Lung Surface Research Articles

Triplet CFTR modulators: future prospects for treatment of cystic fibrosis.

Cystic fibrosis (CF) is an autosomal recessive genetic disease characterized by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a chloride channel responsible for ion flow across epithelial surfaces of lung, sinuses, pancreas, intestine, and liver. Researchers have grouped CFTR genetic mutations into various protein defects: reduced protein synthesis (class 1 mutations), abnormal protein folding and maturation (class 2 mutation), and abnormal gating (class 3 mutation). These mutations usually present as severe forms of CF due to complete absence of CFTR at cell surfaces. Milder forms (eg, protein maturation and conductance defects, classes 4–6) present as less severe forms of CF related to the presence of CFTR at the cell surface. Differences in severity are directly due to CFTR function which is based on the severity of CFTR mutation. This knowledge has proven useful for designing therapy for individual mutations and mutation classes. The discovery and US Food and Drug Administration approval of Kalydeco® (ivacaftor) in early 2011 marked the beginning of a new era of therapies that are focused on improving defective CFTR protein function. However, due to its specificity for the G551D mutation, ivacaftor only benefitŝ5% of CF patients. Approximately 50% of CF patients have two copies of the F508Del mutation, while other CF patients carry only one copy of this gene. More recently, Orkambi®, a two compound medication composed of lumacaftor and ivacaftor, has provided the foundation necessary to further build on molecular concepts of: correction of trafficking, potentiation, and amplification of defective CFTR. These new concepts will form the basis of future CF therapies and extend CFTR treatment to almost 50% of CF patients. Evolving knowledge of the molecular mechanisms responsible for defective CFTR has prompted new research focused on “repair” of each phase of CFTR expression and function, thus creating a new class of combination “CFTR correctors” referred to as “triplet CFTR compounds.” This article will review how patients can be selected and treated with these newer agents that are based on specific mutations. In the future, many CF practitioners have expectations that initiation of treatment for CF patients will occur simply by use of biomarkers of CFTR expression (eg, sweat chloride, nasal potential difference, rectal organoids) rather than testing for specific mutations. As continued research identifies biomarkers with greater specificity and which predict clinical response, therapies can potentially be tailored to individual responses.

Advances in techniques for identifying small pulmonary nodules.

Since the introduction of video-assisted thoracoscopic surgery, the demand for its use in resecting small pulmonary nodules has increased. In parallel, the development of high-resolution computed tomography has led to an increase in the detection of the early lung cancers appearing as nodules with ground-glass opacity. Several techniques to resect these small lesions have been devised, the most familiar of which is the use of a computed tomography-guided percutaneous hook wire. We recently developed virtual-assisted lung mapping to achieve safer and more reliable resection of these lesions. Virtual-assisted lung mapping is carried out using three-dimensional computed tomography, bronchoscopy, and fluoroscopically guided navigation to mark the lung surface with dye. A prospective study showed that this technique was safe and had a high success rate. Multiple marking around the targeted lesion allows for a sufficient surgical margin at resection. We recently introduced an electromagnetic navigation bronchoscopy system to confirm the sites to be marked by virtual-assisted lung mapping in the operating room prior to video-assisted thoracoscopic surgery. We are now studying a method to enable minimally invasive, safe, and reliable resection of lesions located deep in the lung parenchyma.

OH-Radical Oxidation of Lung Surfactant Protein B on Aqueous Surfaces.

Air pollutants generate reactive oxygen species on lung surfaces. Here we report how hydroxyl radicals (·OH) injected on the surface of water react with SP-B1–25, a 25-residue polypeptide surrogate of human lung surfactant protein B. Our experiments consist of intersecting microjets of aqueous SP-B1–25 solutions with O3/O2/H2O/N2(g) gas streams that are photolyzed into ·OH(g) in situ by 266 nm laser nanosecond pulses. Surface-sensitive mass spectrometry enables us to monitor the prompt (<10 μs) and simultaneous formation of primary On-containing products/intermediates (n≤5) triggered by the reaction of ·OH with interfacial SP-B1–25. We found that O-atoms from both O3 and ·OH are incorporated into the reactive cysteine Cys8 and Cys11 and tryptophan Trp9 components of the hydrophobic N-terminus of SP-B1–25 that lies at the topmost layers of the air–liquid interface. Remarkably, these processes are initiated by ·OH additions rather than by H-atom abstractions from S–H, C–H, or N–H groups. By increasing the hydrophilicity of the N-terminus region of SP-B1–25, these transformations will impair its role as a surfactant.

