Assessment of peripheral lung mechanics

The mechanical properties of the lung periphery are major determinants of overall lung function, and can change dramatically in disease. In this review we examine the various experimental techniques that have provided data pertaining to the mechanical properties of the lung periphery, together with the mathematical models that have been used to interpret these data. These models seek to make a clear distinction between the central and peripheral compartments of the lung by encapsulating functional differences between the conducing airways, the terminal airways and the parenchyma. Such a distinction becomes problematic in disease, however, because of the inevitable onset of regional variations in mechanical behavior throughout the lung. Accordingly, lung models are used both in the inverse sense as vehicles for extracting physiological insight from experimental data, and in the forward sense as virtual laboratories for the testing of specific hypothesis about mechanisms such as the effects of regional heterogeneities. Pathologies such as asthma, acute lung injury and emphysema can alter the mechanical properties of the lung periphery through the direct alteration of intrinsic tissue mechanics, the development of regional heterogeneities in mechanical function, and the complete derecruitment of airspaces due to airway closure and alveolar collapse. We are now beginning to decipher the relative contributions of these various factors to pathological alterations in peripheral lung mechanics, which may eventually lead to the development and assessment of novel therapies.     

Neuroepithelial bodies and growth of the airway epithelium in developing hamster lung

Clusters of small-granule endocrine cells, neuroepithelial bodies (NEBs), appear in the airway lining of pseudoglandular lungs, but their prenatal function has remained obscure. Transplacental labeling of S-phase cells in Syrian golden hamsters has allowed us to relate NEBs to patterns of replication in the surrounding endoderm. Two methods were used: (1) continuous exposure to ³H-thymidine for the last 25% (4 days) of gestation, and 2) 2-hr exposure to 5-bromo-2′-deoxyuridine (BrdU) on fetal day 15. ³H-thymidine incorporation was assessed in autoradiographs of neonatal lung by grain counting from 923 nonendocrine and 251 endocrine cells in 28 airway epithelial terrains, each centered on a NEB: 12 in the perihilar, 8 in the middle, and 8 in the distal third of the left axial bronchus. Grain densities for 10–25 nonendocrine cells on either side of the NEB were plotted vs. position relative to the endocrine cell cluster and analyzed by rank-order correlation and linear regression. Label was highest in cells closest to NEBs in all 12 terrains (P < 0.05–0.001) in the perihilar airway, in 3 of 8 terrains (P < 0.025–0.001) in the middle third of the bronchus, and in respective, pooled populations (P < 0.001). The effect was not demonstrable in the distal third of the airway. In the 15-day fetus 243 mm of airway perimeter were measured and 3,218 BrdU-labeled epithelial cells counted from sections through the entire length of the left axial airway and the lobar bronchus, intermediate, and terminal bronchioles of the infracardiac (IC) lobe. Overall, 43% of BrdU-labeled cells and only 24% of epithelium lay within 20 μm of NEBs. Preferential concentration of S-phase cells around NEBs was significant (P < 0.001) by X² test at all airway levels. Net density of NEB-associated BrdU + cells was 10/mm of basal lamina in the trachea, rose distally along the left axial airway to 22/mm at the end of the undivided bronchus, and fell to 15/mm in the terminal channels. It was 9 cells/mm in terminal bronchioles of the infracardiac lobe. Regional differences in ³H-thymidine and BrdU labeling patterns can be correlated with differences in the age of NEBs. We conclude that NEBs regulate local cell proliferation in developing hamster airway, probably activated in a proximal-to-distal wave reflecting maturational changes in the NEBs along the same gradient. © 1993 Wiley-Liss, Inc.     

Maternal malnutrition during lactation reduces skull growth in weaned rat pups: experimental and morphometric investigation

The purpose of the present study was to evaluate the effects of maternal protein and energy restriction during lactation on the bodyweight and skull dimensions of pups at weaning. At parturition, Wistar rat dams were randomly assigned to the following groups: (i) control group (C), free access to a standard laboratory diet containing 23% protein; (ii) protein–energy-restricted group (PER), free access to an isoenergetic, protein-restricted diet containing 8% protein; and (iii) energy-restricted group (ER), restricted amounts of a standard laboratory diet. The dimensions of excised pup skulls were measured directly using pre-established anatomical points. Morphometrical analysis of the skulls showed that most of the measurements in the ER and PER groups were significantly lower than in the control group, with the greatest reductions occurring in the PER group. These results show that protein and energy restriction during lactation have an important influence on pup skull development.     

