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Since the 19th century, underwater explosions have posed a significant threat to service members. While there have been attempts to establish injury criteria for the most vulnerable organs, namely the lungs, existing criteria are highly variable due to insufficient human data and the corresponding inability to understand the underlying injury mechanisms. This study presents an experimental characterization of isolated human lung dynamics during simulated exposure to underwater shock waves. We found that the large acoustic impedance at the surface of the lung severely attenuated transmission of the shock wave into the lungs. However, the shock wave initiated large bulk pressure-volume cycles that are distinct from the response of the solid organs under similar loading. These pressure-volume cycles are due to compression of the contained gas, which we modeled with the Rayleigh-Plesset equation. The extent of these lung dynamics was dependent on physical confinement, which in real underwater blast conditions is influenced by factors such as rib cage properties and donned equipment. Findings demonstrate a potential causal mechanism for implosion injuries, which has significant implications for the understanding of primary blast lung injury due to underwater blast exposures., Competing Interests: The authors declare no competing interests., (Copyright: © 2024 Bar-Kochba et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The Incentive Spirometer (IS) increases lung volume and improves gas exchange by visually stimulating patients to take slow, deep breaths. It prevents respiratory complications and treats postoperative atelectasis in patients undergoing abdominal, thoracic, and neurosurgical procedures. Its effectiveness has been validated in studies that support improved lung capacities and volumes in individuals with respiratory complications, postoperative thoracic surgery, upper abdominal surgery, and bariatric surgery. The modified Pachón incentive spirometer (MPIS) is a cost-effective alternative to branded IS. It is crucial to validate whether the MPIS distributes ventilation as effectively as commercial devices do. Ventilation distribution will be measured using electrical impedance tomography., Objective: The aim is to compare the distribution of pulmonary ventilation between the MPIS and another commercial IS in healthy adults using electrical impedance tomography., Methods: A crossover clinical trial is proposed to evaluate the measurement of pulmonary ventilation distribution using EIT in a sample of healthy adults. All participants will use a commercial flow IS and the MPIS, with the order of assignment randomized. This research will use electrical impedance tomography to validate the operation of the MPIS., Conclusions: This study protocol will compare two incentive spirometers' impact on pulmonary ventilation, potentially endorsing the adoption of a cost-effective device to enhance accessibility for targeted populations., Trial Registration: The study was registered in ClinicalTrials.gov (NTC05532748)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mera et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Cathelicidin (also known as LL-37 in humans) is an antimicrobial peptide secreted by epithelial and immune cells and regulated by vitamin D. The immunological roles of cathelicidin make it a putative biomarker to identify individuals at risk for reduced lung function. The objective of this study is to determine potential independent associations between low plasma cathelicidin and longitudinal lung function in current or former smokers without COPD. Methods: In a nested analysis of 308 participants from an observational cohort study, plasma cathelicidin and serum 25-hydroxy-vitamin D measurements were obtained at baseline, years three and five. The independent association between lowest quartile cathelicidin (<35 ng/ml) and forced-expiratory-volume-in-1-second (FEV1) at baseline, six and 18 months from each cathelicidin measurement was assessed with generalized estimating equations after adjusting for age, sex, race, smoking status and intensity. The long-term stability of cathelicidin and relationship with vitamin D was evaluated. Results: The cohort was 91% African-American, mean age 48.6 years, 32% female, and 81% current smokers. Participants with low cathelicidin were more likely to be female and have lower FEV1. Low cathelicidin was not independently associated with baseline FEV1. There was an independent association between low cathelicidin and reduced FEV1 at six months [-72 ml (95% CI, -140 to -8ml); p = 0.027] and 18 months [-103 ml (95% CI, -180 to -27 ml); p = 0.007]. Cathelicidin was stable over time and not correlated with vitamin D level. Conclusion: In current and former smokers with preserved lung function, low cathelicidin is associated with sustained lung function reductions at six and 18 months, suggesting that cathelicidin may be an informative biomarker to predict persistent lung function disparities among at-risk individuals. [ABSTRACT FROM AUTHOR]

Pneumonia remains a global health threat, in part due to expanding categories of susceptible individuals and increasing prevalence of antibiotic resistant pathogens. However, therapeutic stimulation of the lungs’ mucosal defenses by inhaled exposure to a synergistic combination of Toll-like receptor (TLR) agonists known as Pam2-ODN promotes mouse survival of pneumonia caused by a wide array of pathogens. This inducible resistance to pneumonia relies on intact lung epithelial TLR signaling, and inducible protection against viral pathogens has recently been shown to require increased production of epithelial reactive oxygen species (ROS) from multiple epithelial ROS generators. To determine whether similar mechanisms contribute to inducible antibacterial responses, the current work investigates the role of ROS in therapeutically-stimulated protection against Pseudomonas aerugnosa challenges. Inhaled Pam2-ODN treatment one day before infection prevented hemorrhagic lung cytotoxicity and mouse death in a manner that correlated with reduction in bacterial burden. The bacterial killing effect of Pam2-ODN was recapitulated in isolated mouse and human lung epithelial cells, and the protection correlated with inducible epithelial generation of ROS. Scavenging or targeted blockade of ROS production from either dual oxidase or mitochondrial sources resulted in near complete loss of Pam2-ODN-induced bacterial killing, whereas deficiency of induced antimicrobial peptides had little effect. These findings support a central role for multisource epithelial ROS in inducible resistance against a bacterial pathogen and provide mechanistic insights into means to protect vulnerable patients against lethal infections. [ABSTRACT FROM AUTHOR]

Initiation of treatment during the pre-symptomatic phase of Yersinia pestis (Y. pestis) infection is particularly critical. The rapid proliferation of Y. pestis typically couples with the manifestation of common flu-like early symptoms that often misguides the medical intervention. Our study used African green monkeys (AGM) that did not exhibit clear clinical symptoms for nearly two days after intranasal challenge with Y. pestis and succumbed within a day after showing the first signs of clinical symptoms. The lung, and mediastinal and submandibular lymph nodes (LN) accumulated significant Y. pestis colonization immediately after the intranasal challenge. Hence, organ-specific molecular investigations are deemed to be the key to elucidating mechanisms of the initial host response. Our previous study focused on the whole blood of AGM, and we found early perturbations in the ubiquitin-microtubule-mediated host defense. Altered expression of the genes present in ubiquitin and microtubule networks indicated an early suppression of these networks in the submandibular lymph nodes. In concert, the upstream toll-like receptor signaling and downstream NFκB signaling were inhibited at the multi-omics level. The inflammatory response was suppressed in the lungs, submandibular lymph nodes and mediastinal lymph nodes. We posited a causal chain of molecular mechanisms that indicated Y. pestis was probably able to impair host-mediated proteolysis activities and evade autophagosome capture by dysregulating both ubiquitin and microtubule networks in submandibular lymph nodes. Targeting these networks in a submandibular LN-specific and time-resolved fashion could be essential for development of the next generation therapeutics for pneumonic plague. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum stress (ER stress) has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a disease of progressive fibrosis and respiratory failure. ER stress activates a signaling pathway called the unfolded protein response (UPR) that either restores homeostasis or promotes apoptosis. The bifunctional kinase/RNase IRE1α is a UPR sensor/effector that promotes apoptosis if ER stress remains high and irremediable (i.e., a “terminal” UPR). Using multiple small molecule inhibitors against IRE1α, we show that ER stress-induced apoptosis of murine alveolar epithelial cells can be mitigated in vitro. In vivo, we show that bleomycin exposure to murine lungs causes early ER stress to activate IRE1α and the terminal UPR prior to development of pulmonary fibrosis. Small-molecule IRE1α kinase-inhibiting RNase attenuators (KIRAs) that we developed were used to evaluate the contribution of IRE1α activation to bleomycin-induced pulmonary fibrosis. One such KIRA—KIRA7—provided systemically to mice at the time of bleomycin exposure decreases terminal UPR signaling and prevents lung fibrosis. Administration of KIRA7 14 days after bleomycin exposure even promoted the reversal of established fibrosis. Finally, we show that KIRA8, a nanomolar-potent, monoselective KIRA compound derived from a completely different scaffold than KIRA7, likewise promoted reversal of established fibrosis. These results demonstrate that IRE1α may be a promising target in pulmonary fibrosis and that kinase inhibitors of IRE1α may eventually be developed into efficacious anti-fibrotic drugs. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the dosimetric accuracy of respiratory gated volumetric modulated arc therapy (VMAT) for lung stereotactic body radiation therapy (SBRT) under simulation conditions similar to the actual clinical situation using patient-specific lung phantoms and realistic target movements. Methods: Six heterogeneous lung phantoms were fabricated using a 3D-printer (3DISON, ROKIT, Seoul, Korea) to be dosimetrically equivalent to actual target regions of lung SBRT cases treated via gated VMAT. They were designed to move realistically via a motion device (QUASAR, Modus Medical Devices, Canada). Using the lung phantoms and a homogeneous phantom (model 500–3315, Modus Medical Devices), film dosimetry was performed with and without respiratory gating for VMAT delivery (TrueBeam STx; Varian Medical Systems, Palo Alto, CA, USA). The measured results were analyzed with the gamma passing rates (GPRs) of 2%/1 mm criteria, by comparing with the calculated dose via the AXB and AAA algorithms of the Eclipse Treatment Planning System (version 10.0.28; Varian Medical Systems). Results: GPRs were greater than the acceptance criteria 80% for all film measurements with the stationary and homogeneous phantoms in conventional QAs. Regardless of the heterogeneity of phantoms, there were no significant differences (p > 0.05) in GPRs obtained with and without target motions; the statistical significance (p = 0.031) was presented between both algorithms under the utilization of heterogeneous phantoms. Conclusions: Dosimetric verification with heterogeneous patient-specific lung phantoms could be successfully implemented as the evaluation method for gated VMAT delivery. In addition, it could be dosimetrically confirmed that the AXB algorithm improved the dose calculation accuracy under patient-specific simulations using 3D printed lung phantoms. [ABSTRACT FROM AUTHOR]

