Lung Surface Research Articles

Functional oral nanoparticles for delivering silibinin and cryptotanshinone against breast cancer lung metastasis

BackgroundBreast cancer lung metastasis occurs in more than 60% of all patients with breast cancer, and most of those afflicted by it eventually die of recurrence. The tumor microenvironment plays vital roles in metastasis. Modulating the tumor microenvironment via multiple pathways could efficiently prevent or inhibit lung metastasis. Silibinin and cryptotanshinone are natural plant products that demonstrate anti-metastasis effects and modulate the tumor microenvironment via different pathways. However, they have poor aqueous solubility, membrane permeability, and oral bioavailability. Oral drug administration may help improve the quality of life and compliance of patients with breast cancer, primarily under long-term and/or follow-up therapy. Herein, we developed poly-N-(2-hydroxypropyl) methacrylamide (pHPMA)-coated wheat germ agglutinin-modified lipid-polymer hybrid nanoparticles, co-loaded with silibinin and cryptotanshinone (S/C-pW-LPNs). We assessed their oral bioavailability, and evaluated their anti-metastasis efficacy in a 4T1 breast cancer tumor-bearing nude mouse model.ResultsAn in vitro mucus diffusion study revealed that pHPMA enhanced W-LPN mucus penetration. After oral administration, pHPMA enhanced nanoparticle distribution in rat jejunum and substantially augmented oral bioavailability. S/C-W-LPNs markedly increased 4T1 cell toxicity and inhibited cell invasion and migration. Compared to LPNs loaded with either silibinin or cryptotanshinone alone, S/C-pW-LPNs dramatically slowed tumor progression in 4T1 tumor-bearing nude mice. S/C-pW-LPNs presented with the most robust anti-metastasis activity on smooth lung surfaces and mitigated lung metastasis foci. They also downregulated tumor microenvironment biomarkers such as CD31, TGF-β1, and MMP-9 that promote metastasis.ConclusionsSilibinin- and cryptotanshinone-co-loaded pW-LPNs efficiently penetrate intestinal barriers, thereby enhancing the oral bioavailability of the drug loads. These nanoparticles exhibit favorable anti-metastasis effects in breast cancer-bearing nude mice. Hence, S/C-pW-LPNs are promising oral drug nanocarriers that inhibit breast cancer lung metastasis.

Binary surface smoothing for abnormal lung segmentation

Accurate lung segmentation in high-resolution computed tomography (HRCT) is important for lung disease diagnosis. When high attenuation patterns with challenging variations in intensity or shape exist in peripheral lung, the binary lung surface generated from coarse segmentation is often uneven, which makes lung segmentation inaccurate. This paper presents a novel surface smoothing method for abnormal lung segmentation, we employ a double-surfaced-based smoothing algorithm to smooth the binary lung surface, which can remove noise while filling holes in uneven surface. Besides, for abnormal lungs with different severity, our method can adaptively refine the uneven areas to achieve the accurate results of segmentation. Fifty-five lung HRCT scans with interstitial lung disease (ILD) are used to evaluate our proposed method, and the experimental results demonstrate that the proposed approach can improve the accuracy of abnormal lung segmentation significantly (overlap rate = 97.14%, Hausdorff Distance = 6.28 mm).

Surfactant Protein-A Protects against IL-13-Induced Inflammation in Asthma.

The lung surfactant proteins are recognized as critical not only for their role in lowering lung surface tension but also in innate host defense. Reports have shown that some asthmatic patients have decreased levels of one member of this protein family in particular, surfactant protein-A (SP-A). Our studies set out to determine the contribution of SP-A to the response of a key effector cytokine in asthma, IL-13. Our studies employ both animal models sufficient and deficient in SP-A challenged with IL-13 and primary epithelial cells from participants with asthma that are exogenously treated with SP-A in the context of IL-13 challenge. The inflammatory response and mucin production were assessed in both model systems. As compared with WT mice, we show that the activity of IL-13 is dramatically augmented in SP-A-/- mice, which have significantly increased neutrophil and eosinophil recruitment, mucin production and asthma-associated cytokines in the bronchoalveolar lavage fluid. In parallel, we show asthma-associated factors are attenuated in human cells from asthma subjects when exogenous SP-A is added during IL-13 challenge. Although many of these phenotypes have previously been associated with STAT6 signaling, SP-A inhibited IL-13-induced STAT3 phosphorylation in mice and in human epithelial cells while having little effect on STAT6 phosphorylation. In addition, when either STAT3 or IL-6 were inhibited in mice, the phenotypes observed in SP-A-/- mice were significantly attenuated. These studies suggest a novel mechanism for SP-A in asthma as a modulator of IL-13-induced inflammation via mediating downstream IL-6/STAT3 signaling.