Vertebrate lungs: structure, topography and mechanics. A comparative perspective of the progressive integration of respiratory system, locomotor apparatus and ontogenetic development

Vertebrate lungs are highly diverse in their structure, topographical position, ventilation mechanisms, constructional integration into the locomotor apparatus, and the interrelationships with the mode of their ontogenetic development. Vertebrate lungs evolved as supplementary air-breathing organs in primary fishes, being ventilated by buccal pumping. In most recent fishes the lungs are transformed into the hydrostatic swimbladder. This basic type of unicameral lungs and their buccal pumping ventilation are also found in recent amphibians. Land vertebrates developed a very efficient aspiration type of ventilation. In most recent reptiles the lungs are subdivided into three rows of lung chambers, enlarging the exchange surface in correlation to their increasing metabolic needs. The avian respiratory apparatus, with its volume-constant lungs and highly compliant air sacs, and the mammalian broncho-alveolar lung, with its very low compliance, are both derived from multicameral lungs. The avian and the mammalian respiratory systems are integrated very differently with the specific constructions of their locomotor apparatusses and the specific mode of their ontogenetic development.     

角化生长因子在慢性肺疾病早产大鼠的表达

目的探讨高氧致CLD早产大鼠KGF表达的变化规律.方法 60只新生早产大鼠随机分为2组,每组30只:A组-对照组;B组-高氧组(吸入95%O2).分别采用Western Blotting及RT-PCR检测肺组织KGF及其mRNA表达.结果高氧组肺内KGF及其mRNA表达高于对照组.结论高氧引起新生早产大鼠肺内KGF及其mRNA的表达随时间发生变化.     

Morphometry and allometry of the postnatal marsupial lung development: an ultrastructural study

An utrastructural morphometric study of the postnatally remodelling lungs of the quokka wallaby (Setonix brachyurus) was undertaken. Allometric scaling of the volumes of the parenchymal components against body mass was performed. Most parameters showed a positive correlation with body mass in all the developmental stages, except the volume of type II pneumocytes during the alveolar stage. The interstitial tissue and type II cell volumes increased slightly faster than body mass in the saccular stage, their growth rates declining in the alveolar stage. Conversely, type I pneumocyte volumes increased markedly in both the saccular and alveolar stages. Both capillary and endothelial volumes as well as the capillary and airspace surface areas showed highest rates of increase during the alveolar stage, at which time the rate was notably higher than that of the body mass. The pulmonary diffusion capacity increased gradually, the rate being highest in the alveolar stage and the adult values attained were comparable to those of eutherians.     

Decreased Beclin-1 expression is correlated with the growth of the primary tumor in patients with squamous cell carcinoma and adenocarcinoma of the lung

Beclin-1 is a Bcl-2-interacting protein, and it may delay cell cycle progression and induce autophagy. The function and expression of Beclin-1 and Bcl-2 in squamous cell carcinoma and adenocarcinoma of the lung remain largely unknown. Herein, we investigated the expression of Beclin-1 and Bcl-2 in squamous cell carcinoma and adenocarcinoma of the lung. Tissue samples from 262 cases were used in this study. Immunohistochemical staining for Beclin-1 and Bcl-2 were conducted using a tissue microarray. In squamous cell carcinoma, Beclin-1 expression was strongly positive in 48 (28.6%) of 168 samples, it was moderately positive in 42 (25.0%) of 168 samples, and it was negative or weakly positive in 78 (46.4%) of 168 samples. In adenocarcinoma, Beclin-1 expression was strongly positive in 26 (27.7%) of 94 samples, it was moderately positive in 27 (28.7%) of 94 samples, and it was negative or weakly positive in 41 (43.6%) of 94 samples. Beclin-1 expression was inversely correlated with the tumor size and the primary tumor stage (pT) in both types of tumor. Especially, the TNM stage of adenocarcinoma was inversely correlated with Beclin-1 expression. Our results suggest that a progressively reduced Beclin-1 expression is correlated with the primary tumor growth of squamous cell carcinoma and adenocarcinoma of the lung.     

