Decreased pulmonary levels of the anti-inflammatory Clara cell 16 kDa protein after induction of airway inflammation in asthmatics

The Clara cell 16 kDa protein (CC16) maps to an atopy-associated region of chromosome 11 and has been ascribed an anti-inflammatory function. Using reverse-phase HPLC and Western blot analysis, we have evaluated the polypeptide pattern in bronchoalveolar lavage (BAL) fluid retrieved from asthmatics, before and after induction of airway inflammation by low-dose allergen inhalation challenge. A prominent decrease of CC16 was seen after induction of inflammation, and a further CC16 decrease was observed in lavage fluid where surfactant had been removed. Reduced levels of pulmonary CC16 may cause loss of anti-inflammatory activity in the airways and contribute to the development of airway inflammation in asthma. Received 22 March 2000; received after revision 4 May 2000; accepted 4 May 2000     

Damage-associated molecular patterns and their receptors in upper airway pathologies

Inflammation of the nasal (rhinitis) and sinus mucosa (sinusitis) are prevalent medical conditions of the upper airways that are concurrent in many patients; hence the terminology “rhinosinusitis”. The disease status is further defined to be “chronic” in case symptoms persist for more than 12 weeks without resolution. A diverse spectrum of external factors including viral and bacterial insults together with epithelial barrier malfunctions could be implicated in the chronicity of the inflammatory responses in chronic rhinosinusitis (CRS). However, despite massive research efforts in an attempt to unveil the pathophysiology, the exact reason for a lack of resolution still remains poorly understood. A novel set of molecules that could be implicated in sustaining the inflammatory reaction may be found within the host itself. Indeed, besides mediators of inflammation originating from outside, some endogenous intracellular and/or extracellular matrix (ECM) components from the host can be released into the extracellular space upon damage induced during the initial inflammatory reaction where they gain functions distinct from those during normal physiology. These “host-self” molecules are known to modulate inflammatory responses under pathological conditions, potentially preventing resolution and contributing to the development of chronic inflammation. These molecules are collectively classified as damage-associated molecular patterns (DAMPs). This review summarizes the current knowledge regarding DAMPs in upper airway pathologies, also covering those that were previously investigated for their intracellular and/or ECM functions often acting as an antimicrobial agent or implicated in tissue/cell homeostasis, and for which their function as a danger signaling molecule was not assessed. It is, however, of importance to assess these molecules again from a point of view as a DAMP in order to further unravel the pathogenesis of CRS.     

Molecular and Cellular Basis of Regeneration and Tissue Repair

The Xenopus tadpole is a favourable organism for regeneration research because it is suitable for a wide range of micromanipulative procedures and for a wide range of transgenic methods. Combination of these techniques enables genes to be activated or inhibited at specific times and in specific tissue types to a much higher degree than in any other organism capable of regeneration. Regenerating systems include the tail, the limb buds and the lens. The study of tail regeneration has shown that each tissue type supplies the cells for its own replacement: there is no detectable de-differentiation or metaplasia. Signalling systems needed for regeneration include the BMP and Notch signalling pathways, and perhaps also the Wnt and FGF pathways. The limb buds will regenerate completely at early stages, but not once they are fully differentiated. This provides a good opportunity to study the loss of regenerative ability using transgenic methods.     

A comparative study of proteoglycans from bovine lung,trachea, tracheal mucosa,and aorta

Summary Proteoglycans were isolated from bovine lung, trachea, tracheal mucosa, and aorta by dissociative extraction with 4M guanidinium hydrochloride. Fractionation of these tissue extracts by cesium chloride density centrifugation and gel chromatography allowed the isolation from each extract of a high molecular weight fraction consisting mainly of proteochondroitin sulfate and hyaluronic acid.Acknowledgment. This work was supported by a National Heart, Lung, and Blood Institute grant to K. Ehrlich (HL21617).     

