Mitogenic signaling pathways in airway smooth muscle

Increased airway smooth muscle mass has been demonstrated in patients with asthma, bronchopulmonary dysplasia and most recently, cystic fibrosis. These observations emphasize the need for further knowledge of the events involved in airway smooth muscle mitogenesis and hypertrophy. Workers in the field have developed cell culture systems involving tracheal and bronchial myocytes from different species. An emergent body of literature indicates that mutual signal transduction pathways control airway smooth muscle cell cycle entry across species lines. This article reviews what is known about mitogen-activated signal transduction in airway myocytes. The extracellular signal regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI 3-kinase) pathways appear to be key positive regulators of airway smooth muscle mitogenesis; recent studies have also demonstrated specific roles for reactive oxygen and the JAK/STAT pathway. It is also possible that growth factor stimulation of airway smooth muscle concurrently elicits signaling through negative regulatory intermediates such as p38 mitogen-activated protein (MAP) kinase and protein kinase C (PKC) delta, conceivably as a defense against extreme growth.     

Characterization of the interstitial lung diseases via density-based and texture-based analysis of computed tomography images of lung structure and function

RATIONALE AND OBJECTIVES: Efforts to establish a quantitative approach to the computed tomography (CT)-based character ization of the lung parenchyma in interstitial lung disease (including emphysema) has been sought. The accuracy of these tools must be site independent. Multi-detector row CT has remained the gold standard for imaging the lung, and it provides the ability to image both lung structure as well as lung function. MATERIAL AND METHODS: Imaging is via multi-detector row CT and protocols include careful control of lung volume during scanning. Characterization includes not only anatomic-based measures but also functional measures including regional parameters derived from measures of pulmonary blood flow and ventilation. Image processing includes the automated detection of the lungs, lobes, and airways. The airways provide the road map to the lung parenchyma. Software automatically detects the airways, the airway centerlines, and the branch points, and then automatically labels the airway tree segments with a standardized set of labels, allowing for intersubject as well intrasubject comparisons across time. By warping all lungs to a common atlas, the atlas provides the range of normality for the various parameters provided by CT imaging. RESULTS: Imaged density and textural changes mark underlying structural changes at the most peripheral regions of the lung. Additionally, texture-based alterations in the parameters of blood flow may provide early evidence of pathologic processes. Imaging of stable xenon gas provides a regional measure of ventilation which, when coupled with measures of flow, provide for a textural analysis regional of ventilation-perfusion matching. CONCLUSION: With the improved resolution and speed of CT imaging, the patchy nature of regional parenchymal pathology can be imaged as texture of structure and function. With careful control of imaging protocols and the use of objective image analysis methods it is possible to provide site-independent tools for the assessment of interstitial lung disease. There remains a need to validate these methods, which requires interdisciplinary and cross-institutional efforts to gather appropriate data bases of images along with a consensus on appropriate ground truths associated with the images. Furthermore, there is the growing need for scanner manufacturers to focus on not just visually pleasing images, but on quantitatifiably accurate images.     

Nilotinib: a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of leukemias

COPD is a syndrome characterised by progressive airflow limitation caused by chronic inflammation of the airways and lung parenchyma. It is the most common lung disease, carrying a significant mortality, morbidity and healthcare costs worldwide. COPD is associated with increased activity of parasympathetic nervous system that plays a dominant role in the regulation of airways tone. As cholinergic tone seems to be the only reversible component of COPD, muscarinic receptor antagonists (MRAs) represent the most effective class of bronchodilators in COPD. Thus MRAs remain the mainstay of pharmacotherapy in COPD as they increase expiratory flow rate by decreasing airway smooth muscle tone and mucus secretion leading to enhanced lung function. The discovery of the different muscarinic receptor subtypes that are involved in the regulation of airway function led to the development of more subtype-selective MRAs for the treatment of COPD. Furthermore, it has been hypothesised that the compounds preferentially antagonise the muscarinic M3 receptor-mediated effects would provide better clinical efficacy with a reduction in adverse events related to the blockade of other muscarinic receptor subtypes. Based on this hypothesis, the present multi-centre, randomised, placebo-controlled study assessed the effectiveness of selective muscarinic receptor (M3) antagonist through oral delivery in COPD patients.     

