Determination of non-uniform pulmonary ventilation by transcutaneous measurement of the oxygen tension in the arterial blood under an oxygen load

A method for determination of uneven ventilation in the lungs by the transcutaneous measurement of oxygen tension in arterial blood (TcPO2) is suggested. The degree of uneven ventilation was estimated by the time of a decrease in the TcPO2 till point of departure (desaturation time) after oxygen inhalation. The TcPO2 was measured by an oxymonitor (Hellige, Model SM 361). Twelve normal controls and 24 patients with chronic obstructive lung diseases were examined. The results showed that desaturation time in controls was 3.4 +/- 0.14 min, and in patients with chronic obstructive lung diseases it was significantly prolonged till 8 +/- 0.75 min; those data were in a good correlation with helium dilution time. The method may be recommended as a diagnostic test for determination of uneven ventilation in the lungs.     

Diesel Exhaust Particle Exposure In Vitro Alters Monocyte Differentiation and Function

Air pollution by diesel exhaust particles is associated with elevated mortality and increased hospital admissions in individuals with respiratory diseases such as asthma and chronic obstructive pulmonary disease. During active inflammation monocytes are recruited to the airways and can replace resident alveolar macrophages. We therefore investigated whether chronic fourteen day exposure to low concentrations of diesel exhaust particles can alter the phenotype and function of monocytes from healthy individuals and those with chronic obstructive pulmonary disease. Monocytes were purified from the blood of healthy individuals and people with a diagnosis of chronic obstructive pulmonary disease. Monocyte-derived macrophages were generated in the presence or absence of diesel exhaust particles and their phenotypes studied through investigation of their lifespan, cytokine generation in response to Toll like receptor agonists and heat killed bacteria, and expression of surface markers. Chronic fourteen day exposure of monocyte-derived macrophages to concentrations of diesel exhaust particles >10 µg/ml caused mitochondrial and lysosomal dysfunction, and a gradual loss of cells over time both in healthy and chronic obstructive pulmonary disease individuals. Chronic exposure to lower concentrations of diesel exhaust particles impaired CXCL8 cytokine responses to lipopolysaccharide and heat killed E. coli, and this phenotype was associated with a reduction in CD14 and CD11b expression. Chronic diesel exhaust particle exposure may therefore alter both numbers and function of lung macrophages differentiating from locally recruited monocytes in the lungs of healthy people and patients with chronic obstructive pulmonary disease.     

A computer-assisted study of the effect of gravitation on the functional state of the lungs

Gravitation influence on lung function was investigated in 115 patients and 21 healthy persons. Changing of an examinee's position from vertical into a horizontal one causes changes in lung function in health and disease. Characteristic features of lung function were determined for each group of examinees in order to improve the diagnosis and differential diagnosis of bronchial cancer and nonspecific chronic pulmonary diseases with a similar x-ray picture. A study of pulmonary ventilation and blood supply of the lungs in vertical and horizontal postures in Hodgkin's disease patients led to a conclusion that irradiation of patients seemed more effective in a phase of deep breath. It made it possible to reduce radiation exposure of healthy parts in a zone to be irradiated.     

Optimization of computed tomographic studies during the diagnosis of chronic nonspecific lung diseases

A comparative study was made of computerized tomograms of 115 patients, of them 78 suffered from nonspecific chronic pulmonary diseases (chronic bronchitis, bullous emphysema, spontaneous pneumothorax, and fibrosing alveolitis), and 37 patients were healthy. Of all transverse sections the most informative ones were defined, and anatomical reference points were determined for. A conclusion was made that computerized tomograms at 5 most informative levels were sufficient to diagnose changes in each of the lung segments in their diffuse affection. CT standardization was shown to have the same advantages as standardization of layins in routine tomography of the lungs, facilitating comparison over time and reducing radiation exposure of a patient.     