Comprehensive study of pulmonary hilam with its clinical correlation

IntroductionAwareness of pulmonary hilar variations is essential for lobectomy of lung. Materials and methodsWe studied 54 left and 49 right hilum of formalin fixed adult cadaveric lungs. Morphologic and mophometric details were recorded and variations were noted. ResultsClassical picture of hilum was found in 35.19% left lung and 40.82% right lung. Morphological variations were more on left side (64.81%) than right side (59.18%) in terms of numbers of structures. On the left side, highest percentage of variable structure was bronchus (46.3%) followed by pulmonary artery (37.31%) and lowest by pulmonary vein (31.48%) whereas on right side, percentage for variable pulmonary artery and vein were same (36.73%) followed by bronchi (20.41%). Maximum number of pulmonary veins was five, pulmonary artery was three and accessory bronchus was two on both side hila. In morphometric measurement, mean vertical length of hilum was more on right side whereas anteroposterior length was more on left side. Right hilum is slightly lower and anteriorly placed than left hilum in the mediastinal surface of lung. Significant correlations between vertical length of lung and hilum and antero-postero length of lung and hilum of left and right sides were found. ConclusionsBy analysis and comparison with previous studies, present study concludes that morphology of pulmonary hila is extremely variable which contributes significant consequences in the field of pulmonary resection.

Inhibition effects of Yuxiao San combined with cisplatin on transplanted tumor growths via upregulation of nm-23 and downregulation of K-ras in Lewis lung cancer mice.

Traditional Chinese medicine applied to cancer therapy has a long history. This study aimed to investigate the effect and underlying mechanism of the traditional Chinese medicine, Yuxiao San, in combination with cisplatin, on Lewis lung cancer mice. Lewis lung cancer mouse models were were established in mice, and were randomly divided into model (normal saline + egg white), cisplatin (cisplatin injection + egg white), traditional Chinese medicine (Yuxiao San + egg white) and combined medication (Yuxiao San + cisplatin injection + egg white) groups. The weight and tumor size of mice was measured every 3 days, and the number of lung surface metastasis nodules were calculated after 14 days. Nucleoside diphosphate kinase (nm-23) and K-ras expression levels in tumor tissues were determined by immunohistochemical methods and reverse transcription- quantitative polymerase chain reaction. The results suggested that compared with the model group, cisplatin, traditional Chinese medicine and combined medication groups significantly inhibited growth of transplanted tumors, reduced the number of lung metastasis nodules, increased the inhibition rate of lung metastasis (P<0.05 or P<0.01), significantly increased tumor suppressor gene nm-23 expression and significantly downregulated oncogene K-ras expression. Among all groups, the effect of the combined medication group for inhibiting tumor growth was most favorable (P<0.01). Compared with the cisplatin group, nm-23 expression in the traditional Chinese medicine group and the combined medication group was significantly increased, and K-ras expression in the traditional Chinese medicine and combined medication groups was significantly reduced (P<0.01). To conclude, Yuxiao San and cisplatin injection effectively inhibited growth of the transplanted tumor. The underlying mechanism may be associate with nm-23 upregulation and K-ras downregulation. Therefore, the Yuxiao San and cisplatin injection may become a potential therapeutic strategy for tumor treatment.