DIFFERENTIAL SUSCEPTIBILITY TO OXIDANT EXPOSURE IN INBRED STRAINS OF MICE: NITROGEN DIOXIDE VERSUS OZONE

The contribution of genetic background to the pathogenesis of airway responses to environmental agents including air pollutants is becoming increasingly clear. Characterization of genetic mechanisms of response to these agents may assist in the identification of susceptible individuals and populations. The primary objective of this investigation was to utilize inbred strains of mice to determine (1) whether there was significant genetic contribution in susceptibility to lung injury and inflammation induced by single and repeated acute exposures to nitrogen dioxide (NO2) and (2) whether similar genetic factors control sus- ceptibility to lung injury induced by NO2 and another oxidant, ozone (O3). Nine strains of inbred mice (male, 5-6 wk) were studied: 129/ J, A/ J, AKR/ J, BALB/ cJ, C3H/ HeJ, C57BL/6J, DBA/2J, SJL/J, and SWR/J. Each was exposed for 3 h to filtered air (controls) or 15 ppm NO2, and cellular inflammation, epithelial injury, and cytotoxicity were measured 2, 6, and 24 h thereafter. NO2 exposure caused significant increases in cytotoxicity and lavageable macrophages, epithelial cells, polymorphonuclear leukocytes, and protein in all strains. Interstrain variation in each of these effects indicated that genetic background contributed a significant portion of the variance in responses to this oxidant. Two strains that were differentially susceptible to 3-h exposure to 15 ppm NO2\[C57BL/6J (B6), C3H/HeJ (C3)] were also exposed for 6 h/ day to 10 ppm NO2 on 5 consecutive days. Each of the responses to NO2 was completely adapted after 5 days in resistant C3 mice. Only the lavageable total protein response was adapted in susceptible B6 mice. To determine whether mechanisms of susceptibility to NO2 and O3 were the same, each strain was exposed for 3 h to filtered air or 2 ppm O3 and inflammation was assessed 6 and 24 h thereafter. Strain distribution patterns (SDPs) for responses to each oxidant were not significantly concordant and indicated that susceptibility mechanisms were different. Results of these studies suggest that there is a strong genetic component to NO2 susceptibility that is partially adaptable and significantly different from O3 susceptibility.     

Occupational asthma (OA) with sensitization to diphenylmethane diisocyanate (MDI) presenting at the onset like a reactive airways dysfunction syndrome (RADS)

BACKGROUND: Two types of OA are distinguished: immunological (OA with sensitization) and non-immunological, i.e., irritant induced asthma or reactive airways dysfunction syndrome (RADS). METHODS: We describe the case of a worker who developed respiratory symptoms after a spill of diphenylmethane diisocyanate (MDI) at the workplace. RADS was initially diagnosed and the worker resumed working. The progressive worsening of symptoms and the appearance of symptoms-work relationship one year later, when concentrations of isocyanates were no longer "irritant," suggested immunological OA. RESULTS: The diagnosis was confirmed by specific inhalation challenge test, followed by removal from exposure and complete recovery. CONCLUSIONS: In the case of RADS due to an agent with both irritant and sensitizing properties, history should be repeatedly assessed for a possible symptom-work relationship. If this is found, further investigations should be carried out, including specific inhalation challenges, to confirm the possibility of immunological OA.     

Finding better therapeutic targets for patients with asthma: adenosine receptors?

Recent observations suggest a potential pathophysiological function for adenosine signalling in chronic inflammation of the airways, and development of new selective agonists or antagonists for adenosine receptor subtypes has recently lead to a number of clinical trials of such agents in asthma. The review by Wilson in this issue of the BJP provides a critical perspective on adenosine receptors as rational targets for drug development for anti-asthma drugs with a focus on their efficacy and safety. Important conclusions can be drawn about the function of adenosine receptors in human asthma and approaches to these important targets with novel therapeutic agents.     

Proliferation during early phases of bronchiolar repair in neonatal rabbits following lung injury by 4-ipomeanol

Nonciliated bronchiolar (Clara cells) are progenitor cells during development. During differentiation, they are more susceptible to injury by environmental toxicants metabolized by the cytochrome P450 monooxygenase system, and injury results in altered bronchiolar repair and development. Squamous cells and abnormal cuboidal epithelium persist into early adulthood. The hypothesis tested in this study was that the failure of bronchiolar epithelium to repair normally in neonates following injury is due to an inhibition of proliferation. A model of differential repair in rabbit kits was used. Proliferation was followed for 1 week post injury in rabbit kits treated with a single dose of the P450-mediated cytotoxicant 4-ipomeanol (IPO) at 7 days old (repair abnormal) and compared to rabbits treated with a single dose of IPO at 21 days old (repair normal). Proliferation was measured by the nuclear incorporation of 5-chloro-2'-deoxyuridine (CldU) within epithelium at the target site (terminal bronchiole). The repair pattern between the two age groups was histologically defined. There was no difference in the CldU labeling index during the week of repair between the two age groups, even though the bronchiolar epithelium did not return to normal in the animals treated at 7 days old. In summary, proliferation (through S-phase) is not inhibited during repair in neonatal rabbits treated with IPO at 7 days old compared to animals treated at 21 days old, and we conclude that other factors may be responsible for the altered repair in the young neonates injured by a P450-mediated cytotoxicant.     

应用鼻塞式持续气道正压治疗新生儿肺透明膜病的疗效分析

目的探讨鼻塞式持续气道正压（NCPAP）通气对新生儿肺透明膜病（Hyaline Membrane Disease,HMD）的疗效。方法在综合治疗基础上,对34例胎龄为33-36周的肺透明膜病早产儿给予NCPAP治疗,观察早产儿在NCPAP前及NCPAP 6h后的疗效。结果实施NCPAP通气6h后,早产儿青紫消失,吸气性呼吸困难减轻,呼吸频率降至（56.8±4.9）次／min,心率降至（145.2±10.4）次／min,吸入氧浓度下调至（38.5±5.3）％,而经皮氧饱和度反而升至（94.8±2.5）％,动脉血氧分压升至（8.5±0.7）kPa,动脉血二氧化碳分压降至（5.6±0.5）kPa,与应用前数值分别为（68.9±7.6）次／min,（162.2±12.7）次／min,（50.7±6.6）％,（86.4±4.2）％,（5.8±0.9）kPa,（6.7±0.6）kPa比较,具有非常显著性差异。应用NCPAP期间无1例发生明显并发症。结论NCPAP对轻症新生儿肺透明膜病有良好疗效,无明显副作用,值得在基层医院推广使用。