lung tissues. AC activation was determined in recombinant human embryonic kidney 293 (HEK293) cells stably expressing human AC isoforms. In addition, ISOF caused trachea relaxation ex vivo were assessed in isolated trachea rings from guinea pigs. ResultsISOF significantly ameliorated pathological damage of lung tissue and improved pulmonary function in COPD rats. ISOF treatment decreased the number of inflammatory cells in peripheral blood, and also the levels of pro-inflammatory cytokines in serum and BALF. Consistent with omics-based analyses, ISOF markedly downregulated the mTOR level in lung tissue. Flow cytometry analysis revealed that ISOF treatment reduced the ratio of Th17/Treg cells in peripheral blood. Furthermore, the expression levels of AC1 and AC2 are relatively higher than other AC isoforms in normal lung tissues, and ISOF could potently activate AC1 and AC2 in vitro and significantly relax isolated guinea pig trachea. ConclusionCollectively, our studies suggest that ISOF exerts its anti-COPD effect by improving lung function, anti-inflammation and trachea relaxation, which may be related to AC activation, mTOR signaling and Th17/Treg balance.

Isoforskolin Alleviates AECOPD by Improving Pulmonary Function and Attenuating Inflammation Which Involves Downregulation of Th17/IL-17A and NF-κB/NLRP3.

Chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide, is widely considered to be related to cigarette smoke (CS), and viral infections trigger acute exacerbation of COPD (AECOPD). Isoforskolin (ISOF) is a bioactive component from the plant Coleus forskohlii, native to Yunnan in China. It has been demonstrated that ISOF has anti-inflammatory effect on acute lung injury animal models. In the present study, we investigated the efficacy and mechanism of ISOF for the prevention and treatment of AECOPD. Mice were exposed to CS for 18 weeks and then infected with influenza virus A/Puerto Rico/8/34 (H1N1). ISOF (0.5, 2 mg/kg) was intragastrically administered once a day after 8 weeks of exposure to cigarette smoke when the body weight and lung function of model mice declined significantly. The viral load, pulmonary function, lung morphology, Th17 cells, and inflammatory cytokines in lung tissues were evaluated. The expression of nuclear factor κB (NF-κB) and NOD-like receptor pyrin domain–containing protein 3 (NLRP3) inflammasome pathways were detected. The results showed that ISOF treatment reduced the viral load in the lung homogenate, decreased the lung index of model mice, and lung pathological injuries were alleviated. ISOF also improved the pulmonary function with increased FEV0.1/FVC and decreased Rn and Rrs. The levels of inflammatory mediators (TNF-α, IL-1β, IL-6, IL-17A, MCP-1, MIG, IP-10, and CRP) in the lung homogenate were reduced after ISOF treatment. ISOF decreased the proportion of Th17 cells in the lung tissues by the flow cytometry test, and the protein expression levels of RORγt and p-STAT3 were also decreased. Furthermore, ISOF significantly inhibited the activation of NF-κB signaling and NLRP3 inflammasome in the lung tissues of model mice. In conclusion, ISOF alleviates AECOPD by improving pulmonary function and attenuating inflammation via the downregulation of proinflammatory cytokines, Th17/IL-17 A, and NF-κB/NLRP3 pathways.

Selenomethionine alleviates LPS-induced JNK/NLRP3 inflammasome-dependent necroptosis by modulating miR-15a and oxidative stress in chicken lungs.