Subgroups of patients with severe asthma are insensitive to inhaled corticosteroids and require novel therapies on top of standard medical care. IL-13 is considered one of the key cytokines in the asthma pathogenesis, however, the effect of IL-13 was mostly studied in rodents. This study aimed to assess IL-13 effect in human lung tissue for the development of targeted therapy approaches such as inhibition of soluble IL-13 or its receptor IL-4Rα subunit. Precision-cut lung slices (PCLS) were prepared from lungs of rodents, non-human primates (NHP) and humans. Direct effect of IL-13 on human lung tissue was observed on inflammation, induction of mucin5AC, and airway constriction induced by methacholine and visualized by videomicroscopy. Anti-inflammatory treatment was evaluated by co-incubation of IL-13 with increasing concentrations of IL-13/IL-13 receptor inhibitors. IL-13 induced a two-fold increase in mucin5AC secretion in human bronchial tissue. Additionally, IL-13 induced release of proinflammatory cytokines eotaxin-3 and TARC in human PCLS. Anti-inflammatory treatment with four different inhibitors acting either on the IL-13 ligand itself (anti-IL-13 antibody, similar to Lebrikizumab) or the IL-4Rα chain of the IL-13/IL-4 receptor complex (anti-IL-4Rα #1, similar to AMG 317, and #2, similar to REGN668) and #3 PRS-060 (a novel anticalin directed against this receptor) could significantly attenuate IL-13 induced inflammation. Contrary to this, IL-13 did not induce airway hyperresponsiveness (AHR) in human and NHP PCLS, although it was effective in rodent PCLS. Overall, this study demonstrates that IL-13 stimulation induces production of mucus and biomarkers of allergic inflammation in human lung tissue ex-vivo but no airway hyperresponsiveness. The results of this study show a more distinct efficacy than known from animals models and a clear discrepancy in AHR induction. Moreover, it allows a translational approach in inhibitor profiling in human lung tissue. [ABSTRACT FROM AUTHOR]

Endothelial cells have been considered the central regulators of cytokine storm in the respiratory system during influenza virus infection. Studies have found that elevated autophagy could be an essential component of viral pathogenesis in influenza infection. However, few studies have been performed to examine whether autophagy occurs in human pulmonary endothelial cells (HPMECs). In addition, specific mechanisms about how inflammatory responses are regulated in the endothelial cells remain unclear. We hypothesized that infection of influenza A viruses subtypes H1N1 and H9N2 triggered autophagy, which played an important role in the induction of proinflammatory cytokines, both in human lung epithelial A549 cells and in HPMECs. In this report, we showed our evidence that blockage of autophagy significantly inhibited influenza virus-induced proinflammatory responses and suppressed viral replication. Our data indicated that the inhibition of the cytokine response and viral replication was affected by increasing the expression of endothelial sphingosine 1-phosphate receptor 1 (S1PR1), which might be through the regulation of NF-κB signaling. Overexpression of S1PR1 decreased p65 phosphorylation and translocation into the nucleus. Furthermore, we demonstrated that S1PR1 stimulation inhibited Akt-mTOR signaling, which might contribute to activation of autophagy in HPMECs. Thus, our study provides knowledge crucial to better understanding novel mechanisms underlying the S1PR1-mediated attenuation of cytokine amplification in the pulmonary system during influenza virus infection. [ABSTRACT FROM AUTHOR]

Accurate estimation of motion field in respiration-correlated 4DCT images, is a precondition for the analysis of patient-specific breathing dynamics and subsequent image-supported treatment planning. However, the lung motion estimation often suffers from the sliding motion. In this paper, a novel lung motion method based on the non-rigid registration of point clouds is proposed, and the tangent-plane distance is used to represent the distance term, which describes the difference between two point clouds. Local affine transformation model is used to express the non-rigid deformation of the lung motion. The final objective function is expressed in the Frobenius norm formation, and matrix optimization scheme is carried out to find out the optimal transformation parameters that minimize the objective function. A key advantage of our proposed method is that it alleviates the requirement that the source point cloud and the reference point cloud should be in one-to-one corresponding relationship, and the requirement is difficult to be satisfied in practical application. Furthermore, the proposed method takes the sliding motion of the lung into consideration and improves the registration accuracy by reducing the constraint of the motion along the tangent direction. Non-rigid registration experiments are carried out to validate the performance of the proposed method using popi-model data. The results demonstrate that the proposed method outperforms the traditional method with about 20% accuracy increase. [ABSTRACT FROM AUTHOR]

Despite the important functions of PPARγ in various cell types of the lung, PPARγ-deficiency in club cells induces only mild emphysema. Peroxisomes are distributed in a similar way as PPARγ in the lung and are mainly enriched in club and AECII cells. To date, the effects of PPARγ-deficiency on the overall peroxisomal compartment and its metabolic alterations in pulmonary club cells are unknown. Therefore, we characterized wild-type and club cell-specific PPARγ knockout-mice lungs and used C22 cells to investigate the peroxisomal compartment and its metabolic roles in the distal airway epithelium by means of 1) double-immunofluorescence labelling for peroxisomal proteins, 2) laser-assisted microdissection of the bronchiolar epithelium and subsequent qRT-PCR, 3) siRNA-transfection of PPARγand PPRE dual-luciferase reporter activity in C22 cells, 4) PPARg inhibition by GW9662, 5) GC-MS based lipid analysis. Our results reveal elevated levels of fatty acids, increased expression of PPARα and PPRE activity, a strong overall upregulation of the peroxisomal compartment and its associated gene expression (biogenesis, α-oxidation, β-oxidation, and plasmalogens) in PPARγ-deficient club cells. Interestingly, catalase was significantly increased and mistargeted into the cytoplasm, suggestive for oxidative stress by the PPARγ-deficiency in club cells. Taken together, PPARα-mediated metabolic induction and proliferation of peroxisomes via a PPRE-dependent mechanism could compensate PPARγ-deficiency in club cells. [ABSTRACT FROM AUTHOR]

This study examines differential effects of immersion, elevated oxygen partial pressure, and exercise on pulmonary function after series of five daily six-hour dives at 130 kPa (1.3 ATA), with 18 hours between dives. Five cohorts of 10 to 14 divers participated. The exposure phases were resting while breathing O2 or air in the water (“wetO2”, “wetAir”) or O2 in the hyperbaric chamber (“dryO2”), and exercise in the water while breathing O2 or air (“wetO2X”, “wetAirX”). Respiratory symptoms were recorded during and after each dive, and pulmonary function (forced flow-volume) was measured twice at baseline before diving, after each dive both immediately and on the following morning, and three days post diving (“Day+3”). The incidences of symptoms and of flow volume changes from baseline greater than normal limits (“ΔFV”) were assessed, as were mean ΔFV. The parameters examined were forced vital capacity (FVC), forced expired volume in 1 second (FEV1), and forced expired flow from 25% to 75% volume expired (FEF25–75). The phases ranked from greatest to least fraction of diver-days with symptoms were wetO2X (56%) > dryO2 (42%) > wetO2 (13%) > [wetAir (2%) or wetAirX (1%)] (p<0.05). FEV1 and FEF25–75 were depressed in the morning following wetO2 and wetO2X and on Day+3 after and wetO2X, but increased immediately following each wetAirX dive. O2 exposures caused symptoms and ΔFV suggestive of pulmonary oxygen toxicity,exacerbated by exercise. Indices of small airway function showed late (17-hour) post-O2 exposure deficits, but, particularly with exercise, improvement was evident early after exposure with or without O2. FEF25–75 and FEV1 remained depressed on Day+3 after wetO2 and wetO2X. [ABSTRACT FROM AUTHOR]

