Fiber deposition pattern in two human respiratory tract replicas

This study consisted of a series of experiments to investigate the factors that might affect the fiber deposition pattern in the human respiratory tract. Carbon fibers with uniform diameter and polydispersed length were chosen as the test material. Two geometry-defined human respiratory tract replicas encompassing the oral cavity, oropharynx, larynx, trachea, and first few bifurcations of the tracheobronchial airways were used in this research. Deposition studies were conducted by delivering aerosolized carbon fibers into the replicas at constant inspiratory flow rates of 15, 43.5, and 60 L/min. The results showed that impaction is the dominant deposition mechanism for both replicas. Most of the fibers with high momentum deposited in the oral airway (oral cavity to larynx), and fibers with low momentum were found to pass through the entire replica easily. When comparing the results between the two replicas, fiber length, inspiratory flow rate, and the geometry of the oral airway were found to be factors that might affect the fiber deposition pattern in the human respiratory tract.     

A semi-empirical model of aerosol deposition in the human respiratory tract for mouth inhalation

A mathematical model for regional deposition of aerosols following inhalation via mouth has been developed. The model is in the form of algebraic equations which make it particularly efficient for computation of deposition of polydisperse aerosols. The parameters of the model were derived from average experimental data for‘head’ and tracheobronchial deposition which were supplemented by results of previous theoretical calculations and mass balance considerations. An example is presented to illustrate an application of the model to a problem in formulation of inhalation aerosols. To make the calculations more reliable for particular patho-physiological groups of patients, some modifications of the parameters used in the model are necessary. The model may be suitable, e.g. for testing the changes in regional deposition which would be likely to result from modification of particle size and related formulation properties of inhalation aerosols.     

Deposition of biomass combustion aerosol particles in the human respiratory tract

Smoke from biomass combustion has been identified as a major environmental risk factor associated with adverse health effects globally. Deposition of the smoke particles in the lungs is a crucial factor for toxicological effects, but has not previously been studied experimentally. We investigated the size-dependent respiratory-tract deposition of aerosol particles from wood combustion in humans. Two combustion conditions were studied in a wood pellet burner: efficient ("complete") combustion and low-temperature (incomplete) combustion simulating "wood smoke." The size-dependent deposition fraction of 15-to 680-nm particles was measured for 10 healthy subjects with a novel setup. Both aerosols were extensively characterized with regard to chemical and physical particle properties. The deposition was additionally estimated with the ICRP model, modified for the determined aerosol properties, in order to validate the experiments and allow a generalization of the results. The measured total deposited fraction of particles from both efficient combustion and low-temperature combustion was 0.21-0.24 by number, surface, and mass. The deposition behavior can be explained by the size distributions of the particles and by their ability to grow by water uptake in the lungs, where the relative humidity is close to saturation. The experiments were in basic agreement with the model calculations. Our findings illustrate: (1) that particles from biomass combustion obtain a size in the respiratory tract at which the deposition probability is close to its minimum, (2) that particle water absorption has substantial impact on deposition, and (3) that deposition is markedly influenced by individual factors.     

The retention of tobacco smoke constituents in the human respiratory tract

Measurements on the retention of cigarette smoke constituents in the human respiratory tract have been undertake for more than 100 years. The first studies on nicotine retention were begun by Lehmann in Germany in 1903 and published in 1908. The first studies on the retention of smoke particulate matter were published by Baumbereger in the United States in 1923. Since those early publications, many studies have been undertaken, more or less continuously. This article is a review of the work that has been done over the last 100 years, including a large number of unpublished studies undertaken by British American Tobacco in Southampton, UK. The techniques used have evolved over the years and there is a certain amount of variation in the data. However, the general trends in the results are reassuringly consistent. The bulk of the studies indicate that, on average, 60 to 80% of the mainstream smoke particulate matter is retained in the lungs after inhalation. For nicotine, carbon monoxide, nitric oxide, and aldehydes the total retentions are of the order of 90-100, 55-65, 100, and approximately 90%, respectively, during cigarette smoke inhalation. For most smoke constituents the retentions in the mouth only are considerably smaller than in the whole respiratory tract. The lung retention values for smoke particulate matter are dependent on the depth of inhalation, hold time in the lungs, exhalation volume, and other factors. However, the degree of nicotine retention following inhalation is not markedly influenced by changes in respiratory parameters. Furthermore, the percentage retentions for smoke particulate matter and nicotine are smaller for nonsmoking subjects exposed to environmental tobacco smoke than with active smoking. The smoke retentions are related to properties of the smoke aerosol particles and gases and their behavior as they travel through the respiratory tract. This includes particle growth in the respiratory tract and evaporation of gases out of the particles, and relevant aspects of these processes are also reviewed.     