Selenium (Se) was involved in many physiological processes in humans and animals. microRNAs (miRNAs) also played important roles in lung diseases. However, the regulatory mechanism of miRNA in chicken lungs and the mechanism of lipopolysaccharide (LPS)-induced pneumonia remained unclear. To further study these mechanisms, we established a supplement of selenomethionine (SeMet) and/or LPS-treated chicken model and a cell model of LPS and/or high and low expression of miR-15a in chicken hepatocellular carcinoma (LMH) cells. We detected the expression of some selenoproteins, p-c-Jun N-terminal kinase (JNK), nod-like receptor protein 3 (NLRP3), caspase1, receptor-interacting serine-threonine kinase 1 (RIPK1), receptor-interacting serine-threonine kinase 3 (RIPK3), mixed lineage kinase domain-like pseudokinase (MLKL), miR-15a, and oxidative stress kits. Additionally, we observed the morphology of lungs by H.E. staining in vitro. The results indicated that necroptosis occurred in LPS-treated chicken and LMH cells. Moreover, LPS stimulation inhibited miR-15a, and increased the expression of JNK, NLRP3, caspase1, RIPK1, RIPK3, and MLKL. We also found that LPS treatment not only increased the content of H2O2 and MDA in the lungs but also increased the activities of iNOS and CAT and the content of GSH decreased. Conclusion: SeMet could reduce the oxidative damage and activate NLRP3 inflammasome reaction by stimulating miR-15a/JNK, thus reduced the pulmonary necroptosis induced by LPS.

Tiny golden angle ultrashort echo-time lung imaging in mice.

Imaging the lung parenchyma with MRI is particularly difficult in small animals due to the high respiratory and heart rates, and ultrashort T2* at high magnetic field strength caused by the high susceptibilities induced by the air-tissue interfaces. In this study, a 2D ultrashort echo-time (UTE) technique was combined with tiny golden angle (tyGA) ordering. Data were acquired continuously at 11.7T and retrospective center-of-k-space gating was applied to reconstruct respiratory multistage images. Lung (proton) density (fP ), T2*, signal-to-noise ratio (SNR), fractional ventilation (FV) and perfusion (f) were quantified, and the application to dynamic contrast agent (CA)-enhanced (DCE) qualitative perfusion assessment tested. The interobserver and intraobserver and interstudy reproducibility of the quantitative parameters were investigated. High-quality images of the lung parenchyma could be acquired in all animals. Over all lung regions a mean T2* of 0.20 ±0.05 ms was observed. FV resulted as 0.31 ±0.13, and a trend towards lower SNR values during inspiration (EX: SNR = 12.48 ±6.68, IN: SNR = 11.79 ±5.86) and a significant (P< 0.001) decrease in lung density (EX: fP =0.69 ±0.13, IN: fP =0.62 ±0.13) were observed. Quantitative perfusion results as 34.63 ±9.05 mL/cm3 /min (systole) and 32.77 ±8.55 mL/cm3 /min (diastole) on average. The CA dynamics could be assessed and, because of the continuous nature of the data acquisition, reconstructed at different temporal resolutions. Where a good to excellent interobserver reproducibility and an excellent intraobserver reproducibility resulted, the interstudy reproducibility was only fair to good. In conclusion, the combination of tiny golden angles with UTE (2D tyGA UTE) resulted in a reliable imaging technique for lung morphology and function in mice, providing uniform k-space coverage and thus low-artefact images of the lung parenchyma after gating.

MicroRNA-139-5p improves sepsis-induced lung injury by targeting Rho-kinase1.