Recent findings show that cerium oxide (CeO2) nanoparticles may undergo in vivo-induced size transformation with the formation of smaller particles that could result in a higher translocation following pulmonary exposure compared to virtually insoluble particles, like titanium dioxide (TiO2). Therefore, we compared liver deposition of CeO2 and TiO2 nanoparticles of similar primary sizes 1, 28 or 180 days after intratracheal instillation of 162 μg of NPs in female C57BL/6 mice. Mice exposed to 162 μg CeO2 or TiO2 nanoparticles by intravenous injection or oral gavage were included as reference groups to assess the amount of NPs that reach the liver bypassing the lungs and the translocation of NPs from the gastrointestinal tract to the liver, respectively. Pulmonary deposited CeO2 nanoparticles were detected in the liver 28 and 180 days post-exposure and TiO2 nanoparticles 180 days post-exposure as determined by darkfield imaging and by the quantification of Ce and Ti mass concentration by inductively coupled plasma-mass spectrometry (ICP-MS). Ce and Ti concentrations increased over time and 180 days post-exposure the translocation to the liver was 2.87 ± 3.37% and 1.24 ± 1.98% of the initial pulmonary dose, respectively. Single particle ICP-MS showed that the size of CeO2 nanoparticles in both lung and liver tissue decreased over time. No nanoparticles were detected in the liver following oral gavage. Our results suggest that pulmonary deposited CeO2 and TiO2 nanoparticles translocate to the liver with similar calculated translocation rates despite their different chemical composition and shape. The observed particle size distributions of CeO2 nanoparticles indicate in vivo processing over time both in lung and liver. The fact that no particles were detected in the liver following oral exposure showed that direct translocation of nanoparticles from lung to the systemic circulation was the most important route of translocation for pulmonary deposited particles. [ABSTRACT FROM AUTHOR]

Nasal intermittent positive pressure ventilation (NIPPV) holds great potential as a primary ventilation support method for Respiratory Distress Syndrome (RDS). The use of NIPPV may also be of great value combined with minimally invasive surfactant delivery. Our aim was to implement an in vivo model of RDS, which can be managed with different non-invasive ventilation (NIV) strategies, including non-synchronized NIPPV, synchronized NIPPV (SNIPPV), and nasal continuous positive airway pressure (NCPAP). Forty-two surfactant-depleted adult rabbits were allocated in six different groups: three groups of animals were treated with only NIV for three hours (NIPPV, SNIPPV, and NCPAP groups), while three other groups were treated with surfactant (SF) followed by NIV (NIPPV+SF, SNIPPV+SF, and NCPAP+SF groups). Arterial gas exchange, ventilation indices, and dynamic compliance were assessed. Post-mortem the lungs were sampled for histological evaluation. Surfactant depletion was successfully achieved by repeated broncho-alveolar lavages (BALs). After BALs, all animals developed a moderate respiratory distress, which could not be reverted by merely applying NIV. Conversely, surfactant administration followed by NIV induced a rapid improvement of arterial oxygenation in all surfactant-treated groups. Breath synchronization was associated with a significantly better response in terms of gas exchange and dynamic compliance compared to non-synchronized NIPPV, showing also the lowest injury scores after histological assessment. The proposed in vivo model of surfactant deficiency was successfully managed with NCPAP, NIPPV, or SNIPPV; this model resembles a moderate respiratory distress and it is suitable for the preclinical testing of less invasive surfactant administration techniques. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the impact of postnatal dexamethasone treatment on the neonatal unit on the school age lung function of very prematurely born children. Children born prior to 29 weeks of gestational age had been entered into a randomised trial of two methods of neonatal ventilation (United Kingdom Oscillation Study). They had comprehensive lung function measurements at 11 to 14 years of age. One hundred and seventy-nine children born at a mean gestational age of 26.9 (range 23–28) weeks were assessed at 11 to 14 years; 50 had received postnatal dexamethasone. Forced expiratory flow at 75% (FEF75), 50%, 25% and 25–75% of the expired vital capacity, forced expiratory volume in one second, peak expiratory flow and forced vital capacity and lung volumes including total lung capacity and residual volume were assessed. Lung function outcomes were compared between children who had and had not been exposed to dexamethasone after adjustment for neonatal factors using linear mixed effects regression. After adjustment for confounders all the mean spirometry results were between 0.38 and 0.87 standard deviations lower in those exposed to dexamethasone compared to the unexposed. For example, the mean FEF75 z-score was 0.53 lower (95% CI 0.21 to 0.85). The mean lung function was lower as the number of courses of dexamethasone increased. In conclusion, postnatal dexamethasone exposure was associated with lower mean lung function at school age in children born extremely prematurely. Our results suggest the larger the cumulative dose the greater the adverse effect on lung function at follow-up. [ABSTRACT FROM AUTHOR]

Introduction: The pro-inflammatory status of cystic fibrosis (CF) patients promotes pulmonary colonization with opportunist and pathogenic bacteria, which is favored by a sticky mucus. Oral supplementation with (n-3) long chain polyunsaturated fatty acids (LC-PUFA) has shown anti-inflammatory effects. The aim of this study was to demonstrate the positive effects of a long-term diet enriched in (n-3) LC-PUFA on the lungs of Cftr F508del mice. Materials and methods: Breeding CftrΔF508del/+ mice received a control diet or a diet enriched in (n-3) LC-PUFA for 5 weeks before mating, gestation and lactation. After weaning, the offspring were given the same diet as their mother until post-natal day 60. The effects of (n-3) LC-PUFA supplementation on the lungs were evaluated in homozygous Cftr F508del mice and their wild-type littermates after acute lung inflammation induced by Pseudomonas aeruginosa lipopolysaccharide (LPS) inhalation. Results: (n-3) LC-PUFA enrichment of mothers contributes to enrichment of mammary milk and cell membrane of suckling pups. Cftr F508del mice exhibited growth retardation and lung damage with collapsed alveoli, hyperplasia of bronchial epithelial cells and inflammatory cell infiltration. The (n-3) LC-PUFA diet corrected the growth delay of Cftr F508del mice and decreased hyperplasia of bronchial epithelial cells. Besides decreasing metaplasia of Club cells after LPS inhalation, (n-3) LC-PUFA modulated lung inflammation and restricted lung damage. Conclusion: Long-term (n-3) LC-PUFA supplementation shows moderate benefits to the lungs of Cftr F508del mice. [ABSTRACT FROM AUTHOR]

The objective of this study was to explore trajectories of lung function decline with age in the general population, and to study the effect of sociodemographic and life style related risk factors, in particular smoking and BMI. For this purpose, we used data from the Doetinchem Cohort Study (DCS) of men and women, selected randomly from the general population and aged 20–59 years at inclusion in 1987–1991, and followed until the present. Participants in the DCS are assessed every five years. Spirometry has been performed as part of this assessment from 1994 onwards. Participants were included in this study if spirometric measurement of FEV1, which in this study was the main parameter of interest, was acceptable and reproducible on at least one measurement round, leading to the inclusion of 5727 individuals (3008 females). Statistical analysis revealed three typical trajectories. The majority of participants followed a trajectory that closely adhered to the Global Lung Initiative Reference values (94.9% of men and 96.4% of women). Two other trajectories showed a more pronounced decline. Smoking and the presence of respiratory complaints were the best predictors of a trajectory with stronger decline. A greater BMI over the follow-up period was associated with a more unfavorable FEV1 course both in men (β = -0.027 (SD = 0.002); P < 0.001) and in women (β = -0.008 (SD = 0.001); P < 0.001). Smokers at baseline who quit the habit during follow-up, showed smaller decline in FEV1 in comparison to persistent smokers, independent of BMI change (In men β = -0.074 (SD = 0.020); P < 0.001. In women β = -0.277 (SD = 0.068); P < 0.001). In conclusion, three typical trajectories of age-related FEV1 decline could be distinguished. Change in the lifestyle related risk factors, BMI and smoking, significantly impact aging-related decline of lung function. Identifying deviant trajectories may help in early recognition of those at risk of a diagnosis of lung disease later in life. [ABSTRACT FROM AUTHOR]

Introduction: Pulmonary rehabilitation, including aerobic exercise and strength training, improves function, such as spirometric indices, in lung disease. However, we found spirometry did not correlate with physical activity (PA) in healthy adolescents (Smith ERJ: 42(4), 2016). To address whether muscle strength did, we measured these adolescents’ handgrip strength and correlated it with spirometry. Methods: In 1846 non-smoking, non-asthmatic Germans (age 15.2 years, 47% male), we modeled spirometric indices as functions of handgrip strength by linear regression in each sex, corrected for factors including age, height, and lean body mass. Results: Handgrip averaged 35.4 (SD 7.3) kg in boys, 26.6 (4.2) in girls. Spirometric volumes and flows increased linearly with handgrip. In boys each kg handgrip was associated with about 28 mL greater FEV1 and FVC; 60 mL/sec faster PEF; and 38 mL/sec faster FEF2575. Effects were 10–30% smaller in girls (all p<0.0001) and stable when Z-scores for spirometry and grip were modeled, after further correction for environment and/or other exposures, and consistent across stages of puberty. Conclusions: Grip strength was associated with spirometry in a cohort of healthy adolescents whose PA was not. Thus, research into PA’s relationship with lung function should consider strength as well as total PA. Strength training may benefit healthy lungs; interventions are needed to prove causality. [ABSTRACT FROM AUTHOR]