Feasibility study of a surface-coated lung model to quantify active agent deposition for preclinical studies

BackgroundMultiple drug resistance of a growing number of bacterial pathogens represents an increasing challenge in conventional curative treatments of infectious diseases. However, the development and testing of new antibiotics is associated with a high number of animal experiments. MethodsA symmetrical parametrized lung test rig allowing the exposure of air-passage surfaces to antibiotics was designed and tested to demonstrate proof-of-principle with aerosols containing allicin, which is an antimicrobial natural product from garlic. An artificial lung surface is coated with bacteria embedded in a hydrogel and growth inhibition is visualized by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, that is reduced from colourless to the dark blue formazan in the presence of metabolically active, living cells. A nebulizer is used to generate the aerosols. FindingsThe results show that allicin has an antibiotic effect as an aerosol and that the deposition pattern of the active agent occurred mainly around the carinal regions. InterpretationThe model represents an integral system for continuous, spatial detection of aerosol deposition and allows the analysis of bacterial behaviour and the toxicity of the active agent. Thus, the deposition of antimicrobial aerosols on the bronchial surfaces is characterized in preliminary tests without any animal experiments.

Morphological characteristics of respiratory and digestive organs of Roman snail (Helix pomatia L., 1758)

The aim of this work was to study the structure of lung and hepatopancreas of Roman snail (Helix of pomatia of L., 1758). The study found that the lung occupies the lower turn of shell and presented by a saccate cavity, in the wall of that there are a kidney and heart with a pericardium, and also a rectum and ureter pass. An external surface of lungs covered by a shell and covered by an epidermis. An internal surface is covered by a flat ciliated epithelium and forms numerous folds in which pulmonary vessels and lacunae are accommodated. The branches of pulmonary vein have a thick muscular wall, that consists of circular and longitudinal muscular layers. An internal surface of lungs covered by the layer of mucus. Inhalation and exhalation are carried out due to reduction and relaxation of muscles of dorsal wall of the body that is named a “diaphragm”. Gas exchange occurs through the hemolymphatic capillaries of the lung wall. Respiratory motions take place not rhythmically, but through the different intervals of time depending on a requirement in oxygen. The frequency of pneumostome closing and opening is typically one time in a minute. At subzero humidity of atmospheric air of pneumostome closed by a mantle, and also one (or a few) epiphragms. The hepatopancreas (“liver” or liver gland) is in the upper rotation of the sink and formed by two parts: right and left, from which two liver ducts enter into the stomach respectively. The liver gland consists of many acinuss, surrounded by connecting tissue, that contains small number of muscular fibres. Calcium cells have a pyramidal form and usually do not reach the lumen of the acinus. Cytoplasm of calcium cells contains inclusions: grains of phosphoricacid lime and drops of fat. The digestive cells of the hepatopencreas are more elongated, often clavicular. Сytoplasm of digestive cells is loose and vacuolated and contain inclusions of yellow-green color. Enzyme cells on histopreparations are difficult to distinguish from digestive ones. They contain transparent vacuoles with a large round inclusion of yellow-green color, which consists of a cluster of several grains of different sizes. Hepatopancreas performs the following functions: secretory (enzyme cells), absorption and intracellular digestion (digestive cells), preservation of nutrients and calcium (calcium cells), and also excretory function.

Preoperative lung surface localization for pulmonary wedge resection: a single-center experience.