Development of superficial lung lesions monitored on farm by serial ultrasonographic examination in sheep with lesions confirmed as ovine pulmonary adenocarcinoma at necropsy

BackgroundThis ultrasonographic study monitored lesions involving the lung surface suspected to be the early stages of ovine pulmonary adenocarcinoma (OPA) tumours over 4 months in commercially farmed sheep. The enlargement of these lesions defined ultrasonographically, which likely represent the development of OPA tumours, have important implications for ultrasound screening schedules in veterinary management plans attempting to eliminate OPA by test-and-cull.ResultsThe lungs of 58 adult Scottish Blackface sheep with ultrasonographic changes at the lung surface consistent with early OPA tumours were examined two to six times over 40 to 290 days. Lesion development, represented in early video recordings by 2–3 mm lesions involving the visceral pleural and comet tails, then a decreasing length of the hyperechoic line representing the normal visceral pleura and increasing depth of the sharply-demarcated and largely uniform hypoechoic areas into the lung parenchyma, was found in 26 of the 58 sheep. The rate at which the sonographic lesions progressed varied considerably and in 10 of 17 Group 1 sheep developed quickly from an estimated depth of 2–30 mm up to 70 mm between 60 and 120 days later. These sonographic lesions were confirmed as OPA at necropsy; histological changes of concurrent bacterial infection were detected in one of these 10 Group 1 sheep. Thirty-one sheep had sonographic changes ≤30 mm consistent with very early OPA at the first examination which had reduced or were not observed at subsequent examination. Five of these 31 sheep were necropsied, 3 had small OPA lesions while 2 had no significant pathology.ConclusionLesions involving the visceral pleura, with sonographic changes consistent with previous published findings of early OPA, developed over 40–120 days to large masses in 10 of 17 Group 1 sheep with the provisional sonographic diagnosis confirmed histologically at necropsy. While it is possible that atalectic lung could have caused some of the minor sonographic changes there was no microscopic evidence of pathologies other than OPA in nine of 10 Group 1 sheep. We conclude that some small tumours progress to large tumours within 3 months questioning the assumption that OPA is a slow growing tumour in adult sheep taking several years to cause clinical disease. The findings that a proportion of small ultrasonographic lesions are not found again at subsequent scanning illustrates the challenges of interpreting small (< 1–2 cm) lesions during rapid whole flock ultrasonographic examination and we continue to recommend re-scanning suspicious sonographic changes 2 months later.

Binding of Pneumocystis carinii to the lung epithelial cell receptor HSPA5 (GRP78).

The importance of lung macrophages in Pneumocystis-host interaction is well known, but little is known about the initial binding/colonization of the airway epithelium. Our prior studies have documented cell-signalling events that occur following binding of the organisms to lung epithelial cells; however, the receptors that mediate Pneumocystis attachment to lung surfaces have not yet been fully defined. Using affinity chromatography, we identified heat shock protein 5 (HSPA5), also known as GRP78, as a potential host receptor that may have relevance in Pneumocystis lung colonization. Pneumocystis carinii (Pc) organisms not only bound HSPA5 on a rat lung epithelial cell line, but also on primary rat airway epithelial cells (AECs). Furthermore, Pc bound CHO1 cells overexpressing HSPA5 more than the CHO1 parent line alone, supporting a role for Pc-HSPA5 protein interaction in mediating organism attachment. These results provide new insights into the interactions of Pneumocystis with host lung epithelium.

Intraoperative Near-Infrared Fluorescence-Guided Peripheral Lung Tumor Localization in Rabbit Models

A novel liposomal nanoparticle, CF800, that co-encapsulates indocyanine green for near-infrared (NIR) imaging and iohexol for computed tomography (CT) imaging has shown preferential tumor accumulation after intravenous injection by the enhanced permeability and retention effect. We hypothesized that CF800-enhanced NIR imaging would facilitate intraoperative localization of small lung nodules. A rabbit VX2 lung tumor model was implemented. CF800 was injected intravenously, followed by sequential CT acquisitions to track the biodistribution of CF800. Eleven rabbits were used for NIR fluorescence evaluation after thoracotomy at time points until 7 days after injection by using a NIR fluorescence thoracoscope invivo. Organs of interests were removed for exvivo analysis by using NIR imaging. Tumor-to-background (inflated lung) ratio was calculated and compared among the time points. Both CT and NIR imaging indicated enhanced accumulation of CF800 within the VX2 tumor. NIR image analysis revealed the highest tumor-to-background ratio on days 4 and 5. High background at day 2 and low tumor signal at day 7 prevented distinct demarcation. Metastatic pulmonary small nodules (less than 2 mm in diameter) were successfully visualized by NIR imaging on day 4. However, NIR signal penetration was limited, resulting in localization failure for the few tumors deep (>0 mm) to the lung surface. NIR image-guided localization of small lung nodules appears to be feasible under certain conditions. However, further refinement will be required to increase tumor signal intensity and to reduce background signal from normal lung parenchyma, which is at least in part a consequence of persistent CF800 in the vasculature.