Dose timing and patient compliance with two antibiotic treatment regimens for lower respiratory tract infections in primary care

The objective of this study was to assess compliance with a 10-day treatment of antibiotics or placebo once-daily (OD) and three-times-daily (TD) for lower respiratory tract infections (LRTIs) using electronic monitoring, and to evaluate whether compliance depends on time since the start of treatment and weekday. Taking compliance, timing compliance, correct dosing compliance and mean interdose intervals were assessed using data from 155 LRTI patients who received either a 10-day treatment of amoxicillin TD and placebo OD or roxithromycin OD and placebo TD using a double-dummy technique. Compliance was assessed by electronic monitoring. Taking compliance was 98.0% for the OD regimen and 91.0% for the TD regimen. Correct dosing was 98.1% for the OD regimen and 91.1% for the TD regimen and timing compliance was 48.2% and 10.9%, respectively. The mean interdose interval before the first daily dose for the TD group was particularly prolonged to >13h. Correct dosing over time showed fewer patients with correct dosing compliance, reaching a low of 79% for the TD group towards the end of the 10-day treatment. Compliance was not influenced by weekday. This study adds important information to the limited evidence on compliance with antibiotics for LRTI, one of the most common reasons for consultation in primary care. Taking compliance was high for both regimens, yet timing compliance was poor. The prolonged mean interdose intervals provide striking new insights into understanding non-compliance with more-than-once-daily regimens. These findings require consideration when exploring ways to improve future compliance in short-term antibiotic treatment for respiratory tract infections.     

Tachykinins in the respiratory tract

Tachykinins as substance P and neurokinin A belong to a family of peptides, which are released from airway nerves after noxious stimulation. They influence numerous respiratory functions under both normal and pathological conditions including the regulation of airway smooth muscle tone, vascular tone, mucus secretion and immune functions. For the most part the synthesis/release of tachykinins is associated with neuronal cells; nevertheless, inflammatory and immune cells can synthesize and release tachykinins under certain physiological conditions. Moreover, this second cellular source of tachykinins may play an important role in inflammatory airway diseases such as bronchial asthma or chronic obstructive pulmonary disease (COPD). Dual tachykinin (NK1 and NK2) receptor antagonists demonstrate a significant bronchoprotection and a possible future role in the development of novel therapeutic approaches. In addition, NK3 receptors could also possess a bronchoprotective action, however, their presence in the human respiratory tract still needs to be confirmed. The family of tachykinins has recently been extended by the discovery of a third tachykinin gene that encodes the previously unknown NK1 receptor selective tachykinins hemokinin 1, endokinin A and B. Together with other novel tachykinin peptides such as C14TKL-1 and virokinin further research is required to define their respiratory biological role in health and disease.     

Dose dependent cytotoxicity of pranoprofen in cultured human corneal endothelial cells by inducing apoptosis

Pranoprofen (PPF), a non-steroidal anti-inflammatory drugs (NSAIDs), is often used in keratitis treatment in clinic. Several studies have assessed in vitro the cytotoxicity of topical NSAIDs to corneal epithelial cells due to its importance for predicting human corneal toxicity. Damage by cytotoxic drugs can result in excessive loss of human corneal endothelial (HCE) cells which lead to decompensation of the endothelium and eventual loss of visual acuity. However, the endothelial cytotoxicity of PPF has not yet been reported using an in vitro model of HCE cells. This study assessed the cytotoxicity of PPF to HCE cells and its underlying mechanism. Cellular viability was determined using inverted phase contrast light microscopy, and plasma membrane permeability, genomic DNA fragmentation, and ultrastructure were detected by acridine orange/ethidium bromide staining, DNA agarose gel electrophoresis, and transmission electron microscopy (TEM), respectively. The results on cellular viability showed that PPF at concentrations ranging from 0.0625 to 1.0?g/l had poignant cytotoxicity to HCE cells, and the extent of its cytotoxicity was dose- and time-dependent. Further characterization indicated that PPF induced plasma membrane permeability elevation, DNA fragmentation, and apoptotic body formation, proving its apoptosis inducing effect on HCE cells. In conclusion, PPF above 0.0625?g/l has poignant cytotoxicity on HCE cells in vitro by inducing cell apoptosis, and should be carefully employed in eye clinic.     