Activation of ERK1/2 implies the phosphorylation of tyrosine (pTyr) and threonine (pThr) by MEK1/2; both reactions were thought to be cytoplasmic, promoting ERK to reach the nucleus where it activates several transcription factors. In addition, H2O2 concentrations are known to modulate ERK intracellular translocation, which impacts on cellular proliferation. In this context, the objective of this work was to study the sequence of ERK phosphorylation under two redox conditions and to analyze a putative mitochondrial contribution to this process, in LP07 murine lung cells. A time-course of H2O2 administration was used and ERK phosphorylation was analyzed in cytosol, mitochondria and nuclei. At 1μM H2O2, a proliferative redox stimulus, immunoblot revealed a fast and transient increase in cytosol pTyr and a sustained increase in mitochondrial pTyr content. The detection for pThr/pTyrERK (2pERK) showed in cytosol a marked increase at 5 minutes with a fast dephosphorylation after that time, for both H2O2 concentrations. However, at 50 μM H2O2, an anti-proliferative condition, 2pERK was gradually retained in mitochondria. Interestingly, these results were confirmed by in vivo experiments using mice treated with a highly oxidizing agent [H2O2]. By the use of two ERK2 mutant constructions, where Tyr and Thr were replaced by alanine, we confirmed that 2pERK relied almost completely on pThr183. Confocal microscopy confirmed ERK subcellular distribution dependence on the incidence of cytosolic pTyr and mitochondrial pThr at 1μM H2O2. This work shows for the first time, both in vitro and in vivo, an ERK cycle involving a cross-talk between cytosol and mitochondria phosphorylation events, which may play a significant role in cell cycle progression, proliferation or differentiation under two different redox conditions. [ABSTRACT FROM AUTHOR]

Obesity, particularly abdominal obesity, might be related to decreased lung function. We aimed to investigate whether obesity indices are associated with forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) in asymptomatic non-smokers through a longitudinal cohort study. The clinical records of 1,145 subjects (428 males, mean age 52.3 years) who underwent a comprehensive health evaluation, including spirometry and abdominal fat computed tomography, at least twice between 2007 and 2014 were retrospectively reviewed and analysed. The mean follow-up period was 1,105 days (over 3.0 years). The baseline total adipose tissue (TAT) and visceral adipose tissue (VAT) were inversely associated with both FEV1 and FVC (P < 0.05). The longitudinal study found that increasing TAT and VAT were significantly related to decreasing FEV1 and FVC, whereas decreasing TAT and VAT were related to increasing FEV1 and FVC in both males and females (P < 0.05). The strength and consistency of these associations were clearer in males than in females. However, no significant relationship was found between changes in subcutaneous adipose tissue and changes in lung function. In Korean non-smokers, longitudinal changes in abdominal visceral fat were found to be inversely related to changes in lung function over a mean period of three years. These results suggest that decreasing abdominal visceral obesity could increase lung function despite ageing. [ABSTRACT FROM AUTHOR]

Rationale and objectives: The oral cavity is united with the airways, and thus poor oral health may affect respiratory health. However, data on the interaction of periodontal and respiratory health is limited. We aimed to evaluate whether periodontal health status, assessed by the Community Periodontal Index (CPI), was related to lung function among young and middle-aged adults in two Norwegian cohorts. Methods: Periodontal health status and lung function were measured among 656 participants in the Norwegian part of the European Community Respiratory Health Survey (ECHRS III) and the RHINESSA offspring study. Each participant was given a CPI-index from 0 to 4 where higher values reflect poorer periodontal status. The association between CPI and lung function was estimated with linear regression adjusting for age, gender, smoking, body mass index, exercise, education, use of antibiotics, inhaled medication and corrected for clustering within families. Main results: Participants with CPI 3–4 had significantly lower FEV1/FVC ratio compared to participants with CPI 0, b (95% CI) = -0.032 (-0.055, -0.009). Poorer periodontal health was associated with a significant decrease in the FEV1/FVC ratio with an adjusted regression coefficient for linear trend b (95% CI) = -0.009 (-0.015, -0.004) per unit increase in CPI. This negative association remained when excluding asthmatics and smokers (-0.014 (-0.022, -0,006)). Conclusions: Poorer periodontal health was associated with increasing airways obstruction in a relatively young, healthy population. The oral cavity is united with the airways and our findings indicate an opportunity to influence respiratory health by improving oral health. [ABSTRACT FROM AUTHOR]

Introduction: In Parkinson’s disease (PD), respiratory insufficiency (including functional and muscle disorders) can impact dysarthria and swallowing. Most studies of this topic have been performed retrospectively in populations of patients with advanced PD. The objective of the present study was to characterize lung function (under off-drug conditions) in early-stage PD patients at baseline and then again two years later. Methods: Forty-one early-stage PD patients (mean ± SD age: 61.7 ± 7.7; mean ± SD disease duration: 1.9 ± 1.7 years) were prospectively enrolled and compared with 36 age-matched healthy controls. Neurological evaluations and pulmonary function testing were performed in the off-drug condition at the inclusion visit and then two years later. Results: Pulmonary function testing did not reveal any restrictive or obstructive disorders; at baseline, inspiratory muscle weakness was the only abnormality observed in the PD group (in 53.7% of the patients, vs. 25% in controls; p = 0.0105). The PD patients had a lower mean maximal inspiratory mouth pressure than controls and a lower sniff nasal inspiratory pressure. Two years after the initiation of chronic treatment with antiparkinsonian medications, the maximal inspiratory mouth pressure and the sniff nasal inspiratory pressure tended to be higher. Lastly, overall motor outcomes were not significantly worse in patients with inspiratory muscle weakness than in patients without inspiratory muscle weakness. Conclusion: Inspiratory muscle weakness seems to be common in patients with early-stage PD, and was seen to be stable over a two-year period. Additional long-term follow-up studies are required to specify the impact of this new feature of PD. [ABSTRACT FROM AUTHOR]

Background: Asthma is a chronic inflammatory respiratory disorder associated with reduced lung function and poor quality of life. The condition is also associated with poor self-rated health, a major predictor of objective health trajectories. Of biological correlates to self-rated health, evidence suggests a role for inflammatory cytokines and related sickness behaviours. However, this is mainly based on cross-sectional data, and the relation has not been investigated in patients with chronic inflammatory conditions. Objective: To investigate inflammatory cytokines, lung function, sickness behaviour and asthma-related quality of life as determinants of self-rated health in patients with asthma, and to investigate if these variables co-vary over time. Methods: Plasma cytokines (IL-5, IL-6), lung function (FEV1), sickness behaviour, asthma-related quality of life and self-rated health were assessed in 181 patients with allergic asthma aged 18–64 years in a one-year longitudinal study. Mixed effect regression models and Spearman’s correlation were performed to analyse the associations between repeated measurements. Results: More sickness behaviour and poorer asthma-related quality of life were associated with poorer self-rated health (p’s<0.001). In men, both low and high levels of interleukin (IL)-6 and poorer lung function were related with poorer self-rated health (p’s<0.05). Over the year, improved asthma-related quality of life was associated with better self-rated health (Spearman’s rho = -0.34 women,-0.36 men, p’s<0.01). Further, if sickness behaviour decreased, self-rated health improved, but only in women (Rho = -0.21, p<0.05). Increased FEV1 in men was associated with an increase in IL-6 (Rho = 0.24, p<0.05) as well as improved self-rated health (Rho = -0.21, p<0.05) and asthma-related quality of life (Rho = 0.29, p<0.01) over the year. Conclusion: The study highlights the importance of subjectively perceived sickness behaviour and asthma-related quality of life together with lung function as determinants of self-rated health in asthmatic patients. The importance of inflammatory activation for patient reported outcomes in chronic inflammatory conditions need further investigation. [ABSTRACT FROM AUTHOR]

Background: Increased airway smooth muscle is observed in large and small airways in asthma. Semi-quantitative estimates suggest that cells containing alpha smooth muscle actin (α-SMA) are also increased in the lung parenchyma. This study quantified and characterized α-SMA positive cells (α-SMA+) in the lung parenchyma of non-asthmatic and asthmatic individuals. Methods: Post-mortem sections of peripheral lung from cases of fatal asthma (FA), persons with asthma dying of non-respiratory causes (NFA) and non-asthma control subjects (NAC) were stained for α-SMA, quantified using point-counting and normalised to alveolar basement membrane length and interstitial area. Results: α-SMA+ fractional area was increased in alveolar parenchyma in both FA (14.7 ± 2.8% of tissue area) and NFA (13.0 ± 1.2%), compared with NAC (7.4 ± 2.4%), p < 0.05 The difference was greater in upper lobes compared with lower lobes (p < 0.01) in both asthma groups. Similar changes were observed in alveolar ducts and alveolar walls. The electron microscopic features of the α-SMA+ cells were characteristic of myofibroblasts. Conclusions: We conclude that in asthma there is a marked increase in α-SMA+ myofibroblasts in the lung parenchyma. The physiologic consequences of this increase are unknown. [ABSTRACT FROM AUTHOR]