Measurement of respiratory mechanics in a mechanically ventilated infant lung simulator: effects of variations in the frequency response of the flow measurement system

The frequency responses of systems used to measure flow and pressure in ventilated infants may differ, and hence affect estimates of resistance and compliance. We estimated resistance and compliance in 16 ventilated mechanical lung models using linear regression while varying the frequency response of the flow measurement system. Lung models comprised combinations of four sections of tubing and four bottles filled with steel wool. The cut-off frequencies of a filter in the flow measurement system were chosen to yield time delays of 0, ±3, ±6, and ±9 ms relative to the pressure signal. When the phase lags in the measurement systems were not equal at 10 Hz, a bias in resistance ≈(relative delay) × (elastance) ensued. The bias in the resistance estimate when resistance is 5 Pa ml⁻¹ s and compliance is 2 ml kPa⁻¹ is approximately 28% per ms of delay mismatch. Time-shifting the flow data to eliminate the phase discrepancy reduced the resistance bias by 85%. The residual resistance bias was assumed to be due to inappropriate amplitude response. Compliance measurements were affected by less than 8% and less than 2% after time correction of the flow data. Pressure and flow signals must be synchronized to within 1 ms at 10 Hz and the amplitude responses of the measurement systems must be adequate for reliable resistance measurement.     

人肺癌细胞中生长因子的自泌循环和癌基因表达

用Ｎｏｒｔｈｅｒｎ核酸杂交技术对４个人肺癌细胞系进行了表皮生长因子（ＥＧＦ）、转化生长因子α（ＴＧＦα）以及表皮生长因子受体（ＥＧＦＲ）的基因表达研究，发现这些肺癌细胞系中均有ＥＧＦ和ＴＧＦ＿α的基因表达，３／４中亦有ＥＧＦＲ的基因表达。这些癌细胞系中自泌的生长因子作用于自身的ＥＧＦ受体形成的自泌循环，不断刺激其自身的增殖，这可能是癌细胞无休止生长的主要原因之一。Ｎｏｒｔｈｅｒｎ核酸杂交结果还表明：在这４个肺癌细胞系中，无ｃ－ｍｙｃ癌基因表达的细胞系中有大量的ＥＧＦ和ＴＧＦα的基因表达。用ＥＧＬ抗ＥＧＦ和抗ＥＧＦＲ抗体处理这些人肺癌细胞系，抗ＥＧＦ和抗ＥＧＦＲ抗体在一定程度上可抑制其增殖，这也说明这些癌细胞中生长因子自泌环路的存在。     

血管内皮生长因子C及其受体3在非小细胞肺癌组织中的表达及意义

目的　探讨血管内皮生长因子C(VEGF C)和受体 (VEGFR) 3在人非小细胞肺癌(NSCLC)组织中的表达及其与微血管、微淋巴管形成、淋巴转移、预后之间的关系。方法　对 76例人NSCLC及相应癌旁组织行VEGF C、VEGFR 3及CD34免疫组织化学染色链霉素抗生物素蛋白 过氧化物酶 (SP)法检测 ,进行淋巴管密度计数、微血管密度 (MVD)计数 ,并结合临床和病理资料进行分析。结果　NSCLC中 ,VEGF C的表达与肺癌分化程度负相关 (P =0 0 0 9)。VEGF C和VEGFR 3的表达水平与淋巴结转移呈正相关 (分别P =0 0 0 8,P =0 0 13) ,与淋巴浸润呈正相关 (分别P =0 0 2 7,P =0 0 2 0 )。VEGF C的表达与VEGFR 3在肺癌细胞中的表达呈正相关 (P =0 0 0 9)。VEGF C与淋巴管密度 (P =0 0 0 6 )、MVD(P =0 0 4 6 )呈正相关。淋巴管密度与淋巴结转移 (P =0 0 10 )、淋巴浸润 (P =0 0 19)、TNM分期 (P =0 0 15 )呈正相关 ,MVD与血行转移 (P <0 0 0 1)、TNM分期 (P <0 0 0 1)呈正相关。VEGF C阳性表达与生存时间、5年生存率呈负相关 (P <0 0 0 1)。结论　NSCLC中 ,VEGF C通过自分泌方式作用于受体VEGFR 3,促进肺癌组织生长 ,抑制分化。VEGF C促使肺癌内淋巴管形成 ,促进肺癌淋巴结转移。VEGF C和VEGFR 3表达增高、淋巴管密度增加     

Postnatal Development of the Central Nervous System: Anomalies in the Formation of Cerebellum Fissures