Role of Nrf2 in host defense against influenza virus in cigarette smoke-exposed mice

Influenza virus is a common respiratory tract viral infection. Although influenza can be fatal in patients with chronic pulmonary diseases such as chronic obstructive pulmonary disease, its pathogenesis is not fully understood. The Nrf2-mediated antioxidant system is essential to protect the lungs from oxidative injury and inflammation. In the present study, we investigated the role of Nrf2 in protection against influenza virus-induced pulmonary inflammation after cigarette smoke exposure with both in vitro and in vivo approaches. For in vitro analyses, peritoneal macrophages isolated from wild-type and Nrf2-deficient mice were treated with poly(I:C) and/or cigarette smoke extract. For in vivo analysis, these mice were infected with influenza A virus with or without exposure to cigarette smoke. In Nrf2-deficient macrophages, NF-κB activation and the induction of its target inflammatory genes were enhanced after costimulation with cigarette smoke extract and poly(I:C) compared with wild-type macrophages. The induction of antioxidant genes was observed for the lungs of wild-type mice but not those of Nrf2-deficient mice after cigarette smoke exposure. Cigarette smoke-exposed Nrf2-deficient mice showed higher rates of mortality than did wild-type mice after influenza virus infection, with enhanced peribronchial inflammation, lung permeability damage, and mucus hypersecretion. Lung oxidant levels and NF-κB-mediated inflammatory gene expression in the lungs were also enhanced in Nrf2-deficient mice. Our data indicate that the antioxidant pathway controlled by Nrf2 is pivotal for protection against the development of influenza virus-induced pulmonary inflammation and injury under oxidative conditions.     

Bedside evaluation of the resistance of large and medium pulmonary veins in various lung diseases.

To evaluate the contribution of large and medium pulmonary veins to the total pulmonary vascular resistance in various human lung diseases, we compared in 64 patients the pulmonary arterial proximal wedge pressure (Ppw), obtained when the balloon of a 7F pulmonary artery catheter was inflated with 1.5 ml air, with the distal wedge pressure (Pdw), obtained after the tip of the catheter was advanced until wedged in a small artery without balloon inflation. Ppw, reflecting the pressure in a large pulmonary vein, approximates the left atrial pressure, whereas Pdw reflects the pressure in a smaller pulmonary vein. Pdw was greater than Ppw in all 64 patients. The Pdw-Ppw gradient was 1.1 +/- 0.5 mmHg in nine patients with normal lungs and was significantly higher in 13 patients with chronic congestive heart failure (3.8 +/- 0.8 mmHg, P less than 0.01) and in 22 patients with adult respiratory distress syndrome (3.8 +/- 0.8 mmHg; P less than 0.01), but not in 20 patients with chronic obstructive pulmonary disease (1.8 +/- 0.7 mmHg). The distribution of the pulmonary vascular resistance was clearly different among the four groups. The fraction of the total pulmonary vascular resistance attributable to large and medium pulmonary veins was significantly increased (P less than 0.01) in adult respiratory distress syndrome (27.5 +/- 12%) and cardiac patients (27.5 +/- 9%) compared with patients with chronic obstructive pulmonary disease (13 +/- 5%) and normal lungs (13.5 +/- 6%).(ABSTRACT TRUNCATED AT 250 WORDS)     

CD46 protects against chronic obstructive pulmonary disease

Background

Chronic obstructive pulmonary disease and emphysema develops in 15% of ex-smokers despite sustained quitting, while 10% are free of emphysema or severe lung obstruction. The cause of the incapacity of the immune system to clear the inflammation in the first group remains unclear.

Methods and Findings

We searched genes that were protecting ex-smokers without emphysema, using microarrays on portions of human lungs surgically removed; we found that loss of lung function in patients with chronic obstructive pulmonary disease and emphysema was associated with a lower expression of CD46 and verified this finding by qRT-PCR and flow cytometry. Also, there was a significant association among decreased CD46⁺ cells with decreased CD4⁺T cells, apoptosis mediator CD95 and increased CD8⁺T cells that were protecting patients without emphysema or severe chronic obstructive pulmonary disease. CD46 not only regulates the production of T regulatory cells, which suppresses CD8⁺T cell proliferation, but also the complement cascade by degradation of C3b. These results were replicated in the murine smoking model, which showed increased C5a (produced by C3b) that suppressed IL12 mediated bias to T helper 1 cells and elastin co-precipitation with C3b, suggesting that elastin could be presented as an antigen. Thus, using ELISA from elastin peptides, we verified that 43% of the patients with severe early onset of chronic obstructive pulmonary disease tested positive for IgG to elastin in their serum compared to healthy controls.

Conclusions

These data suggest that higher expression of CD46 in the lungs of ex-smoker protects them from emphysema and chronic obstructive pulmonary disease by clearing the inflammation impeding the proliferation of CD8⁺ T cells and necrosis, achieved by production of T regulatory cells and degradation of C3b; restraining the complement cascade favors apoptosis over necrosis, protecting them from autoimmunity and chronic inflammation.     