Systemic sclerosis-related interstitial lung disease (SSc-ILD) is the leading cause of death in SSc. In this study, we aimed to describe the baseline severity and evolution of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) in patients with SSc-ILD and to assess the baseline clinical, biological and high-resolution CT scan (HRCT) predictors of this evolution. Baseline and serial FVC and DLCO were collected in 75 SSc-ILD patients followed during 6.4±4.2 years (n = 557 individual data). FVC and DLCO evolution was modelled using a linear mixed model with random effect. During follow-up, FVC was stable while DLCO significantly decreased (-1.5±0.3%/year (p<0.0001). Baseline NYHA functional class III/IV, extensive SSc-ILD on HRCT and DLCO<80% were associated with a lower baseline FVC. Absence of digital ulcers extensive SSc-ILD, and FVC<80% and were associated with a lower baseline DLCO. Presence or history of digital ulcers and presence of pulmonary hypertension at baseline or during follow-up were associated with a faster decline of DLCO overtime. Neither age, gender, subtype of SSc nor specificity of autoantibodies were associated with baseline severity or outcome of lung function tests. In this SSc-ILD population, FVC was therefore stable while DLCO significantly declined over time. ILD extension was associated with baseline FVC and DLCO but not with their evolution. Presence or history of digital ulcers and pulmonary hypertension were predictors of a faster decline of DLCO over time. [ABSTRACT FROM AUTHOR]

Pulmonary responses to the air pollutant, ozone, are increased in obesity. Both obesity and ozone cause changes in systemic metabolism. Consequently, we examined the impact of ozone on the lung metabolomes of obese and lean mice. Lean wildtype and obese db/db mice were exposed to acute ozone (2 ppm for 3 h) or air. 24 hours later, the lungs were excised, flushed with PBS to remove blood and analyzed via liquid-chromatography or gas-chromatography coupled to mass spectrometry for metabolites. Both obesity and ozone caused changes in the lung metabolome. Of 321 compounds identified, 101 were significantly impacted by obesity in air-exposed mice. These included biochemicals related to carbohydrate and lipid metabolism, which were each increased in lungs of obese versus lean mice. These metabolite changes may be of functional importance given the signaling capacity of these moieties. Ozone differentially affected the lung metabolome in obese versus lean mice. For example, almost all phosphocholine-containing lysolipids were significantly reduced in lean mice, but this effect was attenuated in obese mice. Glutathione metabolism was also differentially affected by ozone in obese and lean mice. Finally, the lung metabolome indicated a role for the microbiome in the effects of both obesity and ozone: all measured bacterial/mammalian co-metabolites were significantly affected by obesity and/or ozone. Thus, metabolic derangements in obesity appear to impact the response to ozone. [ABSTRACT FROM AUTHOR]

The receptor for advanced glycation endproducts (RAGE) is highly expressed in the lung but its physiological functions in this organ is still not completely understood. To determine the contribution of RAGE to physiological functions of the lung, we analyzed pulmonary mechanics and structure of wildtype and RAGE deficient (RAGE-/-) mice. RAGE deficiency spontaneously resulted in a loss of lung structure shown by an increased mean chord length, increased respiratory system compliance, decreased respiratory system elastance and increased concentrations of serum protein albumin in bronchoalveolar lavage fluids. Pulmonary expression of RAGE was mainly localized on alveolar epithelial cells and alveolar macrophages. Primary murine alveolar epithelial cells isolated from RAGE-/- mice revealed an altered differentiation and defective barrier formation under in vitro conditions. Stimulation of interferone-y (IFNy)-activated alveolar macrophages deficient for RAGE with Toll-like receptor (TLR) ligands resulted in significantly decreased release of proinflammatory cytokines and chemokines. Exposure to chronic cigarette smoke did not affect emphysema-like changes in lung parenchyma in RAGE-/- mice. Acute cigarette smoke exposure revealed a modified inflammatory response in RAGE-/- mice that was characterized by an influx of macrophages and a decreased keratinocyte-derived chemokine (KC) release. Our data suggest that RAGE regulates the differentiation of alveolar epithelial cells and impacts on the development and maintenance of pulmonary structure. In cigarette smoke-induced lung pathology, RAGE mediates inflammation that contributes to lung damage. [ABSTRACT FROM AUTHOR]

Objectives: Hemoglobin vesicles (HbVs) function as a red blood cell (RBC) substitute and are composed of purified hemoglobin encapsulated in a phospholipid bilayer membrane. The performance of HbVs as a substitute for RBC transfusions was examined in a mouse model of pneumonectomy following acute 40% exchange-transfusion with HbVs. Methods: Before performing left pneumonectomies, 40% of the blood volume of mice was replaced with a) lactated Ringer’s solution (control), b) 5% recombinant human serum albumin (rHSA), c) mouse RBCs shed in rHSA (mRBCs/rHSA), or d) HbV suspended in rHSA (HbV/rHSA). We compared postoperative a) survival, b) functional recovery, and c) histopathological, immunohistochemical, and inflammatory responses among the study groups. Results: In the HbV/rHSA and mRBC/rHSA groups, all mice survived ≥7 days after pneumonectomy, whereas 100% of the control mice died within a few h and 50% of mice in the rHSA group died within 24 h after pneumonectomy. Immunohistochemical staining for hypoxia-inducible factor-1α showed that hepatic and renal hypoxic injuries were prominently mitigated by HbV and mRBCs. Conclusions: The oxygen-carrying performance of HbV was similar to that of mRBCs, even with impaired lung functions following pneumonectomy. HbV infusion did not interfere with the recovery from surgical injury. In the near future, HbVs could be used clinically as a substitute for the perioperative transfusion of RBCs, when or where donated RBCs are not immediately available. [ABSTRACT FROM AUTHOR]

Considering the limited number of available lung donors, lung bioengineering using whole lung scaffolds has been proposed as an alternative approach to obtain lungs suitable for transplantation. However, some decellularization protocols can cause alterations on the structure, composition, or mechanical properties of the lung extracellular matrix. Therefore, the aim of this study was to compare the acellular lung mechanical properties when using two different routes through the trachea and pulmonary artery for the decellularization process. This study was performed by using the lungs excised from 30 healthy male C57BL/6 mice, which were divided into 3 groups: tracheal decellularization (TDG), perfusion decellularization (PDG), and control groups (CG). Both decellularized groups were subjected to decellularization protocol with a solution of 1% sodium dodecyl sulfate. The behaviour of mechanical properties of the acellular lungs was measured after decellularization process. Static (Est) and dynamic (Edyn) elastances were obtained by the end-inspiratory occlusion method. TDG and PDG showed reduced Est and Edyn elastances after lung decellularization. Scanning electron microscopy showed no structural changes after lung decellularization of the TDG and PDG. In conclusion, was demonstrated that there is no significant difference in the behaviour of mechanical properties and extracellular matrix of the decellularized lungs by using two different routes through the trachea and pulmonary artery. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was to investigate the influence of lung density changes as well as bone proximity on the attenuation correction of lung standardized uptake values (SUVs). Methods and materials: 15 patients with mostly oncologic diseases were examined in 18F-FDG-PET/CT and subsequently in a fully integrated PET/MR scanner. From each PET dataset acquired in PET/MR, four different PET reconstructions were computed using different attenuation maps (μ-maps): i) CT-based μ-map (gold standard); ii) CT-based μ-map in which the linear attenuation coefficients (LAC) of the lung tissue was replaced by the lung LAC from the MR-based segmentation method; iii) based on reconstruction ii), the LAC of bone structures was additionally replaced with the LAC from the MR-based segmentation method; iv) the vendor-provided MR-based μ-map (segmentation-based method). Those steps were performed using MATLAB. CT Hounsfield units (HU) and SUVmean was acquired in different levels and regions of the lung. Relative differences between the differently corrected PETs were computed. Results: Compared to the gold standard, reconstruction ii), iii) and iv) led to a relative underestimation of SUV in the posterior regions of -9.0%, -13.4% and -14.0%, respectively. Anterior and middle regions were less affected with an overestimation of about 6–8% in reconstructions ii)–iv). Conclusion: It could be shown that both, differences in lung density and the vicinity of bone tissue in the μ-map may have an influence on SUV, mostly affecting the posterior lung regions. [ABSTRACT FROM AUTHOR]

Objective: Pseudomonas aeruginosa has been suggested as a major determinant of poor pulmonary outcomes in cystic fibrosis (CF), although other factors play a role. Our objective was to investigate the association of early childhood Pseudomonas infection on differences in lung function in adolescence with CF. Methods: Two populations of subjects with CF were studied: from the Gene Modifier Study (GMS), 346 F508del homozygotes with severe vs. mild adolescent lung disease, and from the Colorado Newborn Screen Study (NBS) 172 subjects diagnosed with CF by newborn screening. Associations of Pseudomonas infection and lung function in early childhood with lung function in adolescence were investigated using multivariate linear regression analyses. Results: Among GMS subjects, those with severe adolescent lung disease had worse lung function in childhood (FEV1 25 percentage points lower) compared to subjects with mild adolescent lung disease, regardless of early childhood Pseudomonas status. Among NBS subjects, those with lowest adolescent lung function had significantly lower early childhood lung function and faster rate of decline in FEV1 than subjects with highest adolescent lung function; early Pseudomonas infection was not associated with rate of FEV1 decline. The strongest predictor of adolescent lung function was early childhood lung function. Subjects with a higher percentage of cultures positive for Pseudomonas before age 6 or a lower BMI at 2–4 years old also had lower adolescent lung function, though these associations were not as strong as with early childhood lung function. Conclusions: In separate analyses of two distinct populations of subjects with CF, we found a strong correlation between lower lung function in early childhood and adolescence, regardless of early childhood Pseudomonas status. Factors in addition to early Pseudomonas infection have a strong impact on lung function in early childhood in CF. Further exploration may identify novel underlying genetic or environmental factors that predispose children with CF to early loss of lung function. [ABSTRACT FROM AUTHOR]

