Visceral pleura mechanics: Characterization of human, pig, and rat lung material properties.

Pulmonary air leaks are amongst the most common complications in lung surgery. Lung sealants are applied to the organ surface and need to synchronously stretch with the visceral pleura, the layer of tissue which encompasses the lung parenchymal tissue. These adhesives are commonly tested on pig and rat lungs, but applied to human lungs. However, the unknown mechanics of human lung visceral pleura undermines the clinical translatability of such animal-tested sealants and the absence of how pig and rat lung visceral pleura compare to human tissues is necessary to address. Here we quantify the biaxial planar tensile mechanics of visceral pleura from healthy transplant-eligible and smoker human lungs for the first time, and further compare the material behaviors to pig and rat lung visceral pleura. Initial and final stiffness moduli, maximum stress, low-to-high strain transition, and stress relaxation are analyzed and compared between and within groups, further considering regional and directional dependencies. Visceral pleura tissue from all species behave isotropically, and pig and human visceral pleura exhibits regional heterogeneity (i.e. upper versus lower lobe differences). We find that pig visceral pleura exhibits similar initial stiffness moduli and regional trends compared to human visceral pleura, suggesting pig tissue may serve as a viable animal model candidate for lung sealant testing. The outcomes and mechanical characterization of these scarce tissues enables future development of biomimetic lung sealants for improved surgical applications. STATEMENT OF SIGNIFICANCE: Surgical lung sealants must synchronously deform with the underlying tissue and with each breath to minimize post-operative air leaks, which remain the most frequent complications of pulmonary intervention. These adhesives are often tested on pig and rat lungs, but applied to humans; however, the material properties of human lung visceral pleura were previously unexplored. Here, for the first time, the mechanics of human visceral pleura tissue are investigated, further contrasting rarely acquired donated lungs from healthy and smoking individuals, and additionally, comparing biaxial planar material characterizations to animal models often employed for pulmonary sealant development. This fundamental material characterization addresses key hindrances in the advancement of biomimetic sealants and evaluates the translatability of animal model experiments for clinical applications.

A Critical Analysis of the CFD-DEM Simulation of Pharmaceutical Aerosols Deposition in Upper Intra-Thoracic Airways: Considerations on Aerosol Transport and Deposition.

The reliability and accuracy of numerical models and computer simulations to study aerosol deposition in the human respiratory system is investigated for a patient-specific tracheobronchial tree geometry. A computational fluid dynamics (CFD) model coupled with discrete elements methods (DEM) is used to predict the transport and deposition of the aerosol. The results are compared to experimental and numerical data available in the literature to study and quantify the impact of the modeling parameters and numerical assumptions. Even if the total deposition compares very well with the reference data, it is clear from the present work how local deposition results can depend significantly upon spatial discretization and boundary conditions adopted to represent the respiratory act. The modeling of turbulent fluctuations in the airflow is also found to impact the local deposition and, to a minor extent, the flow characteristics at the inlet of the computational domain. Using the CFD-DEM model, it was also possible to calculate the airflow and particles splitting at bifurcations, which were found to depart from the assumption of being equally distributed among branches adopted by some of the simplified deposition models. The results thus suggest the need for further studies towards improving the quantitative prediction of aerosol transport and deposition in the human airways.

A critical analysis of the CFD-DEM simulation of pharmaceutical aerosols deposition in upper intra-thoracic airways: Considerations on air flow.

A well-corroborated numerical methodology ensuring reproducibility in the modeling of pharmaceutical aerosols deposition in the respiratory system via CFD-DEM simulations within the RANS framework is currently missing. Often, inadequately clarified assumptions and approximations and the lack of evidences on their quantitative impact on the simulated deposition phenomenology, make a direct comparison among the different theoretical studies and the limited number of experiments a very challenging task. Here, with the ultimate goal of providing a critical analysis of some crucial computational aspects of aerosols deposition, we address the issues of velocity fluctuations propagation in the upper intra-thoracic airways and of the persistence of secondary flows using the SimInhale reference benchmark. We complement the investigation by describing how methodologies used to drive the flow through a truncated lung model may affect numerical results and how small discrepancies are observed in velocity profiles when comparing simulations based on different meshing strategies.