BackgroundPreoperative lung surface localization is effective in sublobar resection for small lung nodules. However, the efficacy may vary depending on the underlying conditions of the lung and tumor, as well as the technique. This study aimed to evaluate the efficacy and limitations of preoperative lung surface localization for wedge resection by analyzing the outcomes of computed tomography (CT)-guided percutaneous marking and virtual-assisted lung mapping (VAL-MAP).MethodsWe investigated 215 patients who underwent curative wedge resection for malignant tumors using CT-guided localization or VAL-MAP from 1998 to 2018 in our institute. Each resected nodule was assessed for successful resection, which was defined as complete resection with adequate margins.ResultsOne-hundred-and-nineteen patients with 153 nodules were included. The overall successful resection rate was 87.6%. The successful resection rate was significantly lower for nodules with intraoperative adhesion than those without intraoperative adhesion (75.0% vs. 90.1%; P=0.034), and for tumors requiring deep resection margins (>31 mm) than those requiring shallow margins (≤31 mm) (76.7% vs. 94.6%; P=0.002). Although the successful resection rate for nodules resected using CT-guided localization was significantly lower in cases with versus without intraoperative adhesion (54.5% vs. 86.7%; P=0.048), the successful resection rate for nodules resected using VAL-MAP was not influenced by the presence or absence of adhesion (85.7% vs. 93.4%; P=0.491).ConclusionsA requirement for deeper resection and the presence of intraoperative adhesion were limitations of preoperative lung surface localization for curative pulmonary wedge resection.

Pulmonary surfactant phosphatidylcholines induce immunological adaptation of alveolar macrophages

Pulmonary surfactant plays an important role in lung surface tension, defense against invading pathogens, and immune response. Furthermore, alveolar macrophages (AM) that comprise the front line of immune defense against inhaled microorganisms are covered by a layer of pulmonary fluid. Phosphatidylcholines (PCs), including unsaturated lipids such as 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), are the most prevalent phospholipids in pulmonary surfactant. POPC reacts with ozone to produce 1-palmitoyl-2-(9-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PONPC), a soluble mediator that initiates an inflammatory reaction in the lungs. However, the modulatory effects of POPC and PONPC on biology and activity of AM remain inconclusive. The exposure of AM (cell line AMJ2-C11) to POPC and PONPC was not directly related to the production of inflammatory mediators. However, AM, pre-incubated with POPC or PONPC, showed enhanced response after lipopolysaccharide (LPS) stimulation, and increased the production of nitric oxide and cytokines. This phenomenon was also observed for classical-polarized macrophages (M1). This increment on the production of inflammatory mediators was not associated with macrophage polarization, but with up-regulation of Tlr4 and Myd88 gene expression, which was in accordance with the adaptation of immune cells. This observation was confirmed by the histone acetylation epigenetic pathway. In contrast to the priming effect of POPC on AM activity, a harmful immune response, induced on incubation with PONPC, improved prostaglandin E2 (PGE2) formation, resulting in diminished bacterial phagocytosis. Additionally, PONPC induced production of CXCL1/KC, which potentially mediates neutrophil recruitment and enhances tissue inflammation. These results disclosed another dynamic mechanism by which pulmonary surfactant lipids (natural or oxidized) primed macrophage activity, thus affecting lung host defense.

Ventilation and Perfusion at the Alveolar Level: Insights From Lung Intravital Microscopy.

Intravital microscopy (IVM) offers unique possibilities for the observation of biological processes and disease related mechanisms in vivo. Especially for anatomically complex and dynamic organs such as the lung and its main functional unit, the alveolus, IVM provides exclusive advantages in terms of spatial and temporal resolution. By the use of lung windows, which have advanced and improved over time, direct access to the lung surface is provided. In this review we will discuss two main topics, namely alveolar dynamics and perfusion from the perspective of IVM-based studies. Of special interest are unanswered questions regarding alveolar dynamics such as: What are physiologic alveolar dynamics? How do these dynamics change under pathologic conditions and how do those changes contribute to ventilator-induced lung injury? How can alveolar dynamics be targeted in a beneficial way? With respect to alveolar perfusion IVM has propelled our understanding of the pulmonary microcirculation and its perfusion, as well as pulmonary vasoreactivity, permeability and immunological aspects. Whereas the general mechanism behind these processes are understood, we still lack a proper understanding of the complex, multidimensional interplay between alveolar ventilation and microvascular perfusion, capillary recruitment, or vascular immune responses under physiologic and pathologic conditions. These are only part of the unanswered questions and problems, which we still have to overcome. IVM as the tool of choice might allow us to answer part of these questions within the next years or decades. As every method, IVM has advantages as well as limitations, which have to be taken into account for data analysis and interpretation, which will be addressed in this review.

Marking method for peripheral non-palpable pulmonary nodules using a mobile computed tomography scanner with a navigation system.