A natural defect in rat cerebellum postnatal development has been found in the fissura prima, consisting in various complex configurations of the cerebellar layers. We investigated the genesis of fissure malformations through immunoreactions for PCNA, GFAP, GABAA α6, and calbindin to label proliferating cells of the external granular layer (egl), radial glial fibers, mature granule cells, and Purkinje cells, respectively. Results on critical stages of rat postnatal development provided interesting evidences on how the malformation develops in fissures prima and secunda. Early (postnatal day 10) at the site of malformation, the Bergmann radial glia was often retracted and showed distortions and irregular running. The interruption of GFAP‐positive radial glial fibers could fit in with the presence of clusters of PCNA‐unlabeled cells in the sites of fusion of the egl; the clusters of cells are granule cells since their soma is labeled by GABAA α6. Moreover, an altered migration of granule cell precursors to the internal granular layer was evident which, in turn, affected Purkinje cell differentiation and the growth of their dendrites. In summary, the changed relationship among glial fiber morphology, granule cell migration, and Purkinje cell differentiation suggests how the Bergmann glial fibers have a basic role in the foliation process, being the driving physical force in directing migration of the granule cells at the base of fissure. Anat Rec, 2010. © 2010 Wiley‐Liss, Inc.     

Ozone Exposure During thE Early Postnatal Period Alters the Timing and Pattern of Alveolar Growth and Development in Nonhuman Primates

Exposure to oxidant air pollutants in early childhood, with ozone as the key oxidant, has been linked to significant decrements in pulmonary function in young adults and exacerbation of airway remodeling in asthma. Development of lung parenchyma in rhesus monkeys is rapid during the first 2 years of life (comparable to the first 6 years in humans). Our hypothesis is that ozone inhalation during infancy alters alveolar morphogenesis. We exposed infant rhesus monkeys biweekly to 5, 8hr/day, cycles of 0.5 ppm ozone with or without house dust mite allergen from 1 to 3 or 1 to 6 months of age. Monkeys were necropsied at 3 and 6 months of age. A morphometric approach was used to quantify changes in alveolar volume and number, the distribution of alveolar size, and capillary surface density per alveolar septa. Quantitative real time PCR was used to measure the relative difference in gene expression over time. Monkeys exposed to ozone alone or ozone combined with allergen had statistically larger alveoli that were less in number at 3 months of age. Alveolar capillary surface density was also decreased in the ozone exposed groups at 3 months of age. At 6 months of age, the alveolar number was similar between treatment groups and was associated with a significant rise in alveolar number from 3 to 6 months of age in the ozone exposed groups. This increase in alveolar number was not associated with any significant increase in microvascular growth as measured by morphometry or changes in angiogenic gene expression. Inhalation of ozone during infancy alters the appearance and timing of alveolar growth and maturation. Understanding the mechanism involved with this altered alveolar growth may provide insight into the parenchymal injury and repair process that is involved with chronic lung diseases such as severe asthma and COPD. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.     

Hyaluronidases and hyaluronan synthases expression is inversely correlated with malignancy in lung/bronchial pre-neoplastic and neoplastic lesions, affecting prognosis

We collected a series of 136 lung/bronchial and 56 matched lung parenchyma tissue samples from patients who underwent lung/bronchial biopsies and presented invasive carcinoma after lung surgery. The lung/bronchial samples included basal cell hyperplasia, squamous metaplasia, moderate dysplasia, adenomatous hyperplasia, severe dysplasia, squamous cell carcinoma and adenocarcinoma. Matched lung parenchyma tissue samples included 25 squamous cell carcinomas and 31 adenocarcinomas. Immunohistochemistry was performed to analyze for the distribution of hyaluronidase (Hyal)-1 and −3, and hyaluronan synthases (HAS)-1, −2, and −3. Hyal-1 showed significantly higher expression in basal cell hyperplasia than in moderate dysplasia (P=0.01), atypical adenomatous hyperplasia (P=0.0001), or severe dysplasia (P=0.03). Lower expression of Hyal-3 was found in atypical adenomatous hyperplasia than in basal cell hyperplasia (P=0.01) or moderate dysplasia (P=0.02). HAS-2 was significantly higher in severe dysplasia (P=0.002) and in squamous metaplasia (P=0.04) compared with basal cell hyperplasia. HAS-3 was significantly expressed in basal cell hyperplasia compared with atypical adenomatous hyperplasia (P=0.05) and severe dysplasia (P=0.02). Lower expression of HAS-3 was found in severe dysplasia compared with squamous metaplasia (P=0.01) and moderate dysplasia (P=0.01). Epithelial Hyal-1 and −3 and HAS-1, −2, and −3 expressions were significantly higher in pre-neoplastic lesions than in neoplastic lesions. Comparative Cox multivariate analysis controlled by N stage and histologic tumor type showed that patients with high HAS-3 expression in pre-neoplastic cells obtained by lung/bronchial biopsy presented a significantly higher risk of death (HR=1.19; P=0.04). We concluded that localization of Hyal and HAS in lung/bronchial pre-neoplastic and neoplastic lesions was inversely related to malignancy, which implied that visualizing these factors could be a useful diagnostic procedure for suspected lung cancer. Finalizing this conclusion will require a wider study in a randomized and prospective trial.     