Structural Characterization of Mouse Neutrophil Serine Proteases and Identification of Their Substrate Specificities: RELEVANCE TO MOUSE MODELS OF HUMAN INFLAMMATORY DISEASES*

It is widely accepted that neutrophil serine proteases (NSPs) play a critical role in neutrophil-associated lung inflammatory and tissue-destructive diseases. To investigate NSP pathogenic role(s), various mouse experimental models have been developed that mimic acutely or chronically injured human lungs. We and others are using mouse exposure to cigarette smoke as a model for chronic obstructive pulmonary disease with or without exacerbation. However, the relative contribution of NSPs to lung disease processes as well as their underlying mechanisms remains still poorly understood. And the lack of purified mouse NSPs and their specific substrates have hampered advances in these studies. In this work, we compared mouse and human NSPs and generated three-dimensional models of murine NSPs based on three-dimensional structures of their human homologs. Analyses of these models provided compelling evidence that peptide substrate specificities of human and mouse NSPs are different despite their conserved cleft and close structural resemblance. These studies allowed us to synthesize for the first time novel sensitive fluorescence resonance energy transfer substrates for individual mouse NSPs. Our findings and the newly identified substrates should better our understanding about the role of NSPs in the pathogenesis of cigarette-associated chronic obstructive pulmonary disease as well as other neutrophils-associated inflammatory diseases.     

慢性呼吸道疾病患者呼吸道微生物群研究进展

过去认为健康人肺部是无菌的,对疾病状态下呼吸道菌群的研究依赖传统培养技术。近年来,DNA测序技术应用于呼吸道标本的微生物检测,发现健康肺部存在复杂的微生物群。越来越多的证据表明,呼吸道微生物群在多种慢性呼吸道疾病发生和发展过程中扮演重要角色,与哮喘、慢性阻塞性肺病等疾病的临床表现、急性加重及预后相关。通过比较急性加重期与稳定期患者的呼吸道标本微生物群,形成了新的疾病假说,阐释了慢性呼吸道疾病急性加重的微生物学基础。未来对微生物测序数据的深度挖掘及基于临床问题的研究,有望为慢性呼吸道疾病的治疗提供新的靶点。     

Autophagy and inflammation in chronic respiratory disease

Persistent inflammation within the respiratory tract underlies the pathogenesis of numerous chronic pulmonary diseases including chronic obstructive pulmonary disease, asthma and pulmonary fibrosis. Chronic inflammation in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to infection and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary inflammation and fundamental for the response of pulmonary leukocytes to infection; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting lung injury. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting.

Abbreviations AR allergic rhinitis

AM alveolar macrophage

ATG autophagy-related

CF cystic fibrosis

CFTR cystic fibrosis transmembrane conductance regulator

COPD chronic obstructive pulmonary disease

CS cigarette smoke

CSE cigarette smoke extract

DC dendritic cell

IH intermittent hypoxia

IPF idiopathic pulmonary fibrosis

ILD interstitial lung disease

MAP1LC3B microtubule associated protein 1 light chain 3 beta

MTB Mycobacterium tuberculosis

MTOR mechanistic target of rapamycin kinase

NET neutrophil extracellular traps

OSA obstructive sleep apnea

PAH pulmonary arterial hypertension

PH pulmonary hypertension

ROS reactive oxygen species

TGFB1 transforming growth factor beta 1

TNF tumor necrosis factor

     

Transient Ascaris suum larval migration induces intractable chronic pulmonary disease and anemia in mice

Ascariasis is one of the most common infections in the world and associated with significant global morbidity. Ascaris larval migration through the host’s lungs is essential for larval development but leads to an exaggerated type-2 host immune response manifesting clinically as acute allergic airway disease. However, whether Ascaris larval migration can subsequently lead to chronic lung diseases remains unknown. Here, we demonstrate that a single episode of Ascaris larval migration through the host lungs induces a chronic pulmonary syndrome of type-2 inflammatory pathology and emphysema accompanied by pulmonary hemorrhage and chronic anemia in a mouse model. Our results reveal that a single episode of Ascaris larval migration through the host lungs leads to permanent lung damage with systemic effects. Remote episodes of ascariasis may drive non-communicable lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and chronic anemia in parasite endemic regions.     