Intraoperative localization is essential for video-assisted thoracoscopic surgery of non-palpable pulmonary nodules. Although a computed tomography (CT) guided hook-wire localization is widely used, it might be accompanied by a rare but fatal complication such as an air embolism. We applied a mobile CT scanner with a navigation system to resolve this problem. The three-dimensional images obtained by the mobile CT scanner were transferred to the navigation system, which allowed for virtual fluoroscopy to scan the nearest skin site from the target lesion using a navigation probe. The lung surface was stamped by a dyed gauze ball anchored just beneath the skin marking and a needle was placed at this point as a landmark. With this method, we could verify the positional relationship between the needle and target lesion by the additional CT scan without any procedure-related morbidity.

Tight junctions in the development of asthma, chronic rhinosinusitis, atopic dermatitis, eosinophilic esophagitis, and inflammatory bowel diseases.

This review focuses on recent developments related to asthma, chronic rhinosinusitis, atopic dermatitis (AD), eosinophilic esophagitis, and inflammatory bowel diseases (IBD), with a particular focus on tight junctions (TJs) and their role in the pathogenetic mechanisms of these diseases. Lung, skin, and intestinal surfaces are lined by epithelial cells that interact with environmental factors and immune cells. Therefore, together with the cellular immune system, the epithelium performs a pivotal role as the first line physical barrier against external antigens. Paracellular space is almost exclusively sealed by TJs and is maintained by complex protein-protein interactions. Thus, TJ dysfunction increases paracellular permeability, resulting in enhanced flux across TJs. Epithelial TJ dysfunction also causes immune cell activation and contributes to the pathogenesis of chronic lung, skin, and intestinal inflammation. Characterization of TJ protein alteration is one of the key factors for enhancing our understanding of allergic diseases as well as IBDs. Furthermore, TJ-based epithelial disturbance can promote immune cell behaviors, such as those in dendritic cells, Th2 cells, Th17 cells, and innate lymphoid cells (ILCs), thereby offering new insights into TJ-based targets. The purpose of this review is to illustrate how TJ dysfunction can lead to the disruption of the immune homeostasis in barrier tissues and subsequent inflammation. This review also highlights the various TJ barrier dysfunctions across different organ sites, which would help to develop future drugs to target allergic diseases and IBD.

Detection of Lung Tumor Progression in Mice by Ultrasound Imaging

With ~1.6 million victims per year, lung cancer contributes tremendously to the worldwide burden of cancer. Lung cancer is partly driven by genetic alterations in oncogenes such as the KRAS oncogene, which constitutes ~25% of lung cancer cases. The difficulty in therapeutically targeting KRAS-driven lung cancer partly stems from having poor models that can mimic the progression of the disease in the lab. We describe a method that permits the relative quantification of primary KRAS lung tumors in a Cre-inducible LSL-KRAS G12D mouse model via ultrasound imaging. This method relies on brightness (B)-mode acquisition of the lung parenchyma. Tumors that are initially formed in this model are visualized as B-lines and can be quantified by counting the number of B-lines present in the acquired images. These would represent the relative tumor number formed on the surface of the mouse lung. As the formed tumors develop with time, they are perceived as deep clefts within the lung parenchyma. Since the circumference of the formed tumor is well-defined, calculating the relative tumor volume is achieved by measuring the length and width of the tumor and applying them in the formula used for tumor caliper measurements. Ultrasound imaging is a non-invasive, fast and user-friendly technique that is often used for tumor quantifications in mice. Although artifacts may appear when obtaining ultrasound images, it has been shown that this imaging technique is more advantageous for tumor quantifications in mice compared to other imaging techniques such as computed tomography (CT) imaging and bioluminescence imaging (BLI). Researchers can investigate novel therapeutic targets using this technique by comparing lung tumor initiation and progression between different groups of mice.

A safe and novel method for video-assisted thoracic surgery preoperative localization of small pulmonary nodules by using ZT medical glue (2-octyl cyanoacrylate)