Although hyperlipidemia is common in COPD, its relationship to comorbidities, risk factors and lung function in COPD has not been studied in detail. Using the baseline data of the COSYCONET cohort we addressed this question. Data from 1746 COPD patients (GOLD stage 1–4; mean age 64.6 y, mean FEV1%pred 57%) were evaluated, focusing on the comorbidities hyperlipidemia, diabetes and cardiovascular complex (CVC; including arterial hypertension, cardiac failure, ischemic heart disease). Risk factors comprised age, gender, BMI, and packyears of smoking. The results of linear and logistic regression analyses were implemented into a path analysis model describing the multiple relationships between parameters. Hyperlipidemia (prevalence 42.9%) was associated with lower intrathoracic gas volume (ITGV) and higher forced expiratory volume in 1 second (FEV1) when adjusting for its multiple relationships to risk factors and other comorbidities. These findings were robust in various statistical analyses. The associations between comorbidities and risk factors were in accordance with previous findings, thereby underlining the validity of our data. In conclusion, hyperlipidemia was associated with less hyperinflation and airway obstruction in patients with COPD. This surprising result might be due to different COPD phenotypes in these patients or related to effects of medication. [ABSTRACT FROM AUTHOR]

Objective: Oxygen enhanced pulmonary MRI is a promising modality for functional lung studies and has been applied to a wide range of pulmonary conditions. The purpose of this study was to characterize the oxygen enhancement effect in the lungs of healthy, never-smokers, in light of a previously established relationship between oxygen enhancement and diffusing capacity of carbon monoxide in the lung (DL,CO) in patients with lung disease. Methods: In 30 healthy never-smoking volunteers, an inversion recovery with gradient echo read-out (Snapshot-FLASH) was used to quantify the difference in longitudinal relaxation rate, while breathing air and 100% oxygen, ΔR1, at 1.5 Tesla. Measurements were performed under multiple tidal inspiration breath-holds. Results: In single parameter linear models, ΔR1 exhibit a significant correlation with age (p = 0.003) and BMI (p = 0.0004), but not DL,CO (p = 0.33). Stepwise linear regression of ΔR1 yields an optimized model including an age-BMI interaction term. Conclusion: In this healthy, never-smoking cohort, age and BMI are both predictors of the change in MRI longitudinal relaxation rate when breathing oxygen. However, DL,CO does not show a significant correlation with the oxygen enhancement. This is possibly because oxygen transfer in the lung is not diffusion limited at rest in healthy individuals. This work stresses the importance of using a physiological model to understand results from oxygen enhanced MRI. [ABSTRACT FROM AUTHOR]

Peak oxygen uptake (VO2peak) is an indicator of cardiovascular health and a useful tool for risk stratification. Direct measurement of VO2peak is resource-demanding and may be contraindicated. There exist several non-exercise models to estimate VO2peak that utilize easily obtainable health parameters, but none of them includes lung function measures or hemoglobin concentrations. We aimed to test whether addition of these parameters could improve prediction of VO2peak compared to an established model that includes age, waist circumference, self-reported physical activity and resting heart rate. We included 1431 subjects aged 69-77 years that completed a laboratory test of VO2peak, spirometry, and a gas diffusion test. Prediction models for VO2peak were developed with multiple linear regression, and goodness of fit was evaluated. Forced expiratory volume in one second (FEV1), diffusing capacity of the lung for carbon monoxide and blood hemoglobin concentration significantly improved the ability of the established model to predict VO2peak. The explained variance of the model increased from 31% to 48% for men and from 32% to 38% for women (p<0.001). FEV1, diffusing capacity of the lungs for carbon monoxide and hemoglobin concentration substantially improved the accuracy of VO2peak prediction when added to an established model in an elderly population. [ABSTRACT FROM AUTHOR]

T1 maps have been shown to yield useful diagnostic information on lung function in patients with chronic obstructive pulmonary disease (COPD) and asthma, both for native T1 and ΔT1, the relative reduction while breathing pure oxygen. As parameter quantification is particularly interesting for longitudinal studies, the purpose of this work was both to examine the reproducibility of lung T1 mapping and to compare T1 found in COPD and asthma patients using IRSnapShotFLASH embedded in a full MRI protocol. 12 asthma and 12 COPD patients (site 1) and further 15 COPD patients (site 2) were examined on two consecutive days. In each patient, T1 maps were acquired in 8 single breath-hold slices, breathing first room air, then pure oxygen. Maps were partitioned into 12 regions each to calculate average values. In asthma patients, the average T1, RA = 1206ms (room air) was reduced to T1, O 2 = 1141ms under oxygen conditions (ΔT1 = 5.3%, p < 5⋅10−4), while in COPD patients both native T1, RA = 1125ms was significantly shorter (p < 10−3) and the relative reduction to T1, O 2 = 1081ms on average ΔT1 = 4.2%(p < 10−5). On the second day, with T1, RA = 1186ms in asthma and T1, RA = 1097ms in COPD, observed values were slightly shorter on average in all patient groups. ΔT1 reduction was the least repeatable parameter and varied from day to day by up to 23% in individual asthma and 30% in COPD patients. While for both patient groups T1 was below the values reported for healthy subjects, the T1 and ΔT1 found in asthmatics lies between that of the COPD group and reported values for healthy subjects, suggesting a higher blood volume fraction and better ventilation. However, it could be demonstrated that lung T1 quantification is subject to notable inter-examination variability, which here can be attributed both to remaining contrast agent from the previous day and the increased dependency of lung T1 on perfusion and thus current lung state. [ABSTRACT FROM AUTHOR]

Nasal continuous positive airway pressure (nCPAP) is a widely accepted technique of non-invasive respiratory support in spontaneously-breathing premature infants with respiratory distress syndrome (RDS). Surfactant administration techniques compatible with nCPAP ventilation strategy are actively investigated. Our aim is to set up and validate a respiratory distress animal model that can be managed on nCPAP suitable for surfactant administration techniques studies. Surfactant depletion was induced by bronchoalveolar lavages (BALs) on 18 adult rabbits. Full depletion was assessed by surfactant component analysis on the BALs samples. Animals were randomized into two groups: Control group (nCPAP only) and InSurE group, consisting of a bolus of surfactant (Poractant alfa, 200 mg/kg) followed by nCPAP. Arterial blood gases were monitored until animal sacrifice, 3 hours post treatment. Lung mechanics were evaluated just before and after BALs, at the time of treatment, and at the end of the procedure. Surfactant phospholipids and protein analysis as well as surface tension measurements on sequential BALs confirmed the efficacy of the surfactant depletion procedure. The InSurE group showed a significant improvement of blood oxygenation and lung mechanics. On the contrary, no signs of recovery were appreciated in animals treated with just nCPAP. The surfactant-depleted adult rabbit RDS model proved to be a valuable and efficient preclinical tool for mimicking the clinical scenario of preterm infants affected by mild/moderate RDS who spontaneously breathe and do not require mechanical ventilation. This population is of particular interest as potential target for the non-invasive administration of surfactant. [ABSTRACT FROM AUTHOR]

A quantitative description of the morphology of lung structure is essential prior to any form of predictive modeling of ventilation or aerosol deposition implemented within the lung. The human lung is a very complex organ, with airway structures that span two orders of magnitude and having a multitude of interfaces between air, tissue and blood. As such, current medical imaging protocols cannot provide medical practitioners and researchers with in-vivo knowledge of deeper lung structures. In this work a detailed algorithm for the generation of an individualized 3D deterministic model of the conducting part of the human tracheo-bronchial tree is described. Distinct initial conditions were obtained from the high-resolution computed tomography (HRCT) images of seven healthy volunteers. The algorithm developed is fractal in nature and is implemented as a self-similar space sub-division procedure. The expansion process utilizes physiologically realistic relationships and thresholds to produce an anatomically consistent human airway tree. The model was validated through extensive statistical analysis of the results and comparison of the most common morphological features with previously published morphometric studies and other equivalent models. The resulting trees were shown to be in good agreement with published human lung geometric characteristics and can be used to study, among other things, structure-function relationships in simulation studies. [ABSTRACT FROM AUTHOR]