Human lung simulants subjected to underwater explosions - An experimental investigation.

An experimental investigation was performed on human lung simulants to evaluate their response to an underwater explosive blast. The artificial lungs were instrumented with sensors to record changes in the internal pressure and strains for a specimen with and without a surrounding ribcage. The lungs were to-scale models representative of a 50th-percentile male. The experiments were performed using 65.5 mg of explosive charge placed 0.5 m from the lungs in an 8,200-liter water tank. The tank was instrumented with blast transducers and high-speed cameras to measure the pressure from the explosive charge and record the lung deformation history through high-speed images and digital image correlation. Results showed a significantly delayed response to the underwater blast due to the lungs' inertia. In addition, the lung response was indifferent to its orientation relative to the shock direction. The lungs initially contracted after the underwater shock and then expanded, showing a 50% change in relative volume, from minimum to maximum volume, over a 7 ms duration. Results and observations qualitatively relate to the types of injuries observed during preexisting case studies.

NaV1.7 channels are expressed in the lower airways of the human respiratory tract.

NaV channels expression have been reported in upper airways and tracheal smooth muscle cells controlling the generation and propagation of action potentials in the respiratory tract sensory neurons, but information about the presence of these proteins in the bronchioalveolar structures in human lungs was missing. The main objective covered in this work was to determine whether the NaV1.7 channels are expressed in lower airways, and to identify the cellular identities expressing these proteins. We detected high levels of the mRNA coding for NaV1.7 channels in isolated lung fibroblasts obtained from both normal lungs, and fibrotic lungs of patients with respiratory diseases. The protein was detected with two different antibodies in the bronchioalveolar tissue, alveolar endothelium, and capillary endothelium, in normal and pathologic lungs. These evidences are useful in the dissection of molecular mechanisms of pulmonary pathologies, and lead to consider the NaV1.7 channels as potential therapeutic targets for the treatment of pulmonary diseases.

Presence, enzymatic activity, and subcellular localization of paraoxonases 1, 2, and 3 in human lung tissues.

AIMS: The human paraoxonases family (PONs) includes three calcium-dependent esterases: PON1, PON2, and PON3. The presence of PONs mRNA in human lungs is known, however, their enzymatic activity and subcellular localization have not been sufficiently explored. MAIN METHODS: In this work, the presence of PONs in human lung tissues, at both mRNA and protein levels, was confirmed by Real-Time RT-PCR and Western blot analysis. Moreover, the activities of PONs were determined in cytosol and microsomes of 30 subjects and in mitochondria of 8 representative lung tissues using selective and non-selective substrates. Besides, to exclude the possible contribution of other esterases on PON1 organophosphate activity, the effect of bis-p-nitrophenyl phosphate (BNPP) and phenylmethylsulfonyl fluoride (PMSF), esterase inhibitors, and ethylenediaminetetraacetic acid (EDTA), a general paraoxonase inhibitor, was tested. Finally, the presence and activities of PONs in the A549 pulmonary cell line were also evaluated in order to be used as a model for studies on paraoxonases' metabolism. KEY FINDINGS: Our results demonstrated high interindividual variability in both PONs mRNA/protein levels and enzymatic activities and pointed out the presence of all PONs in human lungs and their subcellular distribution in the cytosol, microsomes, and mitochondria. SIGNIFICANCE: These findings add further information to our knowledge of pulmonary metabolism and, given that PON1 can metabolize some drugs used for respiratory diseases, the presence of PON1 activity in the lung tissue should no longer be ignored in the development of treatment plans and the design of new drugs.

Retrospective determination of U and Pu isotopes and atom ratios in lung samples from Vienna, Austria.

Uranium and plutonium isotope concentrations as well as 236U/238U and 240Pu/239Pu atom ratios were measured by AMS in human lung samples from the early 1960s. The 236U concentrations as well as the 236U/238U atom ratios show a maximum in 1964, 239Pu and 240Pu concentrations are increasing continually from 1962 to 1965. 236U/238U atom ratios are lower by two orders of magnitude compared to corresponding aerosol data from Vienna, probably due to older 238U deposited in the lungs, enhanced 238U concentrations in the city air, and activity partition within different particle sizes. The 236U/239Pu atom ratios in lung samples are also lower than expected from the aerosol data, while 240Pu/239Pu atom ratios lie well within the range typical for nuclear bomb fallout.