Analysis of nicotine-induced DNA damage in cells of the human respiratory tract

Epithelium of the upper and lower airways is a common origin of tobacco-related cancer. The main tobacco alkaloid nicotine may be associated with tumor progression. The potential of nicotine in inducing DNA mutations as a step towards cancer initiation is still controversially discussed. Different subtypes of nicotinic acetylcholine receptors (nAChR) are expressed in human nasal mucosa and a human bronchial cell line representing respiratory mucosa as a possible target for receptor-mediated pathways. In the present study, both cell systems were investigated with respect to DNA damage induced by nicotine and its mechanisms.Specimens of human nasal mucosa were harvested during surgery of the nasal air passage. After enzymatic digestion over night, single cells were exposed to an increasing nicotine concentration between 0.001 mM and 4.0 mM. In a second step co-incubation was performed using the antioxidant N-acetylcysteine (NAC) and the nAChR antagonist mecamylamine. DNA damage was assessed using the alkali version of the comet assay. Dose finding experiments for mecamylamine to evaluate the maximal inhibitory effect were performed in the human bronchial cell line BEAS-2B with an increasing mecamylamine concentration and a constant nicotine concentration. The influence of nicotine in the apoptotic pathway was evaluated in BEAS-2B cells with the TUNEL assay combined with flow cytometry.After 1 h of nicotine exposure with 0.001, 0.01, 0.1, 1.0 and 4.0 mM, significant DNA damage was determined at 1.0 mM. Further co-incubation experiments with mecamylamine and NAC were performed using 1.0 mM of nicotine. The strongest inhibitory effect was measured at 1.0 mM mecamylamine and this concentration was used for co-incubation. Both, the antioxidant NAC at a concentration of 1.0 mM, based on the literature, as well as the receptor antagonist were capable of complete inhibition of the nicotine-induced DNA migration in the comet assay. A nicotine-induced increase or decrease in apoptosis as assessed by the TUNEL assay in BEAS-2B could not be detected.These results support the hypothesis that oxidative stress is responsible for nicotine-induced DNA damage. Similar results exist for other antioxidants in different cell systems. The decrease in DNA damage after co-incubation with a nAChR antagonist indicates a receptor-dependent pathway of induction for oxidative stress. Further investigations concerning pathways of receptor-mediated DNA damage via nAChR, the role of reactive oxygen species and apoptosis in this cell system will elucidate underlying mechanisms.     

Dosimetry modeling of inhaled formaldehyde: the human respiratory tract.

Formaldehyde (HCHO), which has been shown to be a nasal carcinogen in rats and mice, is used widely and extensively in various manufacturing processes. Studies in rhesus monkeys suggest that the lower respiratory tract may be at risk and some epidemiologic studies have reported an increase in lung cancer associated with HCHO; other studies have not. Thus, an assessment of possible human risk to HCHO exposure based on dosimetry information throughout the respiratory tract (RT) is desirable. To obtain dosimetry estimates for a risk assessment, two types of models were used. The first model (which is the subject of another investigation) used computational fluid dynamics (CFD) to estimate local fluxes in a 3-dimensional model of the nasal region. The subject of the present investigation (the second model) applied a 1-dimensional equation of mass transport to each generation of an adult human symmetric, bifurcating Weibel-type RT anatomical model, augmented by an upper respiratory tract. The two types of modeling approaches were made consistent by requiring that the 1-dimensional version of the nasal passages have the same inspiratory air-flow rate and uptake during inspiration as the CFD simulations for 4 daily human activity levels. Results obtained include the following: (1) More than 95% of the inhaled HCHO is predicted to be retained by the RT. (2) The CFD predictions for inspiration, modified to account for the difference in inspiration and complete breath times, are a good approximation to uptake in the nasal airways during a single breath. (3) In the lower respiratory tract, flux is predicted to increase for several generations and then decrease rapidly. (4) Compared to first pulmonary region generation fluxes, the first few tracheobronchial generations fluxes are over 1000 times larger. Further, there is essentially no flux in the alveolar sacs. (5) Predicted fluxes based on the 1-dimensional model are presented that can be used in a biologically based dose-response model for human carcinogenesis. Use of these fluxes will reduce uncertainty in a risk assessment for formaldehyde carcinogenicity.     