Sepsis-induced acute lung injury (ALI) is an inflammatory process that involves inflammatory cytokine production and cell apoptosis. In the present study, the regulatory role of microRNA (miR)-139-5p in sepsis-induced ALI was investigated using a murine model of cecal ligation puncture (CLP) and an in vitro model using lipopolysaccharide (LPS)-induced normal human bronchial epithelial cells (NHBEs). Sepsis-induced pathological changes in the lungs of ALI mice were detected using hematoxylin and eosin staining. Lung water content was determined, and the expression of proinflammatory cytokines in the bronchoalveolar lavage fluid and serum of sepsis-induced ALI mice were quantified using ELISA. The levels of oxidative stress in lung tissues were determined using commercial kits. The degree of apoptosis was determined using a TUNEL assay. The expression levels of miR-139-5p and Rho-kinase 1 (ROCK1) were determined using reverse transcription-quantitative PCR and western blot analyses. A dual-luciferase reporter assay was used to confirm the direct targeting of ROCK1 by miR-139-5p. NHBEs were co-transfected with vectors expressing ROCK1 (or empty vector) and miR-139-5p mimics or control mimics prior to LPS treatment. The transcriptional activity of caspase-3, the ratio of apoptotic cells, the expression levels of mucin 5AC, mucin 1, TNF-α, IL-1β, IL-6, NLR family pyrin domain containing 3, apoptosis-associated speck-like protein containing a CARD and caspase-1 were evaluated. Compared with the normal group, mice that underwent CLP exhibited abnormal lung morphology, enhanced production of TNF-α, IL-1β and IL-6, increased reactive oxygen species (ROS), malondialdehyde and lactate dehydrogenase levels, an increased proportion of apoptotic cells and increased ROCK1 expression. Superoxide dismutase, glutathione peroxidase and miR-139-5p levels were decreased following CLP. In the NHBEs, stimulation with LPS caused a marked increase in inflammatory cytokine levels and apoptosis compared with the untreated cells. Overexpression of miR-139-5p attenuated cell apoptosis and inflammation. Overexpression of ROCK1 in NHBEs restored the ROS levels and proinflammatory cytokine production inhibited by miR-139-5p. In conclusion, miR-139-5p alleviated sepsis-induced ALI via suppression of its downstream target, ROCK1, suggesting that miR-139-5p may hold promise in the treatment of sepsis-induced ALI.

Aggressive alveolar recruitment in ARDS: More shadows than lights

Alveolar recruitment in acute respiratory distress syndrome (ARDS) is defined as the penetration of gas into previously unventilated areas or poorly ventilated areas. Alveolar recruitment during recruitment maneuvering (RM) depends on the duration of the maneuver, the recruitable lung tissue, and the balance between the recruitment of collapsed areas and over-insufflation of the ventilated areas. Alveolar recruitment is estimated using computed tomography of the lung and, at the patient bedside, through assessment of the recruited volume using pressure-volume curves and assessing lung morphology with pulmonary ultrasound and/or impedance tomography. The scientific evidence on RM in patients with ARDS remains subject to controversy. Randomized studies on ARDS have shown no benefit or have even reflected an increase in mortality. The routine use of RM is therefore not recommended.

Lung Ultrasound Assisted Comparison of Volume Effects of Fluid Replacement Regimens in Pediatric Patients Undergoing Penile Hypospadias Repair: A Randomized Controlled Trial.

BackgroundEffective perioperative fluid therapy is a great consideration.ObjectivesUsing lung ultrasound (LUS), this study evaluated the preference of the conventional and restrictive fluid replacement regimens for their volume impact in pediatric patients undergoing a relatively long procedure with limited volume loss (hypospadias repair).MethodsEighty pediatric patients scheduled for hypospadias repair surgery were enrolled for conventional (CG) or restrictive fluid management groups (RG). The CG obtained Ringer's lactate at the conventional calculated doses, while the RG obtained infusion of Ringer's lactate at a rate of 3 mL/kg/h. B-line numbers in the LUS, recovery score, urine output, blood pressure (BP), heart rate HR, and oxygen saturation (SpO2) were recorded.ResultsAs evidenced by the LUS, RG showed a higher incidence of normal lung morphology with a mean and SD of 1.3 ± 2.2 for B-line numbers, whereas, in CG, they were 3.1 ± 2.2 with a P-value < 0.001. Urine output was 3.2 ± 0.8 and 2.9 ± 0.7 for CG and RG, respectively, with a P-value equal to 0.07. HR, BP, and SpO2 differences between groups were statistically insignificant. The recovery score was higher in RG (5.8 ± 0.4) than in CG (5.1 ± 0.8) at the first postoperative 20 minutes, with a P-value < 0.001.ConclusionsIn lengthy procedures with limited volume loss, using a moderately restrictive regimen is preferred over the conventional intraoperative fluid regimen considering both respiratory dysfunctions and recovery score.

The effect of human amnion epithelial cells on lung development and inflammation in preterm lambs exposed to antenatal inflammation.