MS21.01 Surgery and its Evolution

MS21.01 Surgery and its Evolution

Congenital absence of right cardiac notch in the lung of a Bunaji calf

The cardiac notch (fissure) is normally present in both right and left lungs of ruminants. The notch is usually smaller on the right lung relative to its left counterpart and distinctly confined to the lower parts of the third and fourth intercostal spaces where the pericardium comes in contact with the thoracic wall. We report a case of congenital absence of right cardiac notch in one out of the five White Fulani calves used for routine dissection in the Department of Veterinary Anatomy, University of Jos, Plateau state, Nigeria. A complete closure of the cardiac notch was observed between the middle and apical lobes of the right lung. Due to this defect, the pericardium was completely obliterated from view of the coastal surface of the middle lung`s lobes which occupied the supposed space for the cardiac notch in the right lung. To the best of our knowledge, congenital absence of cardiac notch has not been reported in literature. Hence, this study would benefit veterinary surgeons operating the thoracic cavity, radiologists examining radiographs and pathologists investigating thoracic cavity and its contents.Keywords: Bunaji calf, cardiac notch, congenital absence, right lung

Analysis of Percutaneous Biopsy of 41 Small Lung Lesions

背景与目的近年来由于肺癌筛查工作的广泛开展，越来越多的肺部小病灶被发现，本研究旨在分析计算机断层扫描（computed tomography, CT）引导下经皮肺小病灶（直径 < 2 cm）穿刺活检结果及并发症、预后。方法选择2015年1月-2017年12月期间行CT引导下经皮肺穿刺活检术41例肺内周围型病灶，单发病灶39例多发病灶2例，病灶最大径5-20（13.1±5.2）mm。病灶距离肺表面深度1-45（16.5±13.7）mm，毛玻璃样成分（ground glass opacity, GGO）比例0%-100%（66.8%±35.2%）。结果41例患者进行43次穿刺。43次穿刺均成功取得病理组织。手术证实其中非典型腺瘤样增生（atypical adenomatous hyperplasia, AAH）3例，鳞癌1例，腺癌37例（原位癌7例，微侵润癌5例，侵润性25例，有2例患者为双原发癌），炎性病变2例。除2例炎性病变正在随访中，活检与手术病理吻合度（特异性）为100%。气胸22例，发生率51.2%，需闭式引流2例，17例发生咯血，发生率39.5%，均为自限性。2例出现颅内空气栓塞经治疗痊愈，发生率4.6%。结论对于肺部小病灶CT引导经皮穿刺技术上可行。但对于肺部小病灶尤其是纯GGO的穿刺活检，目前还需要持谨慎态度。

Quantitative assessment of pulmonary vascular alterations in chronic obstructive lung disease: Associations with pulmonary function test and survival in the KOLD cohort