Knowledge translation: airway epithelial cell migration and respiratory diseases

Airway epithelial cell migration is essential for lung development and growth, as well as the maintenance of respiratory tissue integrity. This vital cellular process is also important for the repair and regeneration of damaged airway epithelium. More importantly, several lung diseases characterized by aberrant tissue remodeling result from the improper repair of damaged respiratory tissue. Epithelial cell migration relies upon extracellular matrix molecules and is further regulated by numerous local, neuronal, and hormonal factors. Under inflammatory conditions, cell migration can also be stimulated by certain cytokines and chemokines. Many well-known environmental factors involved in the pathogenesis of chronic lung diseases (e.g., cigarette smoking, air pollution, alcohol intake, inflammation, viral and bacterial infections) can inhibit airway epithelial cell migration. Further investigation of cellular and molecular mechanisms of cell migration with advanced techniques may provide knowledge that is relevant to physiological and pathological conditions. These studies may eventually lead to the development of therapeutic interventions to improve lung repair and regeneration and to prevent aberrant remodeling in the lung.     

Novel approaches to the treatment of small-cell lung cancer

Small-cell lung cancer (SCLC) is characterized by its initial responsiveness to chemotherapy and the appearance of early metastases. Although combination chemotherapy, in some instances together with radiation, has improved the prognosis of this disease, in most patients SCLC ultimately recurs in a drug-resistant form. Several new strategies for the eradication of SCLC are being explored at the preclinical level. The identification of selective target molecules on the surface of SCLC cells, together with the progress made in antibody engineering, have provided new generations of antibodies and immunoconjugates as well as growth factor antagonists and inhibitors. In addition, recent advances in understanding the biology of SCLC have stimulated new investigations searching to counter the molecular basis underlying the increased proliferation and the apoptosis deficiency of SCLC cells. This can be achieved using antisense oligodeoxynucleotides that repress the expression of growth factor receptors and anti-apoptosis genes, or by gene replacement to compensate for the loss or inactivation of tumor suppressor genes.     

iPSCs-based generation of vascular cells: reprogramming approaches and applications

Recent advances in the field of induced pluripotent stem cells (iPSCs) research have opened a new avenue for stem cell-based generation of vascular cells. Based on their growth and differentiation potential, human iPSCs constitute a well-characterized, generally unlimited cell source for the mass generation of lineage- and patient-specific vascular cells without any ethical concerns. Human iPSCs-derived vascular cells are perfectly suited for vascular disease modeling studies because patient-derived iPSCs possess the disease-causing mutation, which might be decisive for full expression of the disease phenotype. The application of vascular cells for autologous cell replacement therapy or vascular engineering derived from immune-compatible iPSCs possesses huge clinical potential, but the large-scale production of vascular-specific lineages for regenerative cell therapies depends on well-defined, highly reproducible culture and differentiation conditions. This review will focus on the different strategies to derive vascular cells from human iPSCs and their applications in regenerative therapy, disease modeling and drug discovery approaches.     

Modelling gene regulation: (De)compositional and template-based strategies

Although the interdisciplinary nature of contemporary biological sciences has been addressed by philosophers, historians, and sociologists of science, the different ways in which engineering concepts and methods have been applied in biology have been somewhat neglected. We examine – using the mechanistic philosophy of science as an analytic springboard – the transfer of network methods from engineering to biology through the cases of two biology laboratories operating at the California Institute of Technology. The two laboratories study gene regulatory networks, but in remarkably different ways. The research strategy of the Davidson lab fits squarely into the traditional mechanist philosophy in its aim to decompose and reconstruct, in detail, gene regulatory networks of a chosen model organism. In contrast, the Elowitz lab constructs minimal models that do not attempt to represent any particular naturally evolved genetic circuits. Instead, it studies the principles of gene regulation through a template-based approach that is applicable to any kinds of networks, whether biological or not. We call for the mechanists to consider whether the latter approach can be accommodated by the mechanistic approach, and what kinds of modifications it would imply for the mechanistic paradigm of explanation, if it were to address modelling more generally.     