慢性阻塞性肺疾病合并糖尿病患者肺部真菌感染病原学及易感因素分析

目的探讨慢性阻塞性肺疾病(COPD)合并糖尿病患者肺部真菌感染的病原学及易感因素。方法对58例COPD合并糖尿病肺部真菌感染患者进行病原学及预后分析,并与无糖尿病的COPD真菌感染患者76例进行比较。结果 2组患者病原菌均以白色念珠菌占首位,研究组真菌发病率高于对照组,预后较对照组更差。抗生素、年龄、糖皮质激素和营养状态等因素对2组患者真菌感染的影响差异无统计学意义。结论白色念珠菌仍是COPD患者肺部真菌感染的主要致病菌。糖尿病增加COPD患者感染真菌的风险,并且加重病情,影响预后。     

The role of ChemR23 in the induction and resolution of cigarette smoke-induced inflammation

Chronic obstructive pulmonary disease is mainly triggered by cigarette smoke (CS) and progresses even after smoking cessation. CS induces an exaggerated influx of inflammatory cells to the bronchoalveolar space and lung parenchyma, likely resulting from a complex interplay between chemoattractants and their respective receptors. In a murine CS model of chronic obstructive pulmonary disease, we studied the importance of chemokine-like receptor ChemR23 for the induction and resolution of inflammation in CS-exposed lungs. Subacute and chronic CS exposure increased protein levels of the ChemR23 ligand and chemoattractant, chemerin, in bronchoalveolar lavage (BAL) fluid of wild-type (WT) mice. Moreover, the proinflammatory chemokines CXCL1, CCL2, and CCL20 were increased in the airways of CS-exposed WT mice, accompanied by a massive accumulation of inflammatory neutrophils and monocytes, CD11b(hi)CD103(-) and CD11b(lo)CD103(+) dendritic cells (DCs), and CD4(+) and CD8(+) T cells. The lung parenchyma of WT mice was infiltrated with inflammatory neutrophils, CD11b(hi)CD103(-) DCs, and activated CD4(+) T cells after CS exposure. CS-induced inflammation was severely attenuated in BAL fluid and lungs of ChemR23 knockout mice with regard to the induction of inflammatory chemokines and the recruitment of inflammatory cells. Neutrophils and CD8(+) T cells persisted in the airways of WT mice, as did the airway-derived conventional DCs in the mediastinal lymph nodes, for at least 14 d after smoking cessation. In the BAL fluid of CS-exposed ChemR23 knockout mice, there was a remarkable delayed accumulation of T cells 14 d after the final exposure. Our data support a role for ChemR23 in directing innate and adaptive immune cells to CS-exposed lungs.     

Noninvasive positive-pressure ventilation in acute respiratory failure

Noninvasive positive-pressure ventilation is a type of mechanical ventilation that does not require an artificial airway. Studies published in the 1990s that evaluated the efficacy of this technique for the treatment of diseases as chronic obstructive pulmonary disease, congestive heart failure and acute respiratory failure have generalized its use in recent years. Important issues include the selection of the ventilation interface and the type of ventilator. Currently available interfaces include nasal, oronasal and facial masks, mouthpieces and helmets. Comparisons of the available interfaces have not shown one to be clearly superior. Both critical care ventilators and portable ventilators can be used for noninvasive positive-pressure ventilation; however, the choice of ventilator type depends on the patient''s condition and therapeutic requirements and on the expertise of the attending staff and the location of care. The best results (decreased need for intubation and decreased mortality) have been reported among patients with exacerbations of chronic obstructive pulmonary disease and cardiogenic pulmonary edema.Noninvasive positive-pressure ventilation is the delivery of mechanical ventilation to patients with respiratory failure without the requirement of an artificial airway. The key change that led to the recent increase in the use of this technique occurred in the early 1980s with the introduction of the nasal continuous positive airway pressure mask for the treatment of obstructive sleep apnea. Studies published in the 1990s that evaluated the efficacy of noninvasive positive-pressure ventilation for treatment of diseases such as chronic obstructive pulmonary disease, congestive heart failure and acute respiratory failure have generalized its use in recent years.¹ In 1998, an international study on the use of mechanical ventilation found that 5% of patients admitted to intensive care units received noninvasive positive-pressure ventilation.²Noninvasive positive-pressure ventilation includes various techniques for augmenting alveolar ventilation without an endotracheal airway. The clinical application of noninvasive ventilation by use of continuous positive airway pressure alone is referred to as “mask CPAP,” and noninvasive ventilation by use of intermittent positive-pressure ventilation with or without continuous positive airway pressure is called noninvasive positive-pressure ventilation.     