PurposeDespite the high prevalence of pulmonary vascular alterations and their substantial impact on chronic obstructive pulmonary disease (COPD), tools for the direct in vivo assessment of pulmonary vascular alterations remain limited. Thus, the purpose of this study was to automatically extract pulmonary vessels from volumetric chest CT and evaluate the associations between the derived quantitative pulmonary vessel features and clinical parameters, including survival, in COPD patients. MethodsThis study included 344 adult COPD patients. Pulmonary vessels were automatically extracted from volumetric chest CT data. Quantitative pulmonary vessel features were obtained from various lung surface areas (LSAs), which are theoretical surface areas drawn at different depths from the pleural borders. The total number of vessels (Ntotal) and number of vessels with vessel area (VA) less than 5 mm2 (N<5mm) were counted as both robust values and as values per 10 cm2 of LSA (Ntotal/LSA; N<5mm/LSA). The average VA (VAmean) and percentage of measured VA in the corresponding LSA (%VA) were measured. Associations between quantitative pulmonary vessel features and clinical parameters, including survival and the pulmonary function test (PFT), were evaluated. ResultsThe pulmonary vessels were automatically extracted with 100% technical success. Cox regression analysis showed Ntotal/LSA, N<5mm/LSA, VAmean, and %VA to be significant predictors of survival (hazard ratio (HR), 0.80, 0.75, 0.70, 0.49, respectively). Patients classified into high-risk groups by %VA18mm (cut-off = 3.258), chosen because it demonstrated the strongest statistical influence on survival in a univariate Cox analysis, were associated with worse overall survival before (HR, 4.83; p < 0.001) and after adjustment for patient age and BMI (HR, 2.18; p = 0.014). Of the quantitative pulmonary vessel features, Ntotal/LSA, N<5mm/LSA, and %VA were correlated with FEV1, FEV1/FVC, and DLCO in all LSAs. The strongest correlation with PFTs was noted at LSA9mm for both Ntotal (FEV1, r = 0.33; FEV1/FVC, r = 0.51) and N<5mm (FEV1, r = 0.35; FEV1/FVC, r = 0.52). For %VA, the association was most evident at LSA18mm (FEV1, r = 0.27; FEV1/FVC, r = 0.47). Significant moderate to strong correlations were consistently observed between the extent of emphysema and quantitative pulmonary vessel features (r = 0.44–0.66; all p < 0.001). ConclusionsThe automated extraction of pulmonary vessels and their quantitative assessment are technically feasible. Various quantitative pulmonary vessel features demonstrated significant relationships with survival and PFT in COPD patients. Of the various quantitative features, the percentage of total VA measured at 18 mm depth from the pleural surface (%VA18mm) and the number of small vessels counted per 10 cm2 of LSA at 9 mm depth from the pleural surface (N<5mm/LSA9mm) had the strongest predictability for the clinical parameters.

Free Desmosine is a Sensitive Marker of Smoke-Induced Emphysema.

While the elastin-specific crosslinks, desmosine and isodesmosine (DID), are increased in blood, urine, and sputum of patients with clinically documented pulmonary emphysema, the usefulness of DID in detecting early lung injury remains untested. To this end, our laboratory has measured DID in a hamster model of smoke-induced emphysema, involving only minimal alveolar wall damage. Animals were either treated with cigarette smoke for 2h/day, 5 days/week, or exposed only to room air (controls) for a period of 3months. DID levels in bronchoalveolar lavage fluid (BALF) and whole lungs were determined at monthly intervals, using liquid chromatography and tandem mass spectrometry. Lung surface area was also determined, as a measure of airspace enlargement. The portion of BALF DID not bound to peptides (free DID) was significantly higher in smoke-exposed animals at 2months (9.2 vs 4.4pg/mg protein; p < 0.05), whereas total BALF DID showed no significant increases over the course of the study, and total lung DID remained unchanged. There was a mild, but significant, loss of lung surface area in the smoke-exposed group at 2months (28.8% vs 25.2%, p < 0.05), which showed no further progression, consistent with the return of free DID to control levels at 3months. These findings support the hypothesis that free DID are sensitive indicators of smoke-induced lung injury. Measurement of free DID in smokers with minimally decreased lung mass may help determine the utility of this parameter as a test for incipient pulmonary emphysema.

Membrane expression of thymidine kinase 1 and potential clinical relevance in lung, breast, and colorectal malignancies