BackgroundAccurate and fast localization of small pulmonary nodules is required for local pulmonary resection. In this study, we introduced and assessed a novel technique for the preoperative localization of small pulmonary nodules by using ZT medical glue (2-octyl cyanoacrylate). Methods101 patients who had a combined total of 106 small pulmonary nodules located by ZT glue and 53patients with 53 small pulmonary nodules located by hookwire were selected. Guided by computed tomography (CT), the surgeon injected certain volume ZT glue into an area adjacent to the small pulmonary nodule, then, the adjacent lung tissue infiltrated by ZT glue formed into a depressed hard nodule which can be used for preoperative localization with an obvious mark on lung surface or different hand touch. After localization, Wedge resection was performed via video-assisted thoracoscopic surgery and the specimen obtained from the procedure was immediately sent for pathological examination, followed by a standard surgical procedure. A contrast has been made between the ZT glue method and the hookwire. Results101 operations were successfully performed by using this novel technique, and 106 small pulmonary nodules were successfully located. Compared with the hookwire location, ZT glue method obviouslyextended the Time interval between localization and operation (P = 0.00) and a same complication rate (P = 0.07). ConclusionsThe use of ZT glue is a safe and effective method for the localization of small pulmonary nodules. Trial registrationThis study was approved by the ethics committee of Shaoxing People's Hospital (Number:2016-004, Date:2016,2,24), and informed consent was obtained from all enrolled patients.

Summary of the Keystone Symposium “Origins of allergic disease: Microbial, epithelial and immune interactions,” March 24-27, Tahoe City, California

The aims of the Keystone Symposium conference, "Origins of allergic disease: Microbial, epithelial and immune interactions" were to present and discuss potential microbial-epithelial-immune interactions underlying the early-life origins of allergic disorders, as well as immune mechanisms that might suggest novel disease prevention or intervention strategies. Cross-talk and sharing of ideas among participating experts in basic science and clinical aspects of allergic diseases provided substantial insight into the concept of allergic disorders as a systems disease. The overriding message distilled from the discussions was that damage to epithelial surfaces lies at the origin of the various manifestations of allergic disease. The epithelium of the lungs, gut, and skin, which operates as a critical sensor of environmental stimuli, is besieged by an onslaught of contemporary environmental forces including an altered microbiome, air pollution, food allergens in a changed diet, and chemicals in modern detergents. Collectively, this onslaught leads to alterations of lung, skin, or gut epithelial surfaces, driving a type 2 immune response that underlies most, if not all, of the atopic diseases. Possible remedies for treatment and prevention of allergic diseases were discussed, including a precision medicine approach using biologics, oral desensitization, targeted gut microbiome alterations, and behavior alteration.

Locally Adaptive Total p-Variation Regularization for Non-Rigid Image Registration With Sliding Motion.

Due to the complicated thoracic movements which contain both sliding motion occurring at lung surfaces and smooth motion within individual organs, respiratory estimation is still an intrinsically challenging task. In this paper, we propose a novel regularization term called locally adaptive total p-variation (LaTpV) and embed it into a parametric registration framework to accurately recover lung motion. LaTpV originates from a modified Lp-norm constraint (1 < p < 2), where a prior distribution of p modeled by the Dirac-shaped function is constructed to specifically assign different values to voxels. LaTpV adaptively balances the smoothness and discontinuity of the displacement field to encourage an expected sliding interface. Additionally, we also analytically deduce the gradient of the cost function with respect to transformation parameters. To validate the performance of LaTpV, we not only test it on two mono-modal databases including synthetic images and pulmonary computed tomography (CT) images, but also on a more difficult thoracic CT and positron emission tomography (PET) dataset for the first time. For all experiments, both the quantitative and qualitative results indicate that LaTpV significantly surpasses some existing regularizers such as bending energy and parametric total variation. The proposed LaTpV based registration scheme might be more superior for sliding motion correction and more potential for clinical applications such as the diagnosis of pleural mesothelioma and the adjustment of radiotherapy plans.

Lung Damage Mechanisms For COVID-19 and Other Lung Infections, and Driving Force in Leukecyte Recruitment and Migration