海藻生物活性物质研究的回顾与展望

本文简要介绍了海藻来源的生物活性物质研究概况，并对生物技术在这一领域的应用前景做了初步的讨论与展望.作为海洋中有机物的原始生产者，海藻含有多种生物活性物质，包括抗肿瘤、抗病毒、抗菌活性物质、抗氧化剂、免疫调节剂、酶抑制剂等.而人工栽培、组织培养、细胞工程、基因工程等生物技术在海藻生物活性物质研究领域的应用将有可能为海藻生物活性物质的研究与开发提供高效费比的药源解决方案。     

海藻酸钠及其复合材料在生物医药中的研究进展

海藻酸钠具有良好的生物相容性和吸湿性能,其复合材料具有优异的力学性能和降解可控性能,可以作为药物的载体材料和组织工程中的支架材料。本文综述了海藻酸钠及其复合材料在缓控释制剂中、组织工程中以及医用敷料中的研究进展。     

A comparison of models for forecasting the discovery of hydrocarbon deposits

There are many geologic resource assessment techniques available that can be used to estimate the hydrocarbon potential of frontier basins. The techniques do not, however, produce discovery rate forecasts, which are critical to government and industry planners. Various methods of predicting the discovery rate in frontier basins are reviewed and appraised within the context of the drilling history of Canada's Scotian Shelf. The reviewed models include a mean historical discovery rate technique, the exponential decline model, a logistic curve technique and a class of models based on a sampling without replacement approach to prediction. Models are found to perform best over the longer forecast horizons, with those models based on the sampling without replacement technique tending to perform best.     

Molecular and engineering approaches to regenerate and repair teeth in mammals

Continuous replacement of teeth throughout the lifespan of an individual is possibly basal for most of the vertebrates including fish and reptiles; however, mammals generally have a limited capacity of tooth renewal. The ability to induce cellular differentiation in adults to replace lost or damaged cells in mammals, or to tissue-engineer organs in vitro, has hence become one of the major goals of regenerative medicine. In this article, we will revisit some of the important signals and tissue interactions that regulate mammalian tooth development, and will offer a synopsis of the latest progress in tooth regeneration and repair via molecular and engineering approaches. It is hoped that this article will not only offer an overview of recent technologies in tooth regeneration and repair but will also stimulate more interdisciplinary research in this field to turn the pursuit of tooth regeneration and repair into practical reality.     

Enzymes and receptors in the leukotriene cascade

Leukotrienes are a family of paracrine hormones derived from the oxidative metabolism of arachidonic acid. These lipid mediators are recognized as important signal molecules in a variety of inflammatory and allergic conditions affecting the skin, joints, gastrointestinal and respiratory systems, in particular asthma. Such conditions are typified by local pain, tissue edema, hyperemia and functional losses. In the tissues, immunocompetent cells accumulate at the site of injury which contribute to tissue damage and perpetuation of the disease process. Leukotrienes can elicit most, if not all, of these signs and symptoms. Thus, leukotriene B₄ is one of the most powerful chemotactic agents known to date and participates in the recruitment of leukocytes. The cysteinyl leukotrienes, on the other hand, contract smooth muscles, particularly in the peripheral airways and microcirculation. Recently, drugs which block the formation and action of leukotrienes have been introduced as novel antiasthmatic medications. This chapter reviews the biochemistry, molecular biology and cell biology of the key enzymes and cognate receptors in the leukotriene cascade.     

An aggregate sales model for consumer durables incorporating a time‐varying mean replacement age

Forecasting category or industry sales is a vital component of a company's planning and control activities. Sales for most mature durable product categories are dominated by replacement purchases. Previous sales models which explicitly incorporate a component of sales due to replacement assume there is an age distribution for replacements of existing units which remains constant over time. However, there is evidence that changes in factors such as product reliability/durability, price, repair costs, scrapping values, styling and economic conditions will result in changes in the mean replacement age of units. This paper develops a model for such time‐varying replacement behaviour and empirically tests it in the Australian automotive industry. Both longitudinal census data and the empirical analysis of the replacement sales model confirm that there has been a substantial increase in the average aggregate replacement age for motor vehicles over the past 20 years. Further, much of this variation could be explained by real price increases and a linear temporal trend. Consequently, the time‐varying model significantly outperformed previous models both in terms of fitting and forecasting the sales data. Copyright © 2001 John Wiley & Sons, Ltd.     