BackgroundLung, breast, and colorectal malignancies are the leading cause of cancer-related deaths in the world causing over 2.8 million cancer-related deaths yearly. Despite efforts to improve prevention methods, early detection, and treatments, survival rates for advanced stage lung, breast, and colon cancer remain low, indicating a critical need to identify cancer-specific biomarkers for early detection and treatment. Thymidine kinase 1 (TK1) is a nucleotide salvage pathway enzyme involved in cellular proliferation and considered an important tumor proliferation biomarker in the serum. In this study, we further characterized TK1’s potential as a tumor biomarker and immunotherapeutic target and clinical relevance.MethodsWe assessed TK1 surface localization by flow cytometry and confocal microscopy in lung (NCI-H460, A549), breast (MDA-MB-231, MCF7), and colorectal (HT-29, SW620) cancer cell lines. We also isolated cell surface proteins from HT-29 cells and performed a western blot confirming the presence of TK1 on cell membrane protein fractions. To evaluate TK1’s clinical relevance, we compared TK1 expression levels in normal and malignant tissue through flow cytometry and immunohistochemistry. We also analyzed RNA-Seq data from The Cancer Genome Atlas (TCGA) to assess differential expression of the TK1 gene in lung, breast, and colorectal cancer patients.ResultsWe found significant expression of TK1 on the surface of NCI-H460, A549, MDA-MB-231, MCF7, and HT-29 cell lines and a strong association between TK1’s localization with the membrane through confocal microscopy and Western blot. We found negligible TK1 surface expression in normal healthy tissue and significantly higher TK1 expression in malignant tissues. Patient data from TCGA revealed that the TK1 gene expression is upregulated in cancer patients compared to normal healthy patients.ConclusionsOur results show that TK1 localizes on the surface of lung, breast, and colorectal cell lines and is upregulated in malignant tissues and patients compared to healthy tissues and patients. We conclude that TK1 is a potential clinical biomarker for the treatment of lung, breast, and colorectal cancer.

The effect of pleural fluid layers on lung surface wave speed measurement: Experimental and numerical studies on a sponge lung phantom

Pleural effusion manifests as compression of pleural fluid on the lung parenchyma contributing to hypoxemia. Medical procedures such as drainage of plural fluid releases this compression and increases oxygenation. However, the effect of pleural effusion on the elasticity of lung parenchyma is unknown. By using lung ultrasound surface wave elastography (LUSWE) and finite element method (FEM), the effect of pleural effusion on the elasticity of superficial lung parenchyma in terms of surface wave speed measurement was evaluated in a sponge phantom study. Different thicknesses of ultrasound transmission gel used to simulated pleural fluid were inserted into a condom, which was placed between the sponge and standoff pad. A mechanical shaker was used to generate vibration on the sponge phantom at different frequencies ranging from 100 to 300 Hz while the ultrasound transducer was used to capture the motion for measurement of surface wave speed of the sponge. FEM was conducted based on the experimental setup and numerically assessed the influence of pleural effusion on the surface wave speed of the sponge. We found from FEM experiments that the influence of thickness of ultrasound transmission gel was statistically insignificant on the surface wave speed of the sponge at 100 and 150 Hz.

Suturing of the laser resection area is recommended over a depth of 2 cm in an experimental porcine lung model.

Lung metastases can be removed by an Nd:YAG laser to save lung parenchyma. At these sites, a coagulated lung surface remains. Airtightness was investigated in relation to the depth of resection on an ex vivo porcine lung model. Freshly slaughtered porcine double lung preparations were connected to a ventilator via a tube. Non-anatomical laser resections were performed with an 800 µm laser fiber and the Nd:YAG laser LIMAX® 120 (power: 40 and 60 watts). The following resection depths (each n=12) from the lung surface were examined: 0.5, 1, 1.5 and 2.0 cm. After resection the lungs were submerged under water and ventilated (frequency 10/min, Pinsp =25 mbar, PEEP =5 mbar). Airtightness of resection surfaces was determined by a leakage score, as well as the measurement of the leakage volume (in mL) per respiration (Group 1). Afterwards, the resection areas were coagulated for 5 seconds with a laser power of 60 watts at a distance of approximately 1 cm from the surface. This was followed by a re-evaluation for airtightness (Group 2). Finally, the resection surface was closed by a suture (PDS USP 4-0) and re-tested for airtightness (Group 3). The individual groups were compared for their significance (P<0.05) using a nonparametric test. Up to a resection depth of 1.5 cm, the ventilated resection surfaces were completely airtight regardless of the laser power. From a depth of resection of 1.5 cm, a mean air volume loss of 28.9±5.3 mL/respiratory cycle at 40 watts and of 26.4±5.8 mL at 60 watts was found. Additional surface coagulation did not significantly reduce the leakage rate. In contrast, suturing significantly reduced (P<0.0001) to 7.2±3.7 mL/ventilation (40 watts) and 6.0±3.4 mL/ventilation. At a resection depth of 2 cm, the leakage volume was 42.9±3.3 mL/respiratory cycle (40 watt) and 46.3±6.4 mL/respiratory cycle (60 watt). Additional surface coagulation failed to significantly reduce leakage volume, but suture closure provided airtightness. In non-ventilated porcine lungs, Nd:YAG laser resection surfaces up to a resection depth of 1.5 cm are airtight after ventilation onset. From a depth of 1.5 cm, closure of resection surfaces by an additional suture is needed. Airtightness of resection surfaces was not increased by additional coagulation.