To understand lung damage caused by COVID-19, we deduced two-phase lung damage mechanisms. After the lungs are infected with SARS-CoV-2 virus, the affected lung tissue swells and surface properties of pulmonary capillaries change, resulting in an increased flow resistance of affected capillaries. If a sufficient number of capillaries are affected by the infection, the swelling and increased cell wall adhesion collectively raise pulmonary vascular resistance. The increased vascular resistance further increases the dwell times of WBCs in affected capillaries and nearly capillaries. When pulmonary pressure is sufficiently higher, WBCs are forced to squeeze into interstitial spaces or alveolar spaces when local pressures are higher than what the capillaries can withstand. When more and more WBCs are dynamically retained, the flow resistance of more capillaries rises, pulmonary vascular resistance rises, and pulmonary pressure rises. The rise in the pulmonary pressure in turn results in elevated capillary pressures. When capillary pressures around the alveoli are sufficiently high, they cause interstitial pressures to change from normally negative values to positive values. The positive pressures cause fluid leakage to the alveolar space and thus degrade lung function. Tissue swelling, and occupation of WBCs in interstitial spaces and alveolar spaces further reduce compressible volume, and thus cause further rise in the pulmonary vascular resistance and pulmonary pressure. When the pulmonary pressure has reached a critical point as in the second phase, the blood breaks capillary walls and squeezes through interstitial spaces to reach alveolar spaces, resulting in irreversible lung damages. The available free volume in the thorax cage, organ usable capacities, temperature and humid are expected to have great impacts on degree of lung damages. The free volume in the thorax cage, lung usable surplus capacity, and other organ usable capacities determine the arrival time of last-phase irreversible damage. The mechanisms imply that the top priority for protecting lungs is maintaining pulmonary micro-circulation and preserving organ functions in the entire disease course while controlling viral reproduction should be stressed in the earliest time possible. The mechanisms also explain leukecytes are recruited and migrated into inflamed tissues by increasing their dwell times caused by increased local flow resistance.

Brain death effects on lung microvasculature in an experimental model of lung donor.

ABSTRACTObjectiveBrain death (BD) triggers important hemodynamic and inflammatory alterations, compromising the viability of organs suitable for transplantation. To better understand the microcirculatory alterations in donor lungs caused by BD. The present study investigated the pulmonary microcirculation in a rodent model of BD via intravital microscopy.MethodsMale Wistar rats were anaesthetized and mechanically ventilated. They were trepanned and BD was induced through the increase in intracranial pressure. As control group, sham-operated (SH) rats were trepanned only. In both groups, expiratory O2 and CO2 were monitored and after three hours, a thoracotomy was performed, and a window was created to observe the lung surface using an epi-fluorescence intravital microscopy. Lung expression of intercellular adhesion molecule (ICAM)-1 and endothelial nitric oxide synthase (eNOS) was evaluated by immunohistochemistry, and cytokines were measured in lung samples.ResultsThree hours after the surgical procedures, pulmonary perfusion was 73% in the SH group. On the other hand, BD animals showed an important decrease in organ perfusion to 28% (p = 0.036). Lung microcirculatory compromise after BD induction was associated with an augmentation of the number of leukocytes recruited to lung tissue, and with a reduction in eNOS expression and an increase in ICAM-1 expression on lung endothelial cells. BD rats showed higher values of expiratory O2 and lower values of CO2 in comparison with SH animals after three hours of monitoring.ConclusionData presented showed that BD triggers an important hypoperfusion and inflammation in the lungs, compromising the donor pulmonary microcirculation.

Role of transthoracic ultrasonography in evaluation of pleural thickening observed during medical thoracoscopy

Background and objective Ultrasound can evaluate pleural thickening; however, medical thoracoscopy permits direct inspection of the pleura, and biopsies are taken under direct vision. This study evaluated the degree of pleural thickening observed during medical thoracoscopy and compared it with the pleural thickness grades assessed and measured using transthoracic ultrasonography (TUS). Patients and methods A total of 118 cases with undiagnosed exudative pleural effusion were included. They were subjected to history taking, clinical examination, routine laboratory investigations, computed tomography chest, TUS to assess degree of parietal pleural thickening, and medical thoracoscopy to evaluate the observed degree of pleural thickening. Results There was a significant positive correlation between pleural thickening measured by US with thoracoscopic grades of thickness and significant positive correlation between pleural thickening grades measured by US and thoracoscopic grades of pleural thickness. Performance of thoracoscopy using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for assessment of pleural thickening in comparison with US as a standard tool for measurement was 36, 77, 52, 77, and 66%, respectively, whereas in assessing the shape of visceral pleura, this performance increased up to 89, 89, 85, 85, and 88%, respectively. Conclusion This study showed the superiority of TUS in assessment of parietal pleura thickening and chest wall invasion. In addition, TUS has other advantages as being noninvasive, less expensive, and no exposure to radiation. However, medical thoracoscopy can detect the visceral pleural shape better owing to the advantage of direct visualization of the lung surface.

Discovery of lung surface intersegmental landmarks by three-dimensional reconstruction and morphological measurement.