The remote effects of chronic exposure to ionizing radiation and electromagnetic fields with respect to hygienic standardization

A variety and rate of non-cancer diseases occurred in humans as a result of chronic exposure to ionizing radiation or to electromagnetic radiation (EMR) of high and superhigh frequency have been compared. The intensity of EMR was slightly higher than a sanitary standard for population. A risk of health impairments in workers having occupational exposure to EMR was assessed on the basis of Selie's concept of development of non-specific reaction of the body to chronic stress factors (general adaptation syndrome), models of changes in the body compensatory reserves and calculations of radiation risk after severe and chronic exposure to ionizing radiation.     

Experimental Emphysema—Histologic Changes and Alterations in Pulmonary Circulation

Detailed study of the pathogenesis of bullous emphysema has been hampered by lack of a suitable animal model of this disease. Prolonged exposure of rats and dogs to elevated partial pressures of oxygen produced a chronic obstructive disease in the lungs of these animals which anatomically resembles bullous emphysema in man. The disease was characterized by extensive bullae formation, alveolar septal destruction, airway obstruction and pronounced circulatory changes. It is suggested that this condition in laboratory animals may serve as a model for the study of pulmonary obstructive disease.     

慢性阻塞性肺疾病急性加重患者下呼吸道病原菌分析

目的了解慢性阻塞性肺疾病急性加重患者（AECOPD）下呼吸道感染病原菌的特点及耐药情况,为临床合理选择抗菌药物提供借鉴。方法取诸暨市人民医院2005年1月至2009年12月住院的273例AECOPD患者的下呼吸道痰标本及纤支镜刷取分泌物进行培养、鉴定、药敏,并对结果进行分析。结果273例AECOPD患者中有225例患者分离到病原菌,分离病原菌282株。病原菌中革兰阴性杆菌最多,占46．8％,依次为铜绿假单胞菌、肺炎克雷伯菌、鲍曼不动杆菌等;革兰阳性球菌占18．4％,以金黄色葡萄球菌最多,肠球菌、肺炎链球菌次之;真菌占20．9％;流感嗜血杆菌占13．8％。药敏结果显示阴性杆菌对美罗培意敏感率最好,其次为亚胺培南、哌拉西林．他唑巴坦。结论AECOPD患者下呼吸道病原菌以革兰阴性杆菌为主,耐药现象明显,流感嗜血杆菌已经成为AECOPD患者重要的致病菌之一。     

SLPI and trappin-2 as therapeutic agents to target airway serine proteases in inflammatory lung diseases: current and future directions

It is now clear that NSPs (neutrophil serine proteases), including elastase, Pr3 (proteinase 3) and CatG (cathepsin G) are major pathogenic determinants in chronic inflammatory disorders of the lungs. Two unglycosylated natural protease inhibitors, SLPI (secretory leucocyte protease inhibitor) and elafin, and its precursor trappin-2 that are found in the lungs, have therapeutic potential for reducing the protease-induced inflammatory response. This review examines the multifaceted roles of SLPI and elafin/trappin-2 in the context of their possible use as inhaled drugs for treating chronic lung diseases such as CF (cystic fibrosis) and COPD (chronic obstructive pulmonary disease).     

臭氧分布及对呼吸系统的影响

臭氧是氧气的同素异形体,在常温条件下它是一种有特殊臭味的淡蓝色气体。臭氧现已成为我国主要的一种环境污染物。臭氧的分布存在着明显的时间特异性和地区特异性,与气象条件、污染物的输送与扩散以及局地光化学反应强度等因素有着重要的关系。同时在人群流行病学和动物实验中发现了臭氧可以提高慢性阻塞性肺疾病、哮喘等呼吸系统疾病的发病率和病死率,同时提示了老年人、有呼吸系统疾病病史的人群和儿童都是易受臭氧影响的高危人群。国内外学者也对臭氧对机体损伤的机制进行了研究,主要集中在臭氧的致炎作用、氧化应激作用、造成机体气道高反应性和对细胞DNA的损伤等方面。本文主要就国内外对臭氧在时空分布、对机体呼吸系统影响和臭氧造成机体损伤的机制这3方面作一简要综述。