Bioassay for hamster macrophage chemotaxis: application to study particle-lung interactions

Attraction of lung macrophages to particle deposition sites has been demonstrated in different animal species. We reported a threefold increase of the number of macrophages to occur within 40 min after polystyrene particle deposition in hamster airways [Geiser et al. (1994) Am. J. Respir. Cell Mol. Biol. 160: 594–603]. Complement-derived chemotactic activity is one of the mechanisms postulated for macrophage recruitment. It was the aim of this study to test whether complement-derived chemotactic activity is involved in the rapid recruitment of macrophages to the site of deposited polystyrene particles in hamster airways. We first developed an in vitro cell migration assay for hamster macrophages to assess complement-derived chemotaxis. Second, the bronchoalveolar lavage fluids (BALF) of four hamsters that had inhaled aerosols of polystyrene microspheres were tested for chemotactic activity by this bioassay and compared with BALF of four sham-exposed hamsters. Chemotactic response of macrophages was found toward complement-activated hamster serum, whereas macrophage migration was not increased toward BALF of particle and sham-exposed hamsters. In contrast, macrophage migration to BALF of both groups was reduced by 1.6-fold. Thus, the stimulus for macrophage recruitment to the site of deposited polystyrene particles in hamster airways could not be demonstrated using this bioassay. Received 10 September 1997; received after revision 24 November 1997; accepted 10 December 1997     

Regulatory peptides in the respiratory system

Many regulatory peptides have been described in the respiratory tract of animals and humans. Some peptides (bombesin, calcitonin, calcitonin gene-related peptide) are localised to neuroendocrine cells and may have a trophic or transmitter role. Others are localised to motor nerves. Vasoactive intestinal peptide and peptide histidine isoleucine are candidates for neurotransmitters of non-adrenergic inhibitory fibres and may be cotransmitters in cholinergic nerves. These peptides may regulate airway smooth muscle tone, bronchial blood flow and airway secretions. Sensory neuropeptides (substance P, neurokinin A and B, calcitonin gene-related peptide) may contract airway smooth muscle, stimulate mucus secretion and regulate bronchial blood flow and microvascular permeability. If released by an axon reflex mechanism these peptides may be involved in the pathogenesis of asthma. Other peptides, such as galanin and neuropeptide Y, are also present but their function is not yet known.     

Regulatory peptides in the respiratory system

Summary Many regulatory peptides have been described in the respiratory tract of animals and humans. Some peptides (bombesin, calcitonin, calcitonin gene-related peptide) are localised to neuroendocrine cells and may have a trophic or transmitter role. Others are localised to motor nerves. Vasoactive intestinal peptide and peptide histidine isoleucine are candidates for neurotransmitters of non-adrenergic inhibitory fibres and may be cotransmitters in cholinergic nerves. These peptides may regulate airway smooth muscle tone, bronchial blood flow and airway secretions. Sensory neuropeptides (substance P, neurokinin A and B, calcitonin gene-related peptide) may contract airway smooth muscle, stimulate mucus secretion and regulate bronchial blood flow and microvascular permeability. If released by an axon reflex mechanism these peptides may be involved in the pathogenesis of asthma. Other peptides, such as galanin and neuropeptide Y, are also present but their function is not yet known.     

Inhaled and exhaled nitric oxide

Inhaled nitric oxide (NO) is used to treat various cardiopulmonary disorders associated with pulmonary hypertension. The rationale is based on the fact that NO, given by inhalation, only dilates those pulmonary vessels that perfuse well-ventilated lung units. As a result, pulmonary gas exchange is improved while pulmonary vascular resistance is reduced and pulmonary blood flow is increased. Inhaled NO has been succesfully applied to treat persistent pulmonary hypertension of the newborn, reducing the need for extracorporeal life support. Although pulmonary hypertension and altered vasoreactivity contribute to profound hypoxaemia in adult and paediatric acute respiratory distress syndrome (ARDS), the benefit of inhaled NO still remains to be established in patients with ARDS. ARDS is a complex response of the lung to direct or indirect insults, leading to pulmonary vasoconstriction and various inflammatory responses. Recent randomized trials suggest that inhaled NO only causes a transient improvement in oxygenation. Whether this effect is important in the long-term management of ARDS remains to be established. NO, measured in the exhaled breath, is an elegant and non-invasive means to monitor inflammation of the upper and lower respiratory tract. In the normal upper airways, the bulk of exhaled NO originates from the paranasal sinuses. Exhaled NO is increased in nasal allergy and decreased in cystic fibrosis, nasal polyposis and chronic sinusitis. That NO production is increased in asthmatic airways is also well established. However, several questions still need to be addressed, in particular evaluation of the sensitivity and specificity of the measurement techniques, and assessment of the bronchodilator action of endogenous NO.