The Genome Analysis of the Human Lung-Associated Streptomyces sp. TR1341 Revealed the Presence of Beneficial Genes for Opportunistic Colonization of Human Tissues.

Streptomyces sp. TR1341 was isolated from the sputum of a man with a history of lung and kidney tuberculosis, recurrent respiratory infections, and COPD. It produces secondary metabolites associated with cytotoxicity and immune response modulation. In this study, we complement our previous results by identifying the genetic features associated with the production of these secondary metabolites and other characteristics that could benefit the strain during its colonization of human tissues (virulence factors, modification of the host immune response, or the production of siderophores). We performed a comparative phylogenetic analysis to identify the genetic features that are shared by environmental isolates and human respiratory pathogens. The results showed a high genomic similarity of Streptomyces sp. TR1341 to the plant-associated Streptomyces sp. endophyte_N2, inferring a soil origin of the strain. Putative virulence genes, such as mammalian cell entry (mce) genes were not detected in the TR1341's genome. The presence of a type VII secretion system, distinct from the ones found in Mycobacterium species, suggests a different colonization strategy than the one used by other actinomycete lung pathogens. We identified a higher diversity of genes related to iron acquisition and demonstrated that the strain produces ferrioxamine B in vitro. These results indicate that TR1341 may have an advantage in colonizing environments that are low in iron, such as human tissue.

19 F MRI of human lungs at 0.5 Tesla using octafluorocyclobutane.

PURPOSE: The aim of this study was to demonstrate the feasibility of fluorine-19 (19 F) MRI of the human lungs using octafluorocyclobutane (OFCB, C4 F8 ). This gas has 8 magnetically equivalent fluorine nuclei and relatively long T1 and T2 (˜50 ms), which render it suitable as an MRI contrast agent. Previous experiments in small laboratory animals showed that OFCB could be successfully used as an alternative to the gases often used for 19 F MRI (sulfur hexafluoride and perfluoropropane). METHODS: One male volunteer participated in this study. Immediately before an MRI scan, the volunteer inhaled the gas mixture-80% OFCB with 20% oxygen-and held his breath. Experiments were performed on a 0.5T whole-body MR scanner with a customized transmit-receive coil tuned at 19 F frequency. Fast spin echo in 2D and 3D modes was used for image acquisition. 2D images were obtained with in-plane resolution of 10 × 10 mm2 without slice selection. 3D images were obtained with the voxel size of 10 × 10 × 30 mm2 . Breath-hold duration was 20 s for 2D and 40 s for 3D imaging, respectively. RESULTS: Anatomically consistent 19 F MR images of the human lungs were obtained with SNR around 50 in 2D mode and 20 in 3D mode. 3D volumetric images of the lungs were reconstructed and provided physiologically reasonable volume estimates. CONCLUSION: The application of OFCB enables informative 19 F lung imaging even at low magnetic field strengths. The OFCB gas shows promise as an inhalable contrast agent for fluorine lung MRI and has a potential for clinical translation.

Anthropometry-based generation of personalized and population-specific human airway models.

Understanding aerosol deposition in the human lung is of great significance in pulmonary toxicology and inhalation pharmacology. Adverse effects of inhaled environmental aerosols and pharmacological efficacy of inhaled therapeutics are dependent on aerosol properties as well as person-specific respiratory tract anatomy and physiology. Anatomical geometry and physiological function of human airways depend on age, gender, weight, fitness, health, and disease status. Tools for the generation of the population- and subject-specific virtual airway anatomical geometry based on anthropometric data and physiological vitals are invaluable in respiratory diagnostics, personalized pulmonary pharmacology, and model-based management of chronic respiratory diseases. Here we present a novel protocol and software framework for the generation of subject-specific airways based on anthropometric measurements of the subject's body, using the anatomical input, and the conventional spirometry, providing the functional (physiological) data. This model can be used for subject-specific simulations of respiration physiology, gas exchange, and aerosol inhalation and deposition.

Particle deposition in the human lung: Health implications of particulate matter from different sources.