Lung inflammation and impaired alveolarization are hallmarks of bronchopulmonary dysplasia (BPD). We hypothesize that human amnion epithelial cells (hAECs) are anti-inflammatory and reduce lung injury in preterm lambs born after antenatal exposure to inflammation. Pregnant ewes received either intra-amniotic lipopolysaccharide (LPS, from E.coli 055:B5; 4mg) or saline (Sal) on day 126 of gestation. Lambs were delivered by cesarean section at 128 d gestation (term ~150 d). Lambs received intravenous hAECs (LPS/hAECs: n = 7; 30x106 cells) or equivalent volumes of saline (LPS/Sal, n = 10; or Sal/Sal, n = 9) immediately after birth. Respiratory support was gradually de-escalated, aimed at early weaning from mechanical ventilation towards unassisted respiration. Lung tissue was collected 1 week after birth. Lung morphology was assessed and mRNA levels for inflammatory mediators were measured. Respiratory support required by LPS/hAEC lambs was not different to Sal/Sal or LPS/Sal lambs. Lung tissue:airspace ratio was lower in the LPS/Sal compared to Sal/Sal lambs (P<0.05), but not LPS/hAEC lambs. LPS/hAEC lambs tended to have increased septation in their lungs versus LPS/Sal (P = 0.08). Expression of inflammatory cytokines was highest in LPS/hAECs lambs. Postnatal administration of a single dose of hAECs stimulates a pulmonary immune response without changing ventilator requirements in preterm lambs born after intrauterine inflammation.

Congenital Deletion of Nedd4-2 in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice.

Recent studies found that expression of NEDD4-2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of Nedd4-2 in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na+ channel (ENaC), TGFβ signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of Nedd4-2 on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of Nedd4-2 in the lung epithelial cells of neonatal doxycycline-induced triple transgenic Nedd4-2fl/fl/CCSP-rtTA2S-M2/LC1 mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP-C trafficking. We found that the congenital deletion of Nedd4-2 caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of Nedd4-2 in lung epithelial cells caused increased expression of Muc5b and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of Nedd4-2 may support studies of the pathogenesis and preclinical development of therapies for chILD.

Physiological Factors Affecting Lung Deposition

Ventilation and mechanics of breathing are an integral part of respiratory physiology that directly affect aerosol transport and deposition in the lung. Although natural breathing pattern varies widely among individuals, breathing pattern is controllable, and by using an appropriate breathing pattern, aerosol deposition can be substantially modified for desired purposes. Effects of breathing pattern have been investigated under carefully controlled inhalation conditions covering a wide range of tidal volumes (VT) and breathing frequencies (f) or respiratory times (T = 1/f). The studies have shown that lung deposition can increase or decrease as much as two times by changing the breathing pattern. Specific functional relationships have been found between lung deposition and breathing pattern parameters such that lung deposition can be estimated for any given breathing pattern. Both VT and T have shown strong effects on lung deposition, but their influence is variable depending on particle size, particularly, ultrafine vs. micron-sized particles. VT is more influential than T for micron-sized particles whereas VT and T are equally influential for ultrafine particles. Although effects of lung morphology are difficult to study systematically, comparison between normals and patients with obstructive airway disease has shown that lung deposition is closely related with the degree of airways obstruction and can be 2-3 times greater in patients with obstructive airway disease compared to normals. Thus, breathing pattern and the status of airways obstruction should be carefully considered in designing aerosol delivery and estimating deposition dose.

Effect of electro-acupuncture at ST 36 on maternal food restriction-induced lung phenotype in rat offspring.