Ex vivo lung perfusion (EVLP) is a promising procedure for evaluation, reconditioning, and treatment of marginal lungs before transplantation. Small animal models can contribute to improve clinical development of this technique and represent a substantial platform for bio-molecular investigations. However, to accomplish this purpose, EVLP models must sustain a prolonged reperfusion without pharmacological interventions. Currently available protocols only partly satisfy this need. The aim of the present research was accomplishment and optimization of a reproducible model for a protracted rat EVLP in the absence of anti-inflammatory treatment. A 180 min, uninjured and untreated perfusion was achieved through a stepwise implementation of the protocol. Flow rate, temperature, and tidal volume were gradually increased during the initial reperfusion phase to reduce hemodynamic and oxidative stress. Low flow rate combined with open atrium and protective ventilation strategy were applied to prevent lung damage. The videos enclosed show management of the most critical technical steps. The stability and reproducibility of the present procedure were confirmed by lung function evaluation and edema assessment. The meticulous description of the protocol provided in this paper can enable other laboratories to reproduce it effortlessly, supporting research in the EVLP field. [ABSTRACT FROM AUTHOR]

Background: Sex and age strongly influence the pathophysiology of human lungs, but scarce information is available about their effects on pulmonary gene expression. Methods: We followed a discovery-validation strategy to identify sex- and age-related transcriptional differences in lung. Results: We identified transcriptional profiles significantly associated with sex (215 genes; FDR < 0.05) and age at surgery (217 genes) in non-involved lung tissue resected from 284 lung adenocarcinoma patients. When these profiles were tested in three independent series of non-tumor lung tissue from an additional 1,111 patients, we validated the association with sex and age for 25 and 22 genes, respectively. Among the 17 sex-biased genes mapping on chromosome X, 16 have been reported to escape X-chromosome inactivation in other tissues or cells, suggesting that this mechanism influences lung transcription too. Our 22 age-related genes partially overlap with genes modulated by age in other tissues, suggesting that the aging process has similar consequences on gene expression in different organs. Finally, seven genes whose expression was modulated by sex in non-tumor lung tissue, but no age-related gene, were also validated using publicly available data from 990 lung adenocarcinoma samples, suggesting that the physiological regulatory mechanisms are only partially active in neoplastic tissue. Conclusions: Gene expression in non-tumor lung tissue is modulated by both sex and age. These findings represent a validated starting point for research on the molecular mechanisms underlying the observed differences in the course of lung diseases among men and women of different ages. [ABSTRACT FROM AUTHOR]

Smoking influences the immune system in different ways and, hypothetically, effects on pulmonary effector and regulatory T cells emerge as potentially detrimental. Therefore, we characterized the frequencies and characteristics of CD4+ and CD8+ T cell subsets in the blood and lungs of young tobacco smokers. Bronchoalveolar lavage (BAL) and peripheral blood were obtained from healthy moderate smokers (n = 18; 2±24 pack-years) and neversmokers (n = 15), all with normal lung function. Cells were stimulated ex vivo and key intracellular cytokines (IFNλ, IL-17, IL-10 and TNFα) and transcription factors (Foxp3, T-bet and Helios) were analyzed using flow cytometry. Our results indicate that smoking is associated with a decline in lung IL-17+ CD4+ T cells, increased IFNλ+ CD8+ T cells and these alterations relate to the history of daily cigarette consumption. There is an increased fraction of Foxp3+ regulatory T cells being Helios- in the lungs of smokers. Cytokine production is mainly confined to the Helios-T cells, both in regulatory and effector subsets. Moreover, we detected a decline of Helios+Foxp3- postulated regulatory CD8+ T cells in smokers. These alterations in the immune system are likely to increase risk for infection and may have implications for autoimmune processes initiated in the lungs among tobacco smokers. [ABSTRACT FROM AUTHOR]

Objective: We compared the longitudinal course of post-bronchodilator Forced Expiratory Volume in 1 second (pFEV1) over a 10-year period in subjects with spontaneous healed pulmonary tuberculosis (SHPTB) with that in normal subjects. Methods: We prospectively investigated 339 subjects with SHPTB and 3211 normal subjects. pFEV1 values measured biannually over 10 years were analyzed using mixed effects model. Results: At baseline, there were no differences in gender, smoking amount, and mean height, except mean age (50.0 ± 8.1 VS. 48.1 ± 7.3, P< 0.001) between the SHPTB and normal group. 52% of the 339 participants with SHPTB and 56% of the 3211 normal participants participated till the end of study. According to the final model, the SHPTB group showed significantly larger decrease in the average pFEV1 over the time than the normal group (P< 0.001) adjusted for gender, age, height, smoking pack years, and time effects. Especially, the interaction effect between time and group was statistically significant (P = 0.036). Conclusion: The average lung function in terms of pFEV1 decreases faster in subjects with SHPTB than in normal individuals over time. [ABSTRACT FROM AUTHOR]

Background: Overweight/obesity has been reported to worsen pulmonary function (PF). This study aimed to examine the association between PF and several body composition (BC) measures in two population-based cohorts. Methods: We performed a cross-sectional analysis of individuals aged 18 and 30 years from two Pelotas Birth Cohorts in southern Brazil. PF was assessed by spirometry. Body measures that were collected included body mass index, waist circumference, skinfold thickness, percentages of total and segmented (trunk, arms and legs) fat mass (FM) and total fat-free mass (FFM). FM and FFM were measured by air-displacement plethysmography (BODPOD) and by dual-energy x-ray absorptiometry (DXA). Associations were verified through linear regressions stratified by sex, and adjusted for weight, height, skin color, and socioeconomic, behavioral, and perinatal variables. Results: A total of 7347 individuals were included in the analyses (3438 and 3909 at 30 and 18 years, respectively). Most BC measures showed a significant positive association between PF and FFM, and a negative association with FM. For each additional percentage point of FM, measured by BOD POD, the forced vital capacity regression coefficient adjusted by height, weight and skin color, at 18 years, was −33 mL (95% CI −38, −29) and −26 mL (95% CI −30, −22), and −30 mL (95% CI −35, −25) and −19 mL (95% CI −23, −14) at 30 years, in men and women, respectively. All the BOD POD regression coefficients for FFM were the same as for the FM coefficients, but in a positive trend (p<0.001 for all associations). Conclusions: All measures that distinguish FM from FFM (skinfold thickness–FM estimation–BOD POD, total and segmental DXA measures–FM and FFM proportions) showed negative trends in the association of FM with PF for both ages and sexes. On the other hand, FFM showed a positive association with PF. [ABSTRACT FROM AUTHOR]

Background: Plasminogen activator inhibitor-1 (PAI-1) is induced in airways by virus and may mediate asthmatic airway remodeling. We sought to evaluate if genetic variants and early life lower respiratory infections jointly affect asthma risk. Methods: We included Latino children, adolescents, and young adults aged 8–21 years (1736 subjects with physician-diagnosed asthma and 1747 healthy controls) from five U.S. centers and Puerto Rico after excluding subjects with incomplete clinical or genetic data. We evaluated the independent and joint effects of a PAI-1 gain of function polymorphism and bronchiolitis / Respiratory Syncytial Virus (RSV) or other lower respiratory infections (LRI) within the first 2 years of life on asthma risk, asthma exacerbations and lung function. Results: RSV infection (OR 9.9, 95%CI 4.9–20.2) and other LRI (OR 9.1, 95%CI 7.2–11.5) were independently associated with asthma, but PAI-1 genotype was not. There were joint effects on asthma risk for both genotype-RSV (OR 17.7, 95% CI 6.3–50.2) and genotype-LRI (OR 11.7, 95% CI 8.8–16.4). A joint effect of genotype-RSV resulted in a 3.1-fold increased risk for recurrent asthma hospitalizations. In genotype-respiratory infection joint effect analysis, FEV1% predicted and FEV1/FVC % predicted were further reduced in the genotype-LRI group (β -2.1, 95% CI -4.0 to -0.2; β -2.0, 95% CI -3.1 to -0.8 respectively). Similarly, lower FEV1% predicted was noted in genotype-RSV group (β -3.1, 95% CI -6.1 to -0.2) with a trend for lower FEV1/FVC % predicted. Conclusions: A genetic variant of PAI-1 together with early life LRI such as RSV bronchiolitis is associated with an increased risk of asthma, morbidity, and reduced lung function in this Latino population. [ABSTRACT FROM AUTHOR]

We previously observed greater ozone-induced lung function decrements in obese than non-obese women. Animal models suggest that obesity enhances ozone-induced airway reactivity and inflammation. In a controlled exposure study, we compared the acute effect of randomized 0.4ppm ozone and air exposures (2 h with intermittent light exercise) in obese (N = 20) (30