Although ambient particulate matter or particles have been found to be associated with morbidity and mortality all over the world, specific health effects of particles from different sources need further elucidation. The objective of this work is to predict the deposition of particles from different sources in the human lung. The whole lung, consisting of 24 generations of branches from trachea to alveoli, was approximated using a one-dimensional lumped "trumpet" model with a variable cross-sectional area. The aerosol dynamics equation was numerically solved using a finite difference method to investigate the transport and deposition of particles in the lung model. Particles from various sources were assumed to be different in both size and density. We found that in general, coarse particles (> 2.5 µm) were mainly deposited in the tracheobronchial (TB) region by impaction, and fine particles (< 2.5 µm) were mainly deposited in the pulmonary (P) region by sedimentation and diffusion. However, the coarse particles with low density can be deposited in P region by sedimentation. As a comparison, our results found that soil particles, which are coarse with low density, were deposited in the deep lung more than traffic particles, which are fine with high density. Modeling of particle deposition in the human lung indicated that coarse particles generated by crustal sources may have adverse health effects as strong as those resulting from fine particles generated from combustion sources.

Numerical investigation of inspiratory airflow in a realistic model of the human tracheobronchial airways and a comparison with experimental results.

In this article, the results of numerical simulations using computational fluid dynamics (CFD) and a comparison with experiments performed with phase Doppler anemometry are presented. The simulations and experiments were conducted in a realistic model of the human airways, which comprised the throat, trachea and tracheobronchial tree up to the fourth generation. A full inspiration/expiration breathing cycle was used with tidal volumes 0.5 and 1 L, which correspond to a sedentary regime and deep breath, respectively. The length of the entire breathing cycle was 4 s, with inspiration and expiration each lasting 2 s. As a boundary condition for the CFD simulations, experimentally obtained flow rate distribution in 10 terminal airways was used with zero pressure resistance at the throat inlet. CCM+ CFD code (Adapco) was used with an SST k-ω low-Reynolds Number RANS model. The total number of polyhedral control volumes was 2.6 million with a time step of 0.001 s. Comparisons were made at several points in eight cross sections selected according to experiments in the trachea and the left and right bronchi. The results agree well with experiments involving the oscillation (temporal relocation) of flow structures in the majority of the cross sections and individual local positions. Velocity field simulation in several cross sections shows a very unstable flow field, which originates in the tracheal laryngeal jet and propagates far downstream with the formation of separation zones in both left and right airways. The RANS simulation agrees with the experiments in almost all the cross sections and shows unstable local flow structures and a quantitatively acceptable solution for the time-averaged flow field.

Distribution of phospholipase C isozymes in normal human lung tissue and their immunohistochemical localization

Phospholipase C(PLC) plays a central role in signal transduction and it is important in cellular growth, differentiation and transformation. There are currently ten known mammalian isozymes of PLC identified and cloned. However, there are no report of PLC distribution in human lung tissue or their significances in pulmonary diseases. Presence of various PLC isozymes in normal human lung tissue was studied from surgical specimens. PLC isozymes in tissue extracts of the lung were partially purified by successive chromatographic steps on heparin-sepharose CL-6B conventional and TSKgel heparin-5PW HPLC columns and their activities were assayed. PLC activity peaks identified in the chromatography were immunoblotted with specific antibodies against ten known mammalian PLC isozymes(PLC-beta 1-4, -gamma 1-2, and -delta 1-4). In addition, immunohistochemical staining of the lung tissue was performed to determine subcellular and histological localization of PLC isozymes. The results indicate that normal human lungs contain beta 1, beta 3, gamma 1, and delta 1, isozymes of PLC. The order of amount present in the lung tissue was PLC-delta 1 > gamma 1 >beta 1 >> beta 3, in descending order. On immunohistochemistry, PLC-gamma 1 was most widely distributed and was present in bronchiolar epithelium, in type I and type II pneumocytes as well as in fibroblasts of the interstitial tissue. PLC-delta 1 was present in the cytoplasm of the bronchiolar epithelium whereas PLC-beta 1 was localized to the apical membranous portion of the same epithelium. PLC-beta 3 was seen in the nucleus of the respiratory and alveolar lining epithelium as well as in the nucleus of lung fibroblasts.