Lung ultrasound surface wave elastography

Lung ultrasound surface wave elastography (LUSWE) was developed for noninvasively measuring superficial lung tissue stiffness. In LUSWE, a 0.1 second harmonic vibration is generated on the chest wall of a subject using a handheld vibrator. An ultrasound probe is aligned with the vibration excitation in the same intercostal space to measure the generated surface wave propagation on the lung. A human subject is examined in a sitting position. The lung is tested at the total lung volume and through three intercostal spaces on each lung. In a prospective clinical study, we measure the lung surface wave speeds at 100 Hz, 150 Hz, and 200 Hz on 91 patients with interstitial lung disease (ILD) and 30 healthy control subjects. Significant differences of wave speed between patients and controls were found in all 6 lung regions and for 3 frequencies. We also found positive correlation between LUSWE and clinical assessments including CT and pulmonary function tests. LUSWE is used to track the changes of surface wave speed for patients. LUSWE is a safe and noninvasive technique for generating and measuring surface wave propagation on the lung. LUSWE may complement the clinical standard high-resolution computed tomography for assessing ILD.Lung ultrasound surface wave elastography (LUSWE) was developed for noninvasively measuring superficial lung tissue stiffness. In LUSWE, a 0.1 second harmonic vibration is generated on the chest wall of a subject using a handheld vibrator. An ultrasound probe is aligned with the vibration excitation in the same intercostal space to measure the generated surface wave propagation on the lung. A human subject is examined in a sitting position. The lung is tested at the total lung volume and through three intercostal spaces on each lung. In a prospective clinical study, we measure the lung surface wave speeds at 100 Hz, 150 Hz, and 200 Hz on 91 patients with interstitial lung disease (ILD) and 30 healthy control subjects. Significant differences of wave speed between patients and controls were found in all 6 lung regions and for 3 frequencies. We also found positive correlation between LUSWE and clinical assessments including CT and pulmonary function tests. LUSWE is used to track the changes of surface wave ...

COPD-Type lung inflammation promotes K-ras mutant lung cancer through epithelial HIF-1α mediated tumor angiogenesis and proliferation.

Chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, is an independent risk factor for lung cancer. Lung tissues obtained from human smokers with COPD and lung cancer demonstrate hypoxia and up-regulated hypoxia inducible factor-1 (HIF-1). HIF-1 activation is the central mechanism for controlling the cellular response to hypoxia during inflammation and tumor development. These facts suggest a link between COPD-related airway inflammation, HIF-1, and lung cancer. We have previously established a mouse model of COPD-like airway inflammation that promotes lung cancer in a K-ras mutant mouse model (CC-LR). Here we show that tumors in the CC-LR model have significantly elevated levels of HIF-1α and HIF-1 activity. To determine the tumor-promoting functions of HIF-1 in CC-LR mice, the gene Hif1a which encodes HIF-1α and is required for HIF-1 activity, was disrupted in the lung epithelium of CC-LR animals. Airway epithelial specific HIF-1α deficient mice demonstrated significant reductions in lung surface tumor numbers, tumor angiogenesis, and tumor cell proliferation in the absence or presence of COPD-like airway inflammation. In addition, when CC-LR mice were bred with transgenic animals that overexpress a constitutively active mutant form of human HIF-1α in the airway epithelium, both COPD- and adenocarcinoma-like phenotypes were observed. HIF-1α overexpressing CC-LR mice had significant emphysema, and they also showed potentiated tumorigenesis, angiogenesis, and cell proliferation accompanied by an invasive metastatic phenotype. Our gain and loss of function studies support a key role for HIF-1α in the promotion of lung cancer by COPD-like inflammation.