Maternal food restriction (MFR) during pregnancy leads to pulmonary dysplasia in the newborn period and increases susceptibility to diseases, such as asthma and chronic lung disease, later in life. Previous studies have shown that maternal electro-acupuncture (EA) applied to "Zusanli" (ST 36) could prevent the abnormal expression of key lung developmental signaling pathways and improve the lung morphology and function in perinatal nicotine exposed offspring. There is a significant overlap in lung developmental signaling pathways affected by perinatal nicotine exposure and MFR during pregnancy; however, whether maternal EA at ST 36 also blocks the MFR-induced lung phenotype is unknown. Here, we examined the effects of EA applied to maternal ST 36 on lung morphology and function and the expression of key lung developmental signaling pathways, and the hypercorticoid state associated with MFR during pregnancy. These effects were compared with those of metyrapone, an intervention known to block MFR-induced offspring hypercorticoid state and the resultant pulmonary pathology. Like metyrapone, maternal EA at ST 36 blocked the MFR-induced changes in key developmental signaling pathways and protected the MFR-induced changes in lung morphology and function. These results offer a novel and safe, nonpharmacologic approach to prevent MFR-induced pulmonary dysplasia in offspring.

Radiological pattern in ARDS patients: partitioned respiratory mechanics, gas exchange and lung recruitability

BackgroundThe ARDS is characterized by different degrees of impairment in oxygenation and distribution of the lung disease. Two radiological patterns have been described: a focal and a diffuse one. These two patterns could present significant differences both in gas exchange and in the response to a recruitment maneuver. At the present time, it is not known if the focal and the diffuse pattern could be characterized by a difference in the lung and chest wall mechanical characteristics. Our aims were to investigate, at two levels of PEEP, if focal vs. diffuse ARDS patterns could be characterized by different lung CT characteristics, partitioned respiratory mechanics and lung recruitability.MethodsCT patterns were analyzed by two radiologists and were classified as focal or diffuse. The changes from 5 to 15 cmH2O in blood gas analysis and partitioned respiratory mechanics were analyzed. Lung CT scan was performed at 5 and 45 cmH2O of PEEP to evaluate lung recruitability.ResultsOne-hundred and ten patients showed a diffuse pattern, while 58 showed a focal pattern. At 5 cmH2O of PEEP, the driving pressure and the elastance, both the respiratory system and of the lung, were significantly higher in the diffuse pattern compared to the focal (14 [11–16] vs 11 [9–15 cmH2O; 28 [23–34] vs 21 [17–27] cmH2O/L; 22 [17–28] vs 14 [12–19] cmH2O/L). By increasing PEEP, the driving pressure and the respiratory system elastance significantly decreased in diffuse pattern, while they increased or did not change in the focal pattern (Δ15-5: − 1 [− 2 to 1] vs 0 [− 1 to 2]; − 1 [− 4 to 2] vs 1 [− 2 to 5]). At 5 cmH2O of PEEP, the diffuse pattern had a lower lung gas (743 [537–984] vs 1222 [918–1974] mL) and higher lung weight (1618 [1388–2001] vs 1222 [1059–1394] g) compared to focal pattern. The lung recruitability was significantly higher in diffuse compared to focal pattern 21% [13–29] vs 11% [6–16]. Considering the median of lung recruitability of the whole population (16.1%), the recruiters were 65% and 22% in the diffuse and focal pattern, respectively.ConclusionsAn early identification of lung morphology can be useful to choose the ventilatory setting. A diffuse pattern has a better response to the increase of PEEP and to the recruitment maneuver.

Changes in Plasma Soluble Receptor for Advanced Glycation End-Products Are Associated with Survival in Patients with Acute Respiratory Distress Syndrome.

The plasma soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury with prognostic value when measured at baseline in acute respiratory distress syndrome (ARDS). However, whether changes in plasma sRAGE could inform prognosis in ARDS remains unknown. In this secondary analysis of the Lung Imaging for Ventilator Setting in ARDS (LIVE) multicenter randomized controlled trial, which evaluated a personalized ventilation strategy tailored to lung morphology, plasma sRAGE was measured upon study entry (baseline) and on days one, two, three, four and six. The association between changes in plasma sRAGE over time and 90-day survival was evaluated. Higher baseline plasma sRAGE (HR per-one log increment, 1.53; 95% CI, 1.16–2.03; p = 0.003) and an increase in sRAGE over time (HR for each one-log increment in plasma sRAGE per time unit, 1.01; 95% CI, 1.01–1.02; p < 10−3) were both associated with increased 90-day mortality. Each 100-unit increase in the plasma sRAGE level per unit of time increased the risk of death at day 90 by 1% in joint modeling. Plasma sRAGE increased over time when a strategy of maximal alveolar recruitment was applied in patients with focal ARDS. Current findings suggest that the rate of change in plasma sRAGE over time is associated with 90-day survival and could be helpful as a surrogate outcome in ARDS.