Single-walled carbon nanotubes downregulate stress-responsive genes in human respiratory tract cells

Carbon nanotubes (CNTs) are currently key promising materials of nanotechnology. However, elucidation of the possible effects of CNTs on the respiratory tract is urgently needed. The present study aimed to clarify the effect of single-walled CNTs (SWCNTs) on the expression of stress-responsive genes, using primary cultured normal human bronchial epithelial (NHBE), diseased HBE (DHBE) cells, and the human carcinoma cell lines A549 and FaDu. Purified SWCNTs were applied at concentrations of 0.1 or 1.0 mg/mL for 6 h, and a polymerase chain reaction (PCR) array was conducted to examine 84 stress-responsive genes. NHBE cell exposure to SWCNTs resulted in global downregulation of genes involved in inflammation, oxidative stress, and apoptosis. Further analysis using DHBE cells and carcinoma cell lines indicated a similar trend, although differences in sensitivity were observed. Downregulation of stress-responsive genes may be involved in the mechanism by which stress response protects against lung injury.     

感染人类呼吸道的病毒及其分类新进展

近年来,随着SAPS、禽流感等重大呼吸道传染病的出现,人们对呼吸道病毒感染给予了高度重视,促进了呼吸道病毒学的发展.这主要表现在三个方面,一是对相关病毒如SARS冠状病毒和高致病性禽流感病毒的致病性、基因与抗原变异、疫苗制备等取得了进展;二是发现了一些新的呼吸道病毒如冠状病毒HCoV-NL63和HCoV-HKU1、博卡病毒;三是一些被认为与呼吸道感染关系不大的"老病毒"如某些疱疹类病毒和细小病毒,现在经常出现在呼吸道感染者的样本中.鉴于目前呼吸道病毒的范围比以前有明显扩大,此文就能够感染人类呼吸道的病毒及其分类作一综述.     

Levofloxacin for the treatment of respiratory tract infections

Introduction: Fluoroquinolone use has dramatically increased since the introduction of the first respiratory fluoroquinolone in the late 1990s. Levofloxacin, like other fluoquinolones, is a potent antibiotic, due to high levels of susceptibility among Gram-negative, Gram-positive (including penicillin-resistant strains of Streptococcus pneumonia) and atypical pathogens. Levofloxacin is recommended for the treatment of community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP) and in the management of acute exacerbations of chronic bronchitis (AECB). Levofloxacin demonstrates good safety, bioavailability and tissue penetration, thus maintaining adequate concentrations at the site of infection. High-dose (750 mg), short-course (5 days) therapy regimens may offer improved treatment, especially in HAP, due to higher drug concentrations, increased adherence and the potential to reduce the development of resistance.

Areas covered: This article covers medical literature published in any language since 1990 until November 2011, on ‘levofloxacin’, identified using PubMed and MEDLINE. The search terms used were ‘levofloxacin’ and ‘community acquired pneumonia’, ‘hospital pneumonia’ or ‘AECB’.

Expert opinion: Levofloxacin is a valuable antimicrobial agent and an optimal treatment option for AECB, CAP (as a monotherapy) and HAP (as combination therapy at a high-dose regimen). Its improved bioavailability and safety profile makes the possibility of shorter hospital stays a reality.     