The lack of anatomic landmarks between segments on the lung surface makes the identification of intersegmental planes one of the greatest challenges in anatomic segmentectomy. Therefore, with the aim to determine the landmarks of intersegmental planes on the lung surface, we used three-dimensional (3D) reconstruction and morphological measurement techniques to reconstruct stereoscopic models of all pulmonary segments, and measured the length of each segment on the lung surface along the lobe's anatomic landmark lines. We downloaded the primary computed tomography (CT) scan data of 619 patients and imported them into a 3D reconstruction system, which could automatically reconstruct the 3D model of the trachea-bronchi system. We manually reconstructed the intersegmental veins to ensure the accuracy of segmental boundary. The 3D models of pulmonary segments could be reconstructed based on the bronchial tree and the pathways of the intersegmental veins. We then measured the length of each segment on the lung surface along the lobe's anatomic landmark lines and calculated the proportions between these lengths. Complete 3D segmental models were successfully reconstructed in 500 patients (241 male and 259 female), and the lengths of every segment on the lung surface along the lobe's anatomic landmark lines were measured. Our data revealed that the length of each segment on lung surface varied among individuals. However, the proportions between these lengths stayed constant, even when stratified by gender, age, height, and weight. We discovered that the proportion between the lengths of adjacent segments on the lung surface stayed constant. The constant proportion reflected and uncovered the lung surface intersegmental landmarks, which could help direct surgeons to identify intersegmental planes during anatomic segmentectomy in an easy and safe way without additional cost.

Biological Characterization of F508delCFTR Protein Processing by the CFTR Corrector ABBV-2222/GLPG2222.

Cystic fibrosis (CF) is the most common monogenic autosomal recessive disease in Caucasians caused by pathogenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (CFTR). Significant small molecule therapeutic advances over the past two decades have been made to target the defective CFTR protein and enhance its function. To address the most prevalent defect of the defective CFTR protein (i.e., F508del mutation) in CF, two biomolecular activities are required, namely, correctors to increase the amount of properly folded F508delCFTR levels at the cell surface and potentiators to allow the effective opening, i.e., function of the F508delCFTR channel. Combined, these activities enhance chloride ion transport yielding improved hydration of the lung surface and subsequent restoration of mucociliary clearance. To enhance clinical benefits to CF patients, a complementary triple combination therapy consisting of two corrector molecules, type 1 (C1) and type 2, with additive mechanisms along with a potentiator are being investigated in the clinic for maximum restoration of mutated CFTR function. We report the identification and in vitro biologic characterization of ABBV-2222/GLPG2222 (4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid),-a novel, potent, and orally bioavailable C1 corrector developed by AbbVie-Galapagos and currently in clinical trials-which exhibits substantial improvements over the existing C1 correctors. This includes improvements in potency and drug-drug interaction (DDI) compared with 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (VX-809, Lumacaftor) and improvements in potency and efficacy compared with 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide (VX-661, Tezacaftor). ABBV-2222/GLPG2222 exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR with an EC50 value <10 nM. SIGNIFICANCE STATEMENT: To address the most prevalent defect of the defective CFTR protein (i.e., F508del mutation) in cystic fibrosis, AbbVie-Galapagos has developed ABBV-2222/GLPG2222, a novel, potent, and orally bioavailable C1 corrector of this protein. ABBV-2222/GLPG2222, which is currently in clinical trials, exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR and substantial improvements over the existing C1 correctors.

An Intriguing Involvement of Mitochondria in Cystic Fibrosis.

Cystic fibrosis (CF) occurs when the cystic fibrosis transmembrane conductance regulator (CFTR) protein is not synthetized and folded correctly. The CFTR protein helps to maintain the balance of salt and water on many body surfaces, such as the lung surface. When the protein is not working correctly, chloride becomes trapped in cells, then water cannot hydrate the cellular surface and the mucus covering the cells becomes thick and sticky. Furthermore, a defective CFTR appears to produce a redox imbalance in epithelial cells and extracellular fluids and to cause an abnormal generation of reactive oxygen species: as a consequence, oxidative stress has been implicated as a causative factor in the aetiology of the process. Moreover, massive evidences show that defective CFTR gives rise to extracellular GSH level decrease and elevated glucose concentrations in airway surface liquid (ASL), thus encouraging lung infection by pathogens in the CF advancement. Recent research in progress aims to rediscover a possible role of mitochondria in CF. Here the latest new and recent studies on mitochondrial bioenergetics are collected. Surprisingly, they have enabled us to ascertain that mitochondria have a leading role in opposing the high ASL glucose level as well as oxidative stress in CF.