Availability of sophisticated statistical modelling for developing robust reference equations has improved interpretation of lung function results. In 2012, the Global Lung function Initiative(GLI) published the first global all-age, multi-ethnic reference equations for spirometry but these lacked equations for those originating from the Indian subcontinent (South-Asians). The aims of this study were to assess the extent to which existing GLI-ethnic adjustments might fit South-Asian paediatric spirometry data, assess any similarities and discrepancies between South-Asian datasets and explore the feasibility of deriving a suitable South-Asian GLI-adjustment. Methods: Spirometry datasets from South-Asian children were collated from four centres in India and five within the UK. Records with transcription errors, missing values for height or spirometry, and implausible values were excluded(n = 110). Results: Following exclusions, cross-sectional data were available from 8,124 children (56.3% male; 5–17 years). When compared with GLI-predicted values from White Europeans, forced expired volume in 1s (FEV1) and forced vital capacity (FVC) in South-Asian children were on average 15% lower, ranging from 4–19% between centres. By contrast, proportional reductions in FEV1 and FVC within all but two datasets meant that the FEV1/FVC ratio remained independent of ethnicity. The ‘GLI-Other’ equation fitted data from North India reasonably well while ‘GLI-Black’ equations provided a better approximation for South-Asian data than the ‘GLI-White’ equation. However, marked discrepancies in the mean lung function z-scores between centres especially when examined according to socio-economic conditions precluded derivation of a single South-Asian GLI-adjustment. Conclusion: Until improved and more robust prediction equations can be derived, we recommend the use of ‘GLI-Black’ equations for interpreting most South-Asian data, although ‘GLI-Other’ may be more appropriate for North Indian data. Prospective data collection using standardised protocols to explore potential sources of variation due to socio-economic circumstances, secular changes in growth/predictors of lung function and ethnicities within the South-Asian classification are urgently required. [ABSTRACT FROM AUTHOR]

Glucose-6-phosphate dehydrogenase (G6PD) provides the reducing agent NADPH to meet the cellular needs for reductive biosynthesis and the maintenance of redox homeostasis. G6PD-deficient cells experience a high level of oxidative stress and an increased susceptibility to viral infections. Cyclooxygenase-2 (COX-2) is a key mediator in the regulation of viral replication and inflammatory response. In the current study, the role of G6PD on the inflammatory response was determined in both scramble control and G6PD-knockdown (G6PD-kd) A549 cells upon tumor necrosis factor-α (TNF-α) stimulation. A decreased expression pattern of induced COX-2 and reduced production of downstream PGE2 occurred upon TNF-α stimulation in G6PD-kd A549 cells compared with scramble control A549 cells. TNF-α-induced antiviral activity revealed that decreased COX-2 expression enhanced the susceptibility to coronavirus 229E infection in G6PD-kd A549 cells and was a result of the decreased phosphorylation levels of MAPK (p38 and ERK1/2) and NF-κB. The impaired inflammatory response in G6PD-kd A549 cells was found to be mediated through NADPH oxidase (NOX) signaling as elucidated by cell pretreatment with a NOX2-siRNA or NOX inhibitor, diphenyleneiodonium chloride (DPI). In addition, NOX activity with TNF-α treatment in G6PD-kd A549 cells was not up-regulated and was coupled with a decrease in NOX subunit expression at the transcriptional level, implying that TNF-α-mediated NOX signaling requires the participation of G6PD. Together, these data suggest that G6PD deficiency affects the cellular inflammatory response and the decreased TNF-α-mediated antiviral response in G6PD-kd A549 cells is a result of dysregulated NOX/MAPK/NF-κB/COX-2 signaling. [ABSTRACT FROM AUTHOR]

Background: Natural surfactant preparations, commonly isolated from porcine or bovine lungs, are used to treat respiratory distress syndrome in preterm infants. Besides biophysical effectiveness, several studies have documented additional immunomodulatory properties. Within the near future, synthetic surfactant preparations may be a promising alternative. CHF5633 is a new generation reconstituted synthetic surfactant preparation with defined composition, containing dipalmitoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylglycerol and synthetic analogs of surfactant protein (SP-) B and SP-C. While its biophysical effectiveness has been demonstrated in vitro and in vivo, possible immunomodulatory abilities are currently unknown. Aim: The aim of the current study was to define a potential impact of CHF5633 and its single components on pro- and anti-inflammatory cytokine responses in human CD4+ lymphocytes. Methods: Purified human CD4+ T cells were activated using anti CD3/CD28 antibodies and exposed to CHF5633, its components, or to the well-known animal-derived surfactant Poractant alfa (Curosurf®). Proliferative response and cell viability were assessed using flow cytometry and a methylthiazolyldiphenyltetrazolium bromide colorimetric assay. The mRNA expression of IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 was measured by quantitative PCR, while intracellular protein expression was assessed by means of flow cytometry. Results: Neither CHF5633 nor any of its phospholipid components with or without SP-B or SP-C analogs had any influence on proliferative ability and viability of CD4+ lymphocytes under the given conditions. IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 mRNA as well as IFNγ, IL-2, IL-4 and IL-10 protein levels were unaffected in both non-activated and activated CD4+ lymphocytes after exposure to CHF5633 or its constituents compared to non-exposed controls. However, in comparison to Curosurf®, expression levels of anti-inflammatory IL-4 and IL-10 mRNA were significantly increased in CHF5633 exposed CD4+ lymphocytes. Conclusion: For the first time, the immunomodulatory capacity of CHF5633 on CD4+ lymphocytes was evaluated. CHF5633 did not show any cytotoxicity on CD4+ cells. Moreover, our in vitro data indicate that CHF5633 does not exert unintended pro-inflammatory effects on non-activated and activated CD4+ T cells. As far as anti-inflammatory cytokines are concerned, it might lack an overall reductive ability in comparison to animal-derived surfactants, potentially leaving pro- and anti-inflammatory cytokine response in balance. [ABSTRACT FROM AUTHOR]

Granzyme A, a serine protease expressed in the granules of cytotoxic T and Natural Killer cells, is involved in the generation of pro-inflammatory cytokines by macrophages. Granzyme A has been described to induce in macrophages in vitro the activation of pro-inflammatory pathways that impair intracellular mycobacterial replication. In the present study, we explored the physiological relevance of Granzyme A in the control of pulmonary Mycobacterium tuberculosis infection in vivo. Our results show that, even though Granzyme A is expressed by cytotoxic cells from mouse lungs during pulmonary infection, its deficiency in knockout mice does not have an effect in the control of M. tuberculosis infection. In addition our findings indicate that absence of Granzyme A does not affect the protection conferred by the live-attenuated M. tuberculosis vaccine MTBVAC. Altogether, our findings are in apparent contradiction with previously published in vitro results and suggest that Granzyme A does not have a crucial role in vivo in the protective response to tuberculosis. [ABSTRACT FROM AUTHOR]

Background: Although several computer-aided computed tomography (CT) analysis methods have been reported to objectively assess the disease severity and progression of idiopathic pulmonary fibrosis (IPF), it is unclear which method is most practical. A universal severity classification system has not yet been adopted for IPF. Objective: The purpose of this study was to test the correlation between quantitative-CT indices and lung physiology variables and to determine the ability of such indices to predict disease severity in IPF. Methods: A total of 27 IPF patients showing radiological UIP pattern on high-resolution (HR) CT were retrospectively enrolled. Staging of IPF was performed according to two classification systems: the Japanese and GAP (gender, age, and physiology) staging systems. CT images were assessed using a commercially available CT imaging analysis workstation, and the whole-lung mean CT value (MCT), the normally attenuated lung volume as defined from −950 HU to −701 Hounsfield unit (NL), the volume of the whole lung (WL), and the percentage of NL to WL (NL%), were calculated. Results: CT indices (MCT, WL, and NL) closely correlated with lung physiology variables. Among them, NL strongly correlated with forced vital capacity (FVC) (r = 0.92, P <0.0001). NL% showed a large area under the receiver operating characteristic curve for detecting patients in the moderate or advanced stages of IPF. Multivariable logistic regression analyses showed that NL% is significantly more useful than the percentages of predicted FVC and predicted diffusing capacity of the lungs for carbon monoxide (Japanese stage II/III/IV [odds ratio, 0.73; 95% confidence intervals (CI), 0.48 to 0.92; P < 0.01]; III/IV [odds ratio. 0.80; 95% CI 0.59 to 0.96; P < 0.01]; GAP stage II/III [odds ratio, 0.79; 95% CI, 0.56 to 0.97; P < 0.05]). Conclusion: The measurement of NL% by threshold-based volumetric CT analysis may help improve IPF staging. [ABSTRACT FROM AUTHOR]

The lung changes functionally and structurally with aging. However, age-related effects on the extracellular matrix (ECM) and corresponding effects on lung cell behavior are not well understood. We hypothesized that ECM from aged animals would induce aging-related phenotypic changes in healthy inoculated cells. Decellularized whole organ scaffolds provide a powerful model for examining how ECM cues affect cell phenotype. The effects of age on ECM composition in both native and decellularized mouse lungs were assessed as was the effect of young vs old acellular ECM on human bronchial epithelial cells (hBECs) and lung fibroblasts (hLFs). Native aged (1 year) lungs demonstrated decreased expression of laminins α3 and α4, elastin and fibronectin, and elevated collagen, compared to young (3 week) lungs. Proteomic analyses of decellularized ECM demonstrated similar findings, and decellularized aged lung ECM contained less diversity in structural proteins compared to young ECM. When seeded in old ECM, hBECs and hLFs demonstrated lower gene expression of laminins α3 and α4, respectively, as compared to young ECM, paralleling the laminin deficiency of aged ECM. ECM changes appear to be important factors in potentiating aging-related phenotypes and may provide clues to mechanisms that allow for aging-related lung diseases. [ABSTRACT FROM AUTHOR]