Levofloxacin for the treatment of respiratory tract infections

INTRODUCTION: Fluoroquinolone use has dramatically increased since the introduction of the first respiratory fluoroquinolone in the late 1990s. Levofloxacin , like other fluoquinolones, is a potent antibiotic, due to high levels of susceptibility among Gram-negative, Gram-positive (including penicillin-resistant strains of Streptococcus pneumonia) and atypical pathogens. Levofloxacin is recommended for the treatment of community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP) and in the management of acute exacerbations of chronic bronchitis (AECB). Levofloxacin demonstrates good safety, bioavailability and tissue penetration, thus maintaining adequate concentrations at the site of infection. High-dose (750 mg), short-course (5 days) therapy regimens may offer improved treatment, especially in HAP, due to higher drug concentrations, increased adherence and the potential to reduce the development of resistance. AREAS COVERED: This article covers medical literature published in any language since 1990 until November 2011, on 'levofloxacin', identified using PubMed and MEDLINE. The search terms used were 'levofloxacin' and 'community acquired pneumonia', 'hospital pneumonia' or 'AECB'. EXPERT OPINION: Levofloxacin is a valuable antimicrobial agent and an optimal treatment option for AECB, CAP (as a monotherapy) and HAP (as combination therapy at a high-dose regimen). Its improved bioavailability and safety profile makes the possibility of shorter hospital stays a reality.     

Appropriate antibiotic use for the respiratory tract infections

Early appropriate antibiotic treatment is vital since respiratory tract infection (RTI) is a potentially fatal disease. Therefore, the Japanese Respiratory Society (JRS) provided four guidelines for the management of RTI in adults. The basic policy and main purposes of the JRS guidelines include; 1) prevention of bacterial resistance and 2) effective and long-term use of medical resources. The JRS guidelines have recommended the exclusion of potential and broad spectrum antibiotics from the list of first-choice drugs for empirical treatment. In addition, the JRS guidelines have recommended short-term usage of antibiotics of an appropriate dose.     

Pharmacotherapy for lower respiratory tract infections

Introduction: Bacterial infections play an important role as etiological agents in acute exacerbations of chronic obstructive pulmonary disease (AECOPD), and exacerbations of non-cystic fibrosis (CF) bronchiectasis. In acute bronchitis and asthma exacerbations their role is less well defined than with patients with COPD. The clinical features, causative pathogens and therapies of common acute respiratory tract infections are detailed in this review.

Areas covered: This article covers medical literature published in any language from 2000 to 2014, on ‘lower respiratory tract infections’, identified using PubMed, MEDLINE and ClinicalTrial.gov. The search terms used were ‘COPD exacerbations’, ‘bronchiectasis’, ‘macrolides’ and ‘inhaled antibiotics’.

Expert opinion: Given that almost half of AECOPD are caused by bacteria, administration of antibacterial agents is recommended for patients with severe exacerbations or severe underlying COPD. Chronic prophylactic use of macrolides seems to be of benefit, particularly in patients with bronchiectasis and chronic mucous hypersecretion. In an effort to manage chronic airway infection non-CF bronchiectasis due to drug-resistant pathogens, aerosolized antibiotics may be of value, and the data from recent studies are examined to demonstrate the potential value of this therapy, which is often used as an adjunctive measure to systemic antimicrobial therapy.     

Reactive nitrogen species in the respiratory tract

Endogenous Nitric Oxide (NO) plays a key role in the physiological regulation of airway functions. In response to various stimuli activated inflammatory cells (e.g., eosinophils and neutrophils) generate oxidants ("oxidative stress") which in conjunction with exaggerated enzymatic release of NO and augmented NO metabolites produce the formation of strong oxidizing reactive nitrogen species, such as peroxynitrite, in various airway diseases including asthma, chronic obstructive pulmonary diseases (COPD), cystic fibrosis and acute respiratory distress syndrome (ARDS). Reactive nitrogen species provoke amplification of inflammatory processes in the airways and lung parenchyma causing DNA damage, inhibition of mitochondrial respiration, protein dysfunction and cell damage ("nitrosative stress"). These effects alter respiratory homeostasis (such as bronchomotor tone and pulmonary surfactant activity) and the long-term persistence of "nitrosative stress" may contribute to the progressive deterioration of pulmonary functions leading to respiratory failure. Recent studies showing that protein nitration can be dynamic and reversible ("denitration mechanisms") open new horizons in the treatment of chronic respiratory diseases affected by the deleterious actions of "nitrosative stress".     