非小细胞肺癌患者血清VEGF水平和外周血CK19 mRNA的表达

目的： 研究非小细胞肺癌（NSCLC）患者血清血管内皮生长因子(VEGF)水平的变化和外周血中细胞角蛋白19（cytokeratin 19,CK19）mRNA的表达及相互关系。方法： 3组研究对象为NSCLC组患者96例，支气管、肺良性病变组40例，健康对照组25例，分别采用ELISA法进行血清VEGF的检测，RT-PCR法进行外周血CK19 mRNA表达水平的测定。结果： NSCLC组的血清VEGF水平为（346.3±95.6）ng/L,外周血CK19 mRNA的阳性率为63.5%，均显著高于其它2组（P<0.01）；且两者均随临床分期的递增而逐步升高，差异显著（P<0.05）；不同病理类型的NSCLC患者的血清VEGF水平及CK19 mRNA阳性率之间无显著差异（P>0.05）；NSCLC患者外周血CK19 mRNA阳性者，其血清VEGF水平为（407.4±121.2）ng/L，显著高于阴性患者（P<0.01）。结论： VEGF血清水平联合外周血CK19 mRNA的检测有助于对NSCLC的病情和预后进行判断，且不受肺癌病理分型的影响。     

IGF-I和IGF-IR在高氧致新生鼠慢性肺疾病中的动态表达及其作用

目的研究IGF-I、IGF-IR在高氧致新生鼠慢性肺疾病（CLD）中的表达及作用。方法将足月新生大鼠144只随机分为高氧组和空气组,分别于实验1d,3d,7d,10d,14d,21d应用免疫组化和RT-PCR技术检测IGF-I、IGF-IR的动态表达。结果CLD时IGF-I和IGF-IR呈动态变化,高氧组和空气组比较,在实验3d～10d IGF-I和IGF-IR表达明显降低（P〈0.05）,14d和21d表达明显增强（P〈0.05）。结论IGF-I和IGF-IR是肺泡发育的正向调节因子,与CLD时肺泡分隔受阻、肺泡成熟障碍和肺纤维化有关。     

仰俯卧位对早产儿肺炎患儿肺功能的影响

目的探讨仰俯卧位对早产儿肺炎患儿肺功能的影响.方法应用美国Bicore CP-100新生儿肺功能仪分别对30名不吸氧组(SaO2≥90%)和18名吸氧组(SaO2<90%)早产儿肺炎患儿的肺功能值进行检测.结果不吸氧组患儿俯卧位呼吸频率明显低于仰卧位(43.4±10.2 v 49.8±11.7);俯卧位潮气量明显高于仰卧位(3.11±0.92 v 2.48±0.77 ml/kg);俯卧位气道阻力明显低于仰卧位(98.6±50.1 v 117.4±41.5cm H2O/L/s,);俯卧位动态肺顺应性明显高于仰卧位(1.115±0.401 v 0.914±0.48ml/cm H2O/kg);俯卧位呼吸功明显高于仰卧位(8.0±3.8 v 5.9±2.7gm cm/kg).吸氧组患儿俯卧位呼吸频率明显低于仰卧位(52.7±10.2 v 56.1±12.4);潮气量明显高于仰卧位(2.13±0.42 v 1.79±0.66 ml/kg);俯卧位气道阻力明显低于仰卧位(290.4±107.0 v 319.1±104.1cm H2O/L/s);俯卧位动态肺顺应性明显高于仰卧位(0.562±0.192 v 0.488±0.217ml/cm H2O/kg);俯卧位呼吸功明显高于仰卧位(10.1±4.7 v 7.3±3.4gm cm/kg).结论无论吸氧与否俯卧位均可提高患儿的潮气量、动态肺顺应性和呼吸功,降低呼吸频率和气道阻力,俯卧位为早产儿肺炎患儿的适宜体位.