Characteristics of pulmonary function and pathological changes following acute lung injury in rats

Objective To investigate the characteristics of pulmonary function and pathological changes in rats with acute lung injury (ALI) and provide experimental basis for further study on the mechanism of ALI. Methods Twenty five male SD rats were randomly divided into the control group (n=5) and acute lung injury (ALI) group (n=20). Lipopolysaccharide (LPS) (4.5 mg/kg) were injected into the ALI group rats to establish the ALI rat model. The rats in control group were given 150 μl isotonic saline. At 12, 24, 48, and 72 hours after injury, lung function of the rats were tested by Buxco small animal lung function test system, including the dynamic lung compliance (Cdyn), forced vital capacity (FVC), functional residual gas (FRC), quasi static compliance (Cchord), 100th millisecond expiratory volume (FEV100), and airway resistance (RI). In addition, the bronchoalveolar lavage fluid (BALF) was collected for detection of protein level and tumor necrosis factor (TNF-alpha) concentration. At the same time, the changes of lung tissues were recorded, and the pathological changes were observed by HE staining. Results Compared with the control group, Cdyn, FVC, FRC, and FEV100 in ALI group were significantly decreased at each time point after injury (P 0.05). The protein level and TNF-alpha concentration of BALF in ALI group were increased significantly (P<0.05 or <0.01) 12-72 hours after injury (P<0.01). Compared with the control group, the whole lung was dark red in ALI group 12 hours after injury, and the most serious bleeding occurred in the pulmonary hilum area with single or multiple hemorrhagic foci of different sizes. Multiple punctate and focal bleeding of different sizes were seen on the lung surface, which were radially distributed around the pulmonary hilum. The color of lung tissue was gradually restored to normal at 72 hours after injury. Under the light microscope, pulmonary interstitial edema, inflammatory cell infiltration, pulmonary vascular congestion and focal pulmonary hemorrhage were observed 12 h after injury, showing typical ALI pathological changes. The pathological changes were the most significant at 24 hours and reduced obviously at 72 hours. Conclusions A single intratracheal injection of LPS can induce typical ALI pathological changes. There is a similar trend between the pulmonary function indexes, lung pathology characteristics, and the protein level of BALF and proinflammatory cytokine level, suggesting that the pulmonary function test parameters can provide reference for evaluation of ALI. Key words: Lipopolysaccharide; Acute lung injuries; Respiratory function tests; Tumor necrosis factor α

Free radicals and ultrafine particulate emissions from the co-pyrolysis of Croton megalocarpus biodiesel and fossil diesel

BackgroundThe atmosphere has become a major transport corridor for free radicals and particulate matter from combustion events. The motivation behind this study was to determine the nature of particulate emissions and surface bound radicals formed during the thermal degradation of diesel blends in order to assess the health and environmental hazards of binary transport fuels.MethodologyAccordingly, this contribution explored the interactions that occur when Croton megalocarpus biodiesel and fossil diesel in the ratio of 1:1 by weight were co-pyrolyzed in a quartz reactor at a residence time of 0.5 s under an inert flow of nitrogen at 600 °C. The surface morphology of the thermal char formed were imaged using a Feld emission gun scanning electron microscope (FEG SEM) while Electron paramagnetic resonance spectrometer (EPR) was used to explore the presence of free radicals on the surface of thermal char. Molecular functional groups adsorbed on the surface of thermal char were explored using Fourier transform infrared spectroscopy (FTIR).ResultsFTIR spectrum showed that the major functional groups on the surface of the char were basically aromatic and some methylene groups. The particulate emissions detected in this work were ultrafine (~ 32 nm). The particulates are consistent with the SEM images observed in this study. Electron paramagnetic resonance results gave a g-value of 2.0027 characteristic of carbon-based radicals of aromatic nature. Spectral peak-to-peak width (∆Hp-p) obtained was narrow (4.42 G).ConclusionsThe free radicals identified as carbon-based are medically notorious and may be transported by various sizes of particulate matter on to the surface of the human lung which may trigger cancer and pulmonary diseases. The nanoparticulates determined in this work can precipitate severe biological health problems among humans and other natural ecosystems.