Multicomponent aerosol particle deposition in a realistic cast of the human upper respiratory tract

Inhalation of aerosols generated by electronic cigarettes leads to deposition of multiple chemical compounds in the human airways. In this work, an experimental method to determine regional deposition of multicomponent aerosols in an in vitro segmented, realistic human lung geometry was developed and applied to two aerosols, i.e. a monodisperse glycerol aerosol and a multicomponent aerosol. The method comprised the following steps: (1) lung cast model preparation, (2) aerosol generation and exposure, (3) extraction of deposited mass, (4) chemical quantification and (5) data processing. The method showed good agreement with literature data for the deposition efficiency when using a monodisperse glycerol aerosol, with a mass median aerodynamic diameter (MMAD) of 2.3?μm and a constant flow rate of 15?L/min. The highest deposition surface density rate was observed in the bifurcation segments, indicating inertial impaction deposition. The experimental method was also applied to the deposition of a nebulized multicomponent aerosol with a MMAD of 0.50?μm and a constant flow rate of 15?L/min. The deposited amounts of glycerol, propylene glycol and nicotine were quantified. The three analyzed compounds showed similar deposition patterns and fractions as for the monodisperse glycerol aerosol, indicating that the compounds most likely deposited as parts of the same droplets. The developed method can be used to determine regional deposition for multicomponent aerosols, provided that the compounds are of low volatility. The generated data can be used to validate aerosol deposition simulations and to gain insight in deposition of electronic cigarette aerosols in human airways.     

Moxifloxacin in respiratory tract infections

Moxifloxacin is a fourth-generation fluoroquinolone that has been shown to be effective against respiratory pathogens, including Gram-positive (Streptococcus pneumoniae), Gram-negative (Haemophilus influenzae, Moraxella catarrhalis), and atypical strains (Chlamydia pneumoniae, Mycoplasma pneumoniae), as well as multi-drug resistant S. pneumoniae, including strains resistant to penicillin, macrolides, tetracyclines, trimethoprim/sulfamethoxazole and some fluoroquinolones. Moxifloxacin is highly concentrated in lung tissue, and has demonstrated rapid eradication rates. The bioavailability and half-life of moxifloxacin provides potent bactericidal effects at a dose of 400mg/day. The ratio of the area under the concentration-time curve to MIC of moxifloxacin is the highest among the fluoroquinolones against S. pneumoniae. The clinical efficacy of moxifloxacin has been shown in controlled studies of community-acquired pneumonia (CAP), exacerbations of chronic bronchitis (CB) and acute bacterial rhinosinusitis. Moxifloxacin has demonstrated a faster resolution of symptoms in CAP and exacerbations of CB patients compared with first-line therapy. It has also demonstrated better eradication in exacerbations of CB compared with standard therapy, in particular the macrolides. Treatment guidelines should take into account the results of clinical trials with moxifloxacin in order to establish the role of this antimicrobial in the therapeutic arsenal against respiratory tract infections.     

Gemifloxacin for the management of community-acquired respiratory tract infections

ObjectivesAll countries are confronted with epidemiology and therapy of community acquired lower respiratory tract infections. New approaches and novel drugs have become necessary. We describe new options in this context and the potential role of a new fluroquinolone.ObservationsLower respiratory tract infections constitute a substantial clinical and financial burden costing billions dollars annually, with an additional complication which is growing: antimicrobial resistance. Such resistance has compromised the use of commonly used antimicrobial compounds. A new fluoroquinolone, gemifloxacin, has been approved for clinical use and is characterized as a potent dual-acting fluoroquinolone with excellent activity against S. pneumoniae (MIC₉₀ 0.03-0.06 mg/L).Clinical applicationGemifloxacin given once daily for as little as 5 days therapy has proven equivalent to, or superior to, comparator agents, it has an acceptable safely profile, and may be a cost-effective agent for lower respiratory tract infections.