Quantifying lung and diaphragm morphology using radiographs in normative pediatric subjects, and predicting CT-derived lung volume.

To quantify the effect of age on two-dimensional (2D) radiographic lung and diaphragm morphology and determine if 2D radiographic lung measurements can be used to estimate computer tomography (CT)-derived lung volume in normative pediatric subjects. Digitally reconstructed radiographs (DRRs) were created using retrospective chest CT scans from 77 pediatric male and female subjects aged birth to 19 years. 2D lung and diaphragm measurements were made on the DRRs using custom MATLAB code, and Spearman correlations and exponential regression equations were used to relate 2D measurements with age. In addition, 3D lung volumes were segmented using CT scans, and power regression equations were fitted to predict each lung's CT-derived volume from 2D lung measurements. The coefficient of determination (R2 ) and standard error of the estimate (SEE) were used to assess the precision of the predictive equations with p < .05 indicating statistical significance. All 2D radiographic lung and diaphragm measurements showed statistically significant positive correlations with age (p < .01), including lung major axis (Spearman rho ≥ 0.90). Precise estimations of CT-derived lung volumes can be made using 2D lung measurements (R2 ≥ 0.95), including lung major axis (R2 ≥ 0.97). The reported pediatric age-specific reference data on 2D lung and diaphragm morphology and growth rates could be clinically used to identify lung and diaphragm pathologies during chest X-ray evaluations. The simple, precise, and clinically adaptable radiographic method for estimating CT-derived lung volumes may be used when pulmonary function tests are not readily available or difficult to perform.

The influence of silicon consumption with drinking water on morphological changes in the lungs of rodents

Currently there is no consensus on the safety effect of silicates presence in drinking water. Known, that inhalation of silicon particles leads to the development of fibrosis in the lungs of laboratory animals, but little is known about how silicon, which enters the body with drinking water, acts on the lungs. We analyzed the lungs of two-month-old non-linear white male rats and two-month-old non-linear white mice: control group (10 rats, 6 mice) received ad libitum bottled drinking water, experimental group (10 rats, 9 mice) received the same water supplemented with sodium metasilicate (Na2SiO3x9H2O,10 mg/liter). After 2 months 3 rats from each group were sacrificed. After 3 months 3 mice from each group were sacrificed and 3 mice that received silicon with drinking water were added to a control group that received water without silicon. The remaining animals were sacrificed 9 months after the start of the experiment. The lungs were isolated immediately after decapitation, fixed in 10% formalin, embedded in paraffin, cut (5 μ), stained with hematoxylin-eosin, and examined under the microscope (Leica DM 2000, Germany). We detected no visible differences in the lung morphology between animal groups (drinking water versus silicon-supplemented water consumption) in rats and mice after two and three months, respectively. After 9 months both experimental groups developed different degrees of fibrosis severity. It was accompanied by the development of emphysema, deformation of the bronchial tree, changes in the state of the blood vessels walls. The number of alveolus in the field of view was decreased, and their diameter was increased, the alveoli fused with each other, the interalveolar septum becomes thinner. Giant Pirogov-Langhans cells become visible, similar to those that appear during the pulmonary tuberculosis. We noticed that in two out of three mice that received silicon for three months, and then received ordinary bottled water for six months, there was a pronounced infiltration of lung tissue with lymphocytes along the bronchial tree. Moreover, after 9 months the body weight was two times less (p < 0.05) in rodents receiving silicon. Such systemic effect of the water-soluble silicon compound was similar for rats and mice. Thus, the daily use of water with the addition of silicon at a concentration of 10mg/l by laboratory rodents negative influence on the morphology of the lungs. The mechanisms of such morphological alterations are most similar to those that cause pathological